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Atefrad S, Yousefnejad A, Faraji N, Keshavarz P. The association between NLGN4 gene variants and the incidence of autism spectrum disorders in Guilan, Iran. IBRO Neurosci Rep 2025; 18:306-310. [PMID: 40034542 PMCID: PMC11874714 DOI: 10.1016/j.ibneur.2025.01.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 01/26/2025] [Accepted: 01/31/2025] [Indexed: 03/05/2025] Open
Abstract
Autism Spectrum Disorder (ASD) is a developmental disorder characterized by impaired social interaction, communication skills, and repetitive behaviours. This study aimed to investigate the association between variants of the Neuroligin-4 (NLGN4) gene (rs1882260 and rs3810688) and the incidence of ASD in North of Iran in the ASD group (n = 60) and control group (n = 60). DNA was isolated from whole blood, saliva, or hair samples. The targeted variants were genotyped using the Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR) technique. Genetic analyses were conducted using SNPAlyze ver. 8.1. Results revealed a significant difference of rs3810688 polymorphism in the NLGN4 gene in both genotypic and allelic frequency distributions between the ASD and control groups (P < 0.05). The GG genotype of rs3810688 polymorphism exhibited a significant association with an elevated risk of ASD in contrast to the CC genotype, as revealed under the co-dominant model (OR=4.2; 95 %CI, 1.25-14.05; P = 0.019). The study illustrated the possible role of rs3810688 polymorphism of NLGN4 in increasing the incidence of ASD among newborns in Guilan province. Also, the G-C haplotype was found to be a protective variant against ASD.
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Affiliation(s)
- Sepideh Atefrad
- Department of Genetics, Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
- Master of Genetics, Razi Clinical Research Development Unit, Guilan University of Medical Sciences, Rasht, Iran
| | - Aidi Yousefnejad
- Department of Genetics, Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Niloofar Faraji
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Parvaneh Keshavarz
- Department of Genetics, Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
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Poquérusse J, Whitford W, Taylor J, Gregersen N, Love DR, Tsang B, Drake KM, Snell RG, Lehnert K, Jacobsen JC. Germline mosaicism in TCF20-associated neurodevelopmental disorders: a case study and literature review. J Hum Genet 2025; 70:215-222. [PMID: 40011607 PMCID: PMC11882450 DOI: 10.1038/s10038-025-01323-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 02/05/2025] [Accepted: 02/06/2025] [Indexed: 02/28/2025]
Abstract
Autosomal dominant variants in transcription factor 20 (TCF20) can result in TCF20-associated neurodevelopmental disorder (TAND), a condition characterized by developmental delay and intellectual disability, autism, dysmorphisms, dystonia, and variable other neurological features. To date, a total of 91 individuals with TAND have been reported; ~67% of cases arose de novo, while ~10% were inherited, and, intriguingly, ~8% were either confirmed or suspected to have arisen via germline mosaicism. Here, we describe two siblings with a developmental condition characterized by intellectual disability, autism, a circadian rhythm sleep disorder, and attention deficit hyperactivity disorder (ADHD) caused by a novel heterozygous single nucleotide deletion in the TCF20 gene, NM_001378418.1:c.4737del; NP_001365347.1:p.Lys1579Asnfs*36 (GRCh38/hg38). The variant was not detected in DNA extracted from peripheral blood in either parent by Sanger sequencing of PCR-generated amplicons, or by deep sequencing of PCR amplicons using MiSeq and MinION. However, droplet digital PCR (ddPCR) of DNA derived from early morning urine detected the variation in 3.2% of the father's urothelial cells, confirming germline mosaicism. This report is only the second to confirm with physical evidence TCF20 germline mosaicism and discusses germline mosaicism as a likely under-detected mode of inheritance in neurodevelopmental conditions.
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Affiliation(s)
- Jessie Poquérusse
- School of Biological Sciences, The University of Auckland, Auckland, New Zealand
- Centre for Brain Research, The University of Auckland, Auckland, New Zealand
| | - Whitney Whitford
- School of Biological Sciences, The University of Auckland, Auckland, New Zealand
- Centre for Brain Research, The University of Auckland, Auckland, New Zealand
| | - Juliet Taylor
- Genetic Health Service New Zealand, Auckland City Hospital, Auckland, New Zealand
| | - Nerine Gregersen
- Genetic Health Service New Zealand, Auckland City Hospital, Auckland, New Zealand
| | - Donald R Love
- Diagnostic Genetics, LabPLUS, Auckland City Hospital, Auckland, New Zealand
- Genetic Pathology, Sidra Medicine, Doha, Qatar
| | - Bobby Tsang
- Pediatrics and Newborn Services, Waitakere Hospital, Auckland, New Zealand
| | - Kylie M Drake
- Canterbury Health Laboratories, Christchurch, New Zealand
| | - Russell G Snell
- School of Biological Sciences, The University of Auckland, Auckland, New Zealand
- Centre for Brain Research, The University of Auckland, Auckland, New Zealand
| | - Klaus Lehnert
- School of Biological Sciences, The University of Auckland, Auckland, New Zealand
- Centre for Brain Research, The University of Auckland, Auckland, New Zealand
| | - Jessie C Jacobsen
- School of Biological Sciences, The University of Auckland, Auckland, New Zealand.
- Centre for Brain Research, The University of Auckland, Auckland, New Zealand.
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Parkhill M, Salmaso N, D'Angiulli A, Lee V, Aguilar-Valles A. Emerging autism and Fragile X syndrome treatments. Trends Pharmacol Sci 2025; 46:357-371. [PMID: 40102109 DOI: 10.1016/j.tips.2025.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 02/12/2025] [Accepted: 02/18/2025] [Indexed: 03/20/2025]
Abstract
The limitations of current symptom-focused treatments drive the urgent need for effective therapies for autism and Fragile X syndrome (FXS). Currently, no approved pharmacological interventions target the core symptoms of these disorders. Advances in understanding the underlying biology of autism and FXS make this an important time to explore novel options. Indeed, several treatments have recently been tested in clinical trials, with promising results in treating core symptoms of autism and FXS. We focus on emerging interventions, such as gut microbiome therapies, anti-inflammatory approaches, bumetanide, phosphodiesterase 4D inhibitors, and endocannabinoid modulators. We also discuss factors, such as disorder heterogeneity, which may have contributed to poor efficacy in previously failed late-phase trials and impact recent trials, emphasizing the need for personalized treatment approaches.
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Affiliation(s)
- Michael Parkhill
- Department of Neuroscience, Carleton University, Ottawa, ON, Canada
| | - Natalina Salmaso
- Department of Neuroscience, Carleton University, Ottawa, ON, Canada; Department of Health Sciences, Carleton University, Ottawa, ON, Canada; Ottawa Brain and Mind Institute, Ottawa, ON, Canada
| | - Amedeo D'Angiulli
- Department of Neuroscience, Carleton University, Ottawa, ON, Canada; Neurodevelopmental Health Unit, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
| | - Vivian Lee
- Department of Psychology, Carleton University, Ottawa, ON, Canada
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Karim A, Alromema N, Malebary SJ, Binzagr F, Ahmed A, Khan YD. eNSMBL-PASD: Spearheading early autism spectrum disorder detection through advanced genomic computational frameworks utilizing ensemble learning models. Digit Health 2025; 11:20552076241313407. [PMID: 39872002 PMCID: PMC11770729 DOI: 10.1177/20552076241313407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 12/18/2024] [Indexed: 01/29/2025] Open
Abstract
Objective Autism spectrum disorder (ASD) is a complex neurodevelopmental condition influenced by various genetic and environmental factors. Currently, there is no definitive clinical test, such as a blood analysis or brain scan, for early diagnosis. The objective of this study is to develop a computational model that predicts ASD driver genes in the early stages using genomic data, aiming to enhance early diagnosis and intervention. Methods This study utilized a benchmark genomic dataset, which was processed using feature extraction techniques to identify relevant genetic patterns. Several ensemble classification methods, including Extreme Gradient Boosting, Random Forest, Light Gradient Boosting Machine, ExtraTrees, and a stacked ensemble of classifiers, were applied to assess the predictive power of the genomic features. TheEnsemble Model Predictor for Autism Spectrum Disorder (eNSMBL-PASD) model was rigorously validated using multiple performance metrics such as accuracy, sensitivity, specificity, and Mathew's correlation coefficient. Results The proposed model demonstrated superior performance across various validation techniques. The self-consistency test achieved 100% accuracy, while the independent set and cross-validation tests yielded 91% and 87% accuracy, respectively. These results highlight the model's robustness and reliability in predicting ASD-related genes. Conclusion The eNSMBL-PASD model provides a promising tool for the early detection of ASD by identifying genetic markers associated with the disorder. In the future, this model has the potential to assist healthcare professionals, particularly doctors and psychologists, in diagnosing and formulating treatment plans for ASD at its earliest stages.
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Affiliation(s)
- Ayesha Karim
- Department of Computer Science, School of Systems and Technology, University of Management and Technology, Lahore, Pakistan
| | - Nashwan Alromema
- Department of Computer Science, Faculty of Computing and Information Technology-Rabigh, King AbdulAziz University, Jeddah, Saudi Arabia
| | - Sharaf J Malebary
- Department of Information Technology, Faculty of Computing and Information Technology, King AbdulAziz University, Rabigh, Saudi Arabia
| | - Faisal Binzagr
- Department of Computer Science, Faculty of Computing and Information Technology-Rabigh, King AbdulAziz University, Jeddah, Saudi Arabia
| | - Amir Ahmed
- College of Information Technology, Information Systems and Security, United Arab Emirates University, Alain, United Arab Emirates
| | - Yaser Daanial Khan
- Department of Computer Science, School of Systems and Technology, University of Management and Technology, Lahore, Pakistan
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Bakoev S, Getmantseva L, Kolosova M, Bakoev F, Kolosov A, Romanets E, Shevtsova V, Romanets T, Kolosov Y, Usatov A. Identifying Significant SNPs of the Total Number of Piglets Born and Their Relationship with Leg Bumps in Pigs. BIOLOGY 2024; 13:1034. [PMID: 39765701 PMCID: PMC11673605 DOI: 10.3390/biology13121034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/26/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025]
Abstract
The aim of this study was to identify genetic variants and pathways associated with the total number of piglets born and to investigate the potential negative consequences of the intensive selection for reproductive traits, particularly the formation of bumps on the legs of pigs. We used genome-wide association analysis and methods for identifying selection signatures. As a result, 47 SNPs were identified, localized in genes that play a significant role during sow pregnancy. These genes are involved in follicle growth and development (SGC), early embryonic development (CCDC3, LRRC8C, LRFN3, TNFRSF19), endometrial receptivity and implantation (NEBL), placentation, and embryonic development (ESRRG, GHRHR, TUSC3, NBAS). Several genes are associated with disorders of the nervous system and brain development (BCL11B, CDNF, ULK4, CC2D2A, KCNK2). Additionally, six SNPs are associated with the formation of bumps on the legs of pigs. These variants include intronic variants in the CCDC3, ULK4, and MINDY4 genes, as well as intergenic variants, regulatory region variants, and variants in the exons of non-coding transcripts. The results suggest important biological pathways and genetic variants associated with sow fertility and highlight the potential negative impacts on the health and physical condition of pigs.
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Affiliation(s)
- Siroj Bakoev
- Biotechnological Faculty, Don State Agrarian University, Persianovsky 346493, Russia; (S.B.); (M.K.); (F.B.); (E.R.); (T.R.); (Y.K.)
| | - Lyubov Getmantseva
- Biotechnological Faculty, Don State Agrarian University, Persianovsky 346493, Russia; (S.B.); (M.K.); (F.B.); (E.R.); (T.R.); (Y.K.)
| | - Maria Kolosova
- Biotechnological Faculty, Don State Agrarian University, Persianovsky 346493, Russia; (S.B.); (M.K.); (F.B.); (E.R.); (T.R.); (Y.K.)
| | - Faridun Bakoev
- Biotechnological Faculty, Don State Agrarian University, Persianovsky 346493, Russia; (S.B.); (M.K.); (F.B.); (E.R.); (T.R.); (Y.K.)
| | - Anatoly Kolosov
- All Russian Research Institute of Animal Breeding, Lesnye Polyany 141212, Russia;
| | - Elena Romanets
- Biotechnological Faculty, Don State Agrarian University, Persianovsky 346493, Russia; (S.B.); (M.K.); (F.B.); (E.R.); (T.R.); (Y.K.)
| | - Varvara Shevtsova
- Southern Scientific Center Russian Academy of Sciences, Rostov-on-Don 344006, Russia;
| | - Timofey Romanets
- Biotechnological Faculty, Don State Agrarian University, Persianovsky 346493, Russia; (S.B.); (M.K.); (F.B.); (E.R.); (T.R.); (Y.K.)
| | - Yury Kolosov
- Biotechnological Faculty, Don State Agrarian University, Persianovsky 346493, Russia; (S.B.); (M.K.); (F.B.); (E.R.); (T.R.); (Y.K.)
| | - Alexander Usatov
- Academy of Biology and Biotechnology Named After D.I. Ivanovsky, Southern Federal University, Rostov-on-Don 344006, Russia;
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Al-Beltagi M, Saeed NK, Bediwy AS, Bediwy EA, Elbeltagi R. Decoding the genetic landscape of autism: A comprehensive review. World J Clin Pediatr 2024; 13:98468. [PMID: 39350903 PMCID: PMC11438927 DOI: 10.5409/wjcp.v13.i3.98468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 07/29/2024] [Accepted: 08/01/2024] [Indexed: 08/30/2024] Open
Abstract
BACKGROUND Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by heterogeneous symptoms and genetic underpinnings. Recent advancements in genetic and epigenetic research have provided insights into the intricate mechanisms contributing to ASD, influencing both diagnosis and therapeutic strategies. AIM To explore the genetic architecture of ASD, elucidate mechanistic insights into genetic mutations, and examine gene-environment interactions. METHODS A comprehensive systematic review was conducted, integrating findings from studies on genetic variations, epigenetic mechanisms (such as DNA methylation and histone modifications), and emerging technologies [including Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 and single-cell RNA sequencing]. Relevant articles were identified through systematic searches of databases such as PubMed and Google Scholar. RESULTS Genetic studies have identified numerous risk genes and mutations associated with ASD, yet many cases remain unexplained by known factors, suggesting undiscovered genetic components. Mechanistic insights into how these genetic mutations impact neural development and brain connectivity are still evolving. Epigenetic modifications, particularly DNA methylation and non-coding RNAs, also play significant roles in ASD pathogenesis. Emerging technologies like CRISPR-Cas9 and advanced bioinformatics are advancing our understanding by enabling precise genetic editing and analysis of complex genomic data. CONCLUSION Continued research into the genetic and epigenetic underpinnings of ASD is crucial for developing personalized and effective treatments. Collaborative efforts integrating multidisciplinary expertise and international collaborations are essential to address the complexity of ASD and translate genetic discoveries into clinical practice. Addressing unresolved questions and ethical considerations surrounding genetic research will pave the way for improved diagnostic tools and targeted therapies, ultimately enhancing outcomes for individuals affected by ASD.
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Affiliation(s)
- Mohammed Al-Beltagi
- Department of Pediatric, Faculty of Medicine, Tanta University, Alghrabia, Tanta 31511, Egypt
- Department of Pediatric, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama 26671, Bahrain
| | - Nermin Kamal Saeed
- Medical Microbiology Section, Department of Pathology, Salmaniya Medical Complex, Ministry of Health, Kingdom of Bahrain, Manama 12, Bahrain
- Medical Microbiology Section, Department of Pathology, Irish Royal College of Surgeon, Muharraq, Busaiteen 15503, Bahrain
| | - Adel Salah Bediwy
- Department of Pulmonology, Faculty of Medicine, Tanta University, Alghrabia, Tanta 31527, Egypt
- Department of Pulmonology, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama 26671, Bahrain
| | - Eman A Bediwy
- Internal Medicine, Faculty of Medicine, Tanta University, Algharbia, Tanta 31527, Egypt
| | - Reem Elbeltagi
- Department of Medicine, The Royal College of Surgeons in Ireland-Bahrain, Muharraq, Busiateen 15503, Bahrain
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Azevedo L, Amaro AP, Niza-Ribeiro J, Lopes-Marques M. Naturally occurring genetic diseases caused by de novo variants in domestic animals. Anim Genet 2024; 55:319-327. [PMID: 38323510 DOI: 10.1111/age.13403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 01/25/2024] [Accepted: 01/25/2024] [Indexed: 02/08/2024]
Abstract
With the advent of next-generation sequencing, an increasing number of cases of de novo variants in domestic animals have been reported in scientific literature primarily associated with clinically severe phenotypes. The emergence of new variants at each generation is a crucial aspect in understanding the pathology of early-onset diseases in animals and can provide valuable insights into similar diseases in humans. With the aim of collecting deleterious de novo variants in domestic animals, we searched the scientific literature and compiled reports on 42 de novo variants in 31 genes in domestic animals. No clear disease-associated phenotype has been established in humans for three of these genes (NUMB, ANKRD28 and KCNG1). For the remaining 28 genes, a strong similarity between animal and human phenotypes was recognized from available information in OMIM and OMIA, revealing the importance of comparative studies and supporting the use of domestic animals as natural models for human diseases, in line with the One Health approach.
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Affiliation(s)
- Luísa Azevedo
- UMIB-Unit for Multidisciplinary Research in Biomedicine, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal
- ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal
| | - Andreia P Amaro
- UMIB-Unit for Multidisciplinary Research in Biomedicine, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal
- ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal
| | - João Niza-Ribeiro
- ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal
- Population Studies Department, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal
- EPIUnit-Epidemiology Research Unit, ISPUP-Institute of Public Health of the University of Porto, Porto, Portugal
| | - Mónica Lopes-Marques
- CIIMAR - Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Porto, Portugal
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Nahas LD, Datta A, Alsamman AM, Adly MH, Al-Dewik N, Sekaran K, Sasikumar K, Verma K, Doss GPC, Zayed H. Genomic insights and advanced machine learning: characterizing autism spectrum disorder biomarkers and genetic interactions. Metab Brain Dis 2024; 39:29-42. [PMID: 38153584 PMCID: PMC10799794 DOI: 10.1007/s11011-023-01322-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 11/02/2023] [Indexed: 12/29/2023]
Abstract
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by altered brain connectivity and function. In this study, we employed advanced bioinformatics and explainable AI to analyze gene expression associated with ASD, using data from five GEO datasets. Among 351 neurotypical controls and 358 individuals with autism, we identified 3,339 Differentially Expressed Genes (DEGs) with an adjusted p-value (≤ 0.05). A subsequent meta-analysis pinpointed 342 DEGs (adjusted p-value ≤ 0.001), including 19 upregulated and 10 down-regulated genes across all datasets. Shared genes, pathogenic single nucleotide polymorphisms (SNPs), chromosomal positions, and their impact on biological pathways were examined. We identified potential biomarkers (HOXB3, NR2F2, MAPK8IP3, PIGT, SEMA4D, and SSH1) through text mining, meriting further investigation. Additionally, we shed light on the roles of RPS4Y1 and KDM5D genes in neurogenesis and neurodevelopment. Our analysis detected 1,286 SNPs linked to ASD-related conditions, of which 14 high-risk SNPs were located on chromosomes 10 and X. We highlighted potential missense SNPs associated with FGFR inhibitors, suggesting that it may serve as a promising biomarker for responsiveness to targeted therapies. Our explainable AI model identified the MID2 gene as a potential ASD biomarker. This research unveils vital genes and potential biomarkers, providing a foundation for novel gene discovery in complex diseases.
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Affiliation(s)
| | - Ankur Datta
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Alsamman M Alsamman
- Agricultural Genetic Engineering Research Institute (AGERI), Agricultural Research Center (ARC), Giza, Egypt
| | - Monica H Adly
- Agricultural Genetic Engineering Research Institute (AGERI), Agricultural Research Center (ARC), Giza, Egypt
| | - Nader Al-Dewik
- Department of Research, Women's Wellness and Research Center, Hamad Medical Corporation, Doha, Qatar
| | - Karthik Sekaran
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
- Center for Brain Research, Indian Institute of Science, Bengaluru, India
| | - K Sasikumar
- Department of Sensor and Biomedical Technology, School of Electronics Engineering, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Kanika Verma
- Department of parasitology and host biology ICMR-NIMR, Dwarka, Delhi, India
| | - George Priya C Doss
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Hatem Zayed
- Department of Biomedical Sciences College of Health Sciences, QU Health, Qatar University, Doha, Qatar.
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Vilela J, Martiniano H, Marques AR, Santos JX, Asif M, Rasga C, Oliveira G, Vicente AM. Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis. Biomedicines 2023; 11:2971. [PMID: 38001974 PMCID: PMC10668950 DOI: 10.3390/biomedicines11112971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 10/26/2023] [Accepted: 11/01/2023] [Indexed: 11/26/2023] Open
Abstract
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by communication deficits and repetitive behavioral patterns. Hundreds of candidate genes have been implicated in ASD, including neurotransmission and synaptic (NS) genes; however, the genetic architecture of this disease is far from clear. In this study, we seek to clarify the biological processes affected by NS gene variants identified in individuals with ASD and the global networks that link those processes together. For a curated list of 1216 NS candidate genes, identified in multiple databases and the literature, we searched for ultra-rare (UR) loss-of-function (LoF) variants in the whole-exome sequencing dataset from the Autism Sequencing Consortium (N = 3938 cases). Filtering for population frequency was carried out using gnomAD (N = 60,146 controls). NS genes with UR LoF variants were used to construct a network of protein-protein interactions, and the network's biological communities were identified by applying the Leiden algorithm. We further explored the expression enrichment of network genes in specific brain regions. We identified 356 variants in 208 genes, with a preponderance of UR LoF variants in the PDE11A and SYTL3 genes. Expression enrichment analysis highlighted several subcortical structures, particularly the basal ganglia. The interaction network defined seven network communities, clustering synaptic and neurotransmitter pathways with several ubiquitous processes that occur in multiple organs and systems. This approach also uncovered biological pathways that are not usually associated with ASD, such as brain cytochromes P450 and brain mitochondrial metabolism. Overall, the community analysis suggests that ASD involves the disruption of synaptic and neurotransmitter pathways but also ubiquitous, but less frequently implicated, biological processes.
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Affiliation(s)
- Joana Vilela
- Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal; (J.V.); (H.M.); (A.R.M.); (J.X.S.); (M.A.); (C.R.)
- BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal
| | - Hugo Martiniano
- Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal; (J.V.); (H.M.); (A.R.M.); (J.X.S.); (M.A.); (C.R.)
- BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal
| | - Ana Rita Marques
- Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal; (J.V.); (H.M.); (A.R.M.); (J.X.S.); (M.A.); (C.R.)
- BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal
| | - João Xavier Santos
- Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal; (J.V.); (H.M.); (A.R.M.); (J.X.S.); (M.A.); (C.R.)
- BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal
| | - Muhammad Asif
- Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal; (J.V.); (H.M.); (A.R.M.); (J.X.S.); (M.A.); (C.R.)
- BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad 38000, Pakistan
| | - Célia Rasga
- Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal; (J.V.); (H.M.); (A.R.M.); (J.X.S.); (M.A.); (C.R.)
- BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal
| | - Guiomar Oliveira
- Unidade de Neurodesenvolvimento e Autismo, Serviço do Centro de Desenvolvimento da Criança, Centro de Investigação e Formação Clínica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra (CHUC), 3000-602 Coimbra, Portugal;
- Coimbra Institute for Biomedical Imaging and Translational Research, University Clinic of Pediatrics, Faculty of Medicine, University of Coimbra, 3000-602 Coimbra, Portugal
| | - Astrid Moura Vicente
- Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal; (J.V.); (H.M.); (A.R.M.); (J.X.S.); (M.A.); (C.R.)
- BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal
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Spirito G, Filosi M, Domenici E, Mangoni D, Gustincich S, Sanges R. Exploratory analysis of L1 retrotransposons expression in autism. Mol Autism 2023; 14:22. [PMID: 37381037 DOI: 10.1186/s13229-023-00554-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 06/15/2023] [Indexed: 06/30/2023] Open
Abstract
BACKGROUND Autism spectrum disorder (ASD) is a set of highly heterogeneous neurodevelopmental diseases whose genetic etiology is not completely understood. Several investigations have relied on transcriptome analysis from peripheral tissues to dissect ASD into homogenous molecular phenotypes. Recently, analysis of changes in gene expression from postmortem brain tissues has identified sets of genes that are involved in pathways previously associated with ASD etiology. In addition to protein-coding transcripts, the human transcriptome is composed by a large set of non-coding RNAs and transposable elements (TEs). Advancements in sequencing technologies have proven that TEs can be transcribed in a regulated fashion, and their dysregulation might have a role in brain diseases. METHODS We exploited published datasets comprising RNA-seq data from (1) postmortem brain of ASD subjects, (2) in vitro cell cultures where ten different ASD-relevant genes were knocked out and (3) blood of discordant siblings. We measured the expression levels of evolutionarily young full-length transposable L1 elements and characterized the genomic location of deregulated L1s assessing their potential impact on the transcription of ASD-relevant genes. We analyzed every sample independently, avoiding to pool together the disease subjects to unmask the heterogeneity of the molecular phenotypes. RESULTS We detected a strong upregulation of intronic full-length L1s in a subset of postmortem brain samples and in in vitro differentiated neurons from iPSC knocked out for ATRX. L1 upregulation correlated with an high number of deregulated genes and retained introns. In the anterior cingulate cortex of one subject, a small number of significantly upregulated L1s overlapped with ASD-relevant genes that were significantly downregulated, suggesting the possible existence of a negative effect of L1 transcription on host transcripts. LIMITATIONS Our analyses must be considered exploratory and will need to be validated in bigger cohorts. The main limitation is given by the small sample size and by the lack of replicates for postmortem brain samples. Measuring the transcription of locus-specific TEs is complicated by the repetitive nature of their sequence, which reduces the accuracy in mapping sequencing reads to the correct genomic locus. CONCLUSIONS L1 upregulation in ASD appears to be limited to a subset of subjects that are also characterized by a general deregulation of the expression of canonical genes and an increase in intron retention. In some samples from the anterior cingulate cortex, L1s upregulation seems to directly impair the expression of some ASD-relevant genes by a still unknown mechanism. L1s upregulation may therefore identify a group of ASD subjects with common molecular features and helps stratifying individuals for novel strategies of therapeutic intervention.
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Affiliation(s)
- Giovanni Spirito
- Scuola Internazionale Superiore di Studi Avanzati (SISSA), Area of Neuroscience, Via Bonomea 265, 34136, Trieste, Italy
- Central RNA Laboratory, Istituto Italiano di Tecnologia - IIT, Via Enrico Melen 83, Building B, 16152, Genoa, Italy
- CMP3vda, Via Lavoratori Vittime del Col Du Mont 28, Aosta, Italy
| | - Michele Filosi
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, TN, Italy
- Eurac Research, Institute for Biomedicine, Bolzano, BZ, Italy
| | - Enrico Domenici
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, TN, Italy
- Fondazione The Microsoft Research - University of Trento Centre for Computational and Systems Biology (COSBI), Rovereto, TN, Italy
| | - Damiano Mangoni
- Central RNA Laboratory, Istituto Italiano di Tecnologia - IIT, Via Enrico Melen 83, Building B, 16152, Genoa, Italy
| | - Stefano Gustincich
- Central RNA Laboratory, Istituto Italiano di Tecnologia - IIT, Via Enrico Melen 83, Building B, 16152, Genoa, Italy.
- CMP3vda, Via Lavoratori Vittime del Col Du Mont 28, Aosta, Italy.
| | - Remo Sanges
- Scuola Internazionale Superiore di Studi Avanzati (SISSA), Area of Neuroscience, Via Bonomea 265, 34136, Trieste, Italy.
- Central RNA Laboratory, Istituto Italiano di Tecnologia - IIT, Via Enrico Melen 83, Building B, 16152, Genoa, Italy.
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11
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Senarathne UD, Indika NLR, Jezela-Stanek A, Ciara E, Frye RE, Chen C, Stepien KM. Biochemical, Genetic and Clinical Diagnostic Approaches to Autism-Associated Inherited Metabolic Disorders. Genes (Basel) 2023; 14:genes14040803. [PMID: 37107561 PMCID: PMC10138025 DOI: 10.3390/genes14040803] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/22/2023] [Accepted: 03/22/2023] [Indexed: 03/29/2023] Open
Abstract
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders characterized by impaired social interaction, limited communication skills, and restrictive and repetitive behaviours. The pathophysiology of ASD is multifactorial and includes genetic, epigenetic, and environmental factors, whereas a causal relationship has been described between ASD and inherited metabolic disorders (IMDs). This review describes biochemical, genetic, and clinical approaches to investigating IMDs associated with ASD. The biochemical work-up includes body fluid analysis to confirm general metabolic and/or lysosomal storage diseases, while the advances and applications of genomic testing technology would assist with identifying molecular defects. An IMD is considered likely underlying pathophysiology in ASD patients with suggestive clinical symptoms and multiorgan involvement, of which early recognition and treatment increase their likelihood of achieving optimal care and a better quality of life.
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Affiliation(s)
- Udara D. Senarathne
- Department of Biochemistry, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda 10250, Sri Lanka
- Department of Chemical Pathology, Monash Health Pathology, Monash Health, Melbourne, VIC 3168, Australia
| | - Neluwa-Liyanage R. Indika
- Department of Biochemistry, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda 10250, Sri Lanka
| | - Aleksandra Jezela-Stanek
- Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, Poland
| | - Elżbieta Ciara
- Department of Medical Genetics, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland
| | - Richard E. Frye
- Autism Discovery and Treatment Foundation, Phoenix, AZ 85050, USA
| | - Cliff Chen
- Clinical Neuropsychology Department, Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Salford M6 8HD, UK
| | - Karolina M. Stepien
- Adult Inherited Metabolic Diseases, Mark Holland Unit, Salford Royal NHS Foundation Trust, Salford M6 8HD, UK
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester M13 9PL, UK
- Correspondence:
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12
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Akter S, Roy AS, Tonmoy MIQ, Islam MS. Deleterious single nucleotide polymorphisms (SNPs) of human IFNAR2 gene facilitate COVID-19 severity in patients: a comprehensive in silico approach. J Biomol Struct Dyn 2022; 40:11173-11189. [PMID: 34355676 DOI: 10.1080/07391102.2021.1957714] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
In humans, the dimeric receptor complex IFNAR2-IFNAR1 accelerates cellular response triggered by type I interferon (IFN) family proteins in response to viral infection including Coronavirus infection. Studies have revealed the association of the IFNAR2 gene with severe illness in Coronavirus infection and indicated the association of genomic variants, i.e. single nucleotide polymorphisms (SNPs). However, comprehensive analysis of SNPs of the IFNAR2 gene has not been performed in both coding and non-coding region to find the causes of loss of function of IFNAR2 in COVID-19 patients. In this study, we have characterized coding SNPs (nsSNPs) of IFNAR2 gene using different bioinformatics tools and identified deleterious SNPs. We found 9 nsSNPs as pathogenic and disease-causing along with a decrease in protein stability. We employed molecular docking analysis that showed 5 nsSNPs to decrease binding affinity to IFN. Later, MD simulations showed that P136R mutant may destabilize crucial binding with the IFN molecule in response to COVID-19. Thus, P136R is likely to have a high impact on disrupting the structure of the IFNAR2 protein. GTEx portal analysis predicted 14 sQTLs and 5 eQTLs SNPs in lung tissues hampering the post-transcriptional modification (splicing) and altering the expression of the IFNAR2 gene. sQTLs and eQTLs SNPs potentially explain the reduced IFNAR2 production leading to severe diseases. These mutants in the coding and non-coding region of the IFNAR2 gene can help to recognize severe illness due to COVID 19 and consequently assist to develop an effective drug against the infection.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Shamima Akter
- Department of Bioinformatics and Computational Biology, George Mason University, Fairfax, VA, USA
| | - Arpita Singha Roy
- Department of Biotechnology and Genetic Engineering, Noakhali Science and Technology University, Noakhali, Bangladesh
| | | | - Md Sajedul Islam
- Department of Biochemistry & Biotechnology, University of Barishal, Barishal, Bangladesh
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13
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Klimara MJ, Nishimura C, Wang D, Kolbe DL, Schaefer AM, Walls WD, Frees KL, Smith RJH, Azaiez H. De novo variants are a common cause of genetic hearing loss. Genet Med 2022; 24:2555-2567. [PMID: 36194208 PMCID: PMC9729384 DOI: 10.1016/j.gim.2022.08.028] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/25/2022] [Accepted: 08/26/2022] [Indexed: 11/06/2022] Open
Abstract
PURPOSE De novo variants (DNVs) are a well-recognized cause of genetic disorders. The contribution of DNVs to hearing loss (HL) is poorly characterized. We aimed to evaluate the rate of DNVs in HL-associated genes and assess their contribution to HL. METHODS Targeted genomic enrichment and massively parallel sequencing were used for molecular testing of all exons and flanking intronic sequences of known HL-associated genes, with no exclusions on the basis of type of HL or clinical features. Segregation analysis was performed, and previous reports of DNVs in PubMed and ClinVar were reviewed to characterize the rate, distribution, and spectrum of DNVs in HL. RESULTS DNVs were detected in 10% (24/238) of trios for whom segregation analysis was performed. Overall, DNVs were causative in at least ∼1% of probands for whom a genetic diagnosis was resolved, with marked variability based on inheritance mode and phenotype. DNVs of MITF were most common (21% of DNVs), followed by GATA3 (13%), STRC (13%), and ACTG1 (8%). Review of reported DNVs revealed gene-specific variability in contribution of DNV to the mutational spectrum of HL-associated genes. CONCLUSION DNVs are a relatively common cause of genetic HL and must be considered in all cases of sporadic HL.
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Affiliation(s)
- Miles J Klimara
- Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA
| | - Carla Nishimura
- Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA
| | - Donghong Wang
- Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA
| | - Diana L Kolbe
- Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA
| | - Amanda M Schaefer
- Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA
| | - William D Walls
- Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA
| | - Kathy L Frees
- Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA
| | - Richard J H Smith
- Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA.
| | - Hela Azaiez
- Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA.
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14
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Perfilyeva A, Bespalova K, Perfilyeva Y, Skvortsova L, Musralina L, Zhunussova G, Khussainova E, Iskakova U, Bekmanov B, Djansugurova L. Integrative Functional Genomic Analysis in Multiplex Autism Families from Kazakhstan. DISEASE MARKERS 2022; 2022:1509994. [PMID: 36199823 PMCID: PMC9529466 DOI: 10.1155/2022/1509994] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 08/21/2022] [Accepted: 09/06/2022] [Indexed: 12/14/2022]
Abstract
The study of extended pedigrees containing autism spectrum disorder- (ASD-) related broader autism phenotypes (BAP) offers a promising approach to the search for ASD candidate variants. Here, a total of 650,000 genetic markers were tested in four Kazakhstani multiplex families with ASD and BAP to obtain data on de novo mutations (DNMs), common, and rare inherited variants that may contribute to the genetic risk for developing autistic traits. The variants were analyzed in the context of gene networks and pathways. Several previously well-described enriched pathways were identified, including ion channel activity, regulation of synaptic function, and membrane depolarization. Perhaps these pathways are crucial not only for the development of ASD but also for ВАР. The results also point to several additional biological pathways (circadian entrainment, NCAM and BTN family interactions, and interaction between L1 and Ankyrins) and hub genes (CFTR, NOD2, PPP2R2B, and TTR). The obtained results suggest that further exploration of PPI networks combining ASD and BAP risk genes can be used to identify novel or overlooked ASD molecular mechanisms.
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Affiliation(s)
| | - Kira Bespalova
- Institute of Genetics and Physiology, 93 Al-Farabi Ave., Almaty 050060, Kazakhstan
- Al-Farabi Kazakh National University, 71 Al-Farabi Ave., Almaty 050040, Kazakhstan
| | - Yuliya Perfilyeva
- M.A. Aitkhozhin's Institute of Molecular Biology and Biochemistry, 86 Dosmukhamedov St., Almaty 050012, Kazakhstan
- Branch of the National Center for Biotechnology, 14 Zhahanger St., Almaty 050054, Kazakhstan
| | - Liliya Skvortsova
- Institute of Genetics and Physiology, 93 Al-Farabi Ave., Almaty 050060, Kazakhstan
| | - Lyazzat Musralina
- Institute of Genetics and Physiology, 93 Al-Farabi Ave., Almaty 050060, Kazakhstan
| | - Gulnur Zhunussova
- Institute of Genetics and Physiology, 93 Al-Farabi Ave., Almaty 050060, Kazakhstan
| | - Elmira Khussainova
- Institute of Genetics and Physiology, 93 Al-Farabi Ave., Almaty 050060, Kazakhstan
| | - Ulzhan Iskakova
- Kazakh National Medical University, 94 Tole Bi St., Almaty 050000, Kazakhstan
| | - Bakhytzhan Bekmanov
- Institute of Genetics and Physiology, 93 Al-Farabi Ave., Almaty 050060, Kazakhstan
| | - Leyla Djansugurova
- Institute of Genetics and Physiology, 93 Al-Farabi Ave., Almaty 050060, Kazakhstan
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15
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Recent Developments in Autism Genetic Research: A Scientometric Review from 2018 to 2022. Genes (Basel) 2022; 13:genes13091646. [PMID: 36140813 PMCID: PMC9498399 DOI: 10.3390/genes13091646] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/12/2022] [Accepted: 09/12/2022] [Indexed: 12/13/2022] Open
Abstract
Genetic research in Autism Spectrum Disorder (ASD) has progressed tremendously in recent decades. Dozens of genetic loci and hundreds of alterations in the genetic sequence, expression, epigenetic transformation, and interactions with other physiological and environmental systems have been found to increase the likelihood of developing ASD. There is therefore a need to represent this wide-ranging yet voluminous body of literature in a systematic manner so that this information can be synthesised and understood at a macro level. Therefore, this study made use of scientometric methods, particularly document co-citation analysis (DCA), to systematically review literature on ASD genetic research from 2018 to 2022. A total of 14,818 articles were extracted from Scopus and analyzed with CiteSpace. An optimized DCA analysis revealed that recent literature on ASD genetic research can be broadly organised into 12 major clusters representing various sub-topics. These clusters are briefly described in the manuscript and potential applications of this study are discussed.
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16
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Vilela J, Martiniano H, Marques AR, Santos JX, Rasga C, Oliveira G, Vicente AM. Disease similarity network analysis of Autism Spectrum Disorder and comorbid brain disorders. Front Mol Neurosci 2022; 15:932305. [PMID: 36061363 PMCID: PMC9434349 DOI: 10.3389/fnmol.2022.932305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 07/18/2022] [Indexed: 12/02/2022] Open
Abstract
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with heterogeneous clinical presentation, variable severity, and multiple comorbidities. A complex underlying genetic architecture matches the clinical heterogeneity, and evidence indicates that several co-occurring brain disorders share a genetic component with ASD. In this study, we established a genetic similarity disease network approach to explore the shared genetics between ASD and frequent comorbid brain diseases (and subtypes), namely Intellectual Disability, Attention-Deficit/Hyperactivity Disorder, and Epilepsy, as well as other rarely co-occurring neuropsychiatric conditions in the Schizophrenia and Bipolar Disease spectrum. Using sets of disease-associated genes curated by the DisGeNET database, disease genetic similarity was estimated from the Jaccard coefficient between disease pairs, and the Leiden detection algorithm was used to identify network disease communities and define shared biological pathways. We identified a heterogeneous brain disease community that is genetically more similar to ASD, and that includes Epilepsy, Bipolar Disorder, Attention-Deficit/Hyperactivity Disorder combined type, and some disorders in the Schizophrenia Spectrum. To identify loss-of-function rare de novo variants within shared genes underlying the disease communities, we analyzed a large ASD whole-genome sequencing dataset, showing that ASD shares genes with multiple brain disorders from other, less genetically similar, communities. Some genes (e.g., SHANK3, ASH1L, SCN2A, CHD2, and MECP2) were previously implicated in ASD and these disorders. This approach enabled further clarification of genetic sharing between ASD and brain disorders, with a finer granularity in disease classification and multi-level evidence from DisGeNET. Understanding genetic sharing across disorders has important implications for disease nosology, pathophysiology, and personalized treatment.
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Affiliation(s)
- Joana Vilela
- Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisbon, Portugal
- Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, University of Lisboa, Lisbon, Portugal
| | - Hugo Martiniano
- Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisbon, Portugal
- Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, University of Lisboa, Lisbon, Portugal
| | - Ana Rita Marques
- Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisbon, Portugal
- Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, University of Lisboa, Lisbon, Portugal
| | - João Xavier Santos
- Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisbon, Portugal
- Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, University of Lisboa, Lisbon, Portugal
| | - Célia Rasga
- Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisbon, Portugal
- Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, University of Lisboa, Lisbon, Portugal
| | - Guiomar Oliveira
- Unidade de Neurodesenvolvimento e Autismo, Serviço do Centro de Desenvolvimento da Criança, Centro de Investigação e Formação Clínica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
- Faculty of Medicine, University Clinic of Pediatrics and Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal
| | - Astrid Moura Vicente
- Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisbon, Portugal
- Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, University of Lisboa, Lisbon, Portugal
- *Correspondence: Astrid Moura Vicente,
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17
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SHANK3 genetic polymorphism and susceptibility to ASD: evidence from molecular, in silico, and meta-analysis approaches. Mol Biol Rep 2022; 49:8449-8460. [PMID: 35819558 DOI: 10.1007/s11033-022-07663-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/28/2022] [Accepted: 05/30/2022] [Indexed: 10/17/2022]
Abstract
BACKGROUND The SHANK3 gene encodes a master synaptic scaffolding protein at the excitatory synapse's postsynaptic density, which is predominantly responsible for constructing a synapse, maintaining synaptic structure, and functions. Recently, evidence from rare mutations and copy number variation provided an important clue about SHANK3 which acts as a strong candidate gene in the pathogenesis of Autism Spectrum Disorder (ASD). MATERIALS AND METHODS To investigate potential allelic variants for the SHANK3 (rs9616915) gene as a genetic risk factor, we performed PCR-RFLP analysis and Sanger sequencing for 90 ASD and 90 healthy subjects. Moreover, to understand the functional and structural impacts of our selected non-synonymous SHANK3 SNP rs9616915, we have performed an in silico analysis. Subsequently, a meta-analysis of rs9616915 with a total of 6 eligible studies (including the present study) containing a total of 795 cases and 12,947 controls was obtained from a comprehensive online database search to evaluate the overall association with ASD. RESULTS Our retrieved data, such as Pearson's chi-square test (p = 0.081) as well as logistic regression analysis of co-dominant (p = 0.1131), dominant (p = 0.3656) and recessive models (p = 0.0569) speculated no significant association between rs9616915 and our studied sample. Interestingly, by in silico analysis, we have observed two hydrogen bonds between amino acids instead of one hydrogen bond in the protein structure of rs9616915, which indicates this mutant structure could affect the proteins' stability. The findings of the meta-analysis revealed that four genetic association models were associated with ASD susceptibility. CONCLUSIONS Our study suggested that targeted SHANK3 SNP of interest rs9616915 might not be associated with ASD in the southern part of the Bangladeshi population.
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Alade A, Awotoye W, Butali A. Genetic and epigenetic studies in non-syndromic oral clefts. Oral Dis 2022; 28:1339-1350. [PMID: 35122708 DOI: 10.1111/odi.14146] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 01/11/2022] [Accepted: 01/20/2022] [Indexed: 11/28/2022]
Abstract
The etiology of non-syndromic oral clefts (NSOFC) is complex with genetics, genomics, epigenetics, and stochastics factors playing a role. Several approaches have been applied to understand the etiology of non-syndromic oral clefts. These include linkage, candidate gene association studies, genome-wide association studies, whole-genome sequencing, copy number variations, and epigenetics. In this review, we shared these approaches, genes, and loci reported in some studies.
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Affiliation(s)
- Azeez Alade
- Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa, Iowa City, Iowa, USA
- Iowa Institute for Oral Health Research, University of Iowa, Iowa City, Iowa, USA
- Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa, USA
| | - Waheed Awotoye
- Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa, Iowa City, Iowa, USA
- Iowa Institute for Oral Health Research, University of Iowa, Iowa City, Iowa, USA
| | - Azeez Butali
- Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa, Iowa City, Iowa, USA
- Iowa Institute for Oral Health Research, University of Iowa, Iowa City, Iowa, USA
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Luo S, Zheng N, Lang B. ULK4 in Neurodevelopmental and Neuropsychiatric Disorders. Front Cell Dev Biol 2022; 10:873706. [PMID: 35493088 PMCID: PMC9039724 DOI: 10.3389/fcell.2022.873706] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 03/29/2022] [Indexed: 11/21/2022] Open
Abstract
The gene Unc51-like kinase 4 (ULK4) belongs to the Unc-51-like serine/threonine kinase family and is assumed to encode a pseudokinase with unclear function. Recently, emerging evidence has suggested that ULK4 may be etiologically involved in a spectrum of neuropsychiatric disorders including schizophrenia, but the underlying mechanism remains unaddressed. Here, we summarize the key findings of the structure and function of the ULK4 protein to provide comprehensive insights to better understand ULK4-related neurodevelopmental and neuropsychiatric disorders and to aid in the development of a ULK4-based therapeutic strategy.
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Affiliation(s)
- Shilin Luo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Provincial Engineering Research Center of Translational Medicine and Innovative Drug, Changsha, China
| | - Nanxi Zheng
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
- *Correspondence: Nanxi Zheng, ; Bing Lang,
| | - Bing Lang
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
- *Correspondence: Nanxi Zheng, ; Bing Lang,
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20
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Lasser M, Bolduc J, Murphy L, O'Brien C, Lee S, Girirajan S, Lowery LA. 16p12.1 Deletion Orthologs are Expressed in Motile Neural Crest Cells and are Important for Regulating Craniofacial Development in Xenopus laevis. Front Genet 2022; 13:833083. [PMID: 35401697 PMCID: PMC8987115 DOI: 10.3389/fgene.2022.833083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 03/09/2022] [Indexed: 12/03/2022] Open
Abstract
Copy number variants (CNVs) associated with neurodevelopmental disorders are characterized by extensive phenotypic heterogeneity. In particular, one CNV was identified in a subset of children clinically diagnosed with intellectual disabilities (ID) that results in a hemizygous deletion of multiple genes at chromosome 16p12.1. In addition to ID, individuals with this deletion display a variety of symptoms including microcephaly, seizures, cardiac defects, and growth retardation. Moreover, patients also manifest severe craniofacial abnormalities, such as micrognathia, cartilage malformation of the ears and nose, and facial asymmetries; however, the function of the genes within the 16p12.1 region have not been studied in the context of vertebrate craniofacial development. The craniofacial tissues affected in patients with this deletion all derive from the same embryonic precursor, the cranial neural crest, leading to the hypothesis that one or more of the 16p12.1 genes may be involved in regulating neural crest cell (NCC)-related processes. To examine this, we characterized the developmental role of the 16p12.1-affected gene orthologs, polr3e, mosmo, uqcrc2, and cdr2, during craniofacial morphogenesis in the vertebrate model system, Xenopus laevis. While the currently-known cellular functions of these genes are diverse, we find that they share similar expression patterns along the neural tube, pharyngeal arches, and later craniofacial structures. As these genes show co-expression in the pharyngeal arches where NCCs reside, we sought to elucidate the effect of individual gene depletion on craniofacial development and NCC migration. We find that reduction of several 16p12.1 genes significantly disrupts craniofacial and cartilage formation, pharyngeal arch migration, as well as NCC specification and motility. Thus, we have determined that some of these genes play an essential role during vertebrate craniofacial patterning by regulating specific processes during NCC development, which may be an underlying mechanism contributing to the craniofacial defects associated with the 16p12.1 deletion.
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Affiliation(s)
- Micaela Lasser
- Department of Biology, Boston College, Chestnut Hill, MA, United States
| | - Jessica Bolduc
- Department of Biology, Boston College, Chestnut Hill, MA, United States
| | - Luke Murphy
- Department of Biology, Boston College, Chestnut Hill, MA, United States
| | - Caroline O'Brien
- Department of Biology, Boston College, Chestnut Hill, MA, United States
| | - Sangmook Lee
- Department of Biology, Boston College, Chestnut Hill, MA, United States
| | - Santhosh Girirajan
- Department of Biochemistry and Molecular Biology, Pennsylvania State University, State College, PA, United States
| | - Laura Anne Lowery
- Alfred B. Nobel Section of Hematology and Medical Oncology, Boston University School of Medicine and Boston Medical Center, Boston, MA, United States
- *Correspondence: Laura Anne Lowery,
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21
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Álvaro-Sánchez S, Abreu-Rodríguez I, Abulí A, Serra-Juhe C, Garrido-Navas MDC. Current Status of Genetic Counselling for Rare Diseases in Spain. Diagnostics (Basel) 2021; 11:2320. [PMID: 34943558 PMCID: PMC8700506 DOI: 10.3390/diagnostics11122320] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/05/2021] [Accepted: 12/06/2021] [Indexed: 12/29/2022] Open
Abstract
Genetic Counselling is essential for providing personalised information and support to patients with Rare Diseases (RD). Unlike most other developed countries, Spain does not recognize geneticists or genetic counsellors as healthcare professionals Thus, patients with RD face not only challenges associated with their own disease but also deal with lack of knowledge, uncertainty, and other psychosocial issues arising as a consequence of diagnostic delay. In this review, we highlight the importance of genetic counsellors in the field of RD as well as evaluate the current situation in which rare disease patients receive genetic services in Spain. We describe the main units and strategies at the national level assisting patients with RD and we conclude with a series of future perspectives and unmet needs that Spain should overcome to improve the management of patients with RD.
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Affiliation(s)
| | - Irene Abreu-Rodríguez
- Genetics Service, Hospital del Mar Research Institute, IMIM, 08003 Barcelona, Spain;
| | - Anna Abulí
- Department of Clinical and Molecular Genetics, Hospital Vall d’Hebron, 08035 Barcelona, Spain;
- Medicine Genetics Group, Vall d’Hebron Research Institute (VHIR), 08035 Barcelona, Spain
| | - Clara Serra-Juhe
- U705 CIBERER, Genetics Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain;
- Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), 28029 Madrid, Spain
| | - Maria del Carmen Garrido-Navas
- CONGEN, Genetic Counselling Services, C/Albahaca 4, 18006 Granada, Spain;
- Genetics Department, Faculty of Sciences, Universidad de Granada, 18071 Granada, Spain
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22
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Nassir N, Bankapur A, Samara B, Ali A, Ahmed A, Inuwa IM, Zarrei M, Safizadeh Shabestari SA, AlBanna A, Howe JL, Berdiev BK, Scherer SW, Woodbury-Smith M, Uddin M. Single-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells. Hum Genomics 2021; 15:68. [PMID: 34802461 PMCID: PMC8607722 DOI: 10.1186/s40246-021-00368-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 11/05/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND In recent years, several hundred autism spectrum disorder (ASD) implicated genes have been discovered impacting a wide range of molecular pathways. However, the molecular underpinning of ASD, particularly from the point of view of 'brain to behaviour' pathogenic mechanisms, remains largely unknown. METHODS We undertook a study to investigate patterns of spatiotemporal and cell type expression of ASD-implicated genes by integrating large-scale brain single-cell transcriptomes (> million cells) and de novo loss-of-function (LOF) ASD variants (impacting 852 genes from 40,122 cases). RESULTS We identified multiple single-cell clusters from three distinct developmental human brain regions (anterior cingulate cortex, middle temporal gyrus and primary visual cortex) that evidenced high evolutionary constraint through enrichment for brain critical exons and high pLI genes. These clusters also showed significant enrichment with ASD loss-of-function variant genes (p < 5.23 × 10-11) that are transcriptionally highly active in prenatal brain regions (visual cortex and dorsolateral prefrontal cortex). Mapping ASD de novo LOF variant genes into large-scale human and mouse brain single-cell transcriptome analysis demonstrate enrichment of such genes into neuronal subtypes and are also enriched for subtype of non-neuronal glial cell types (astrocyte, p < 6.40 × 10-11, oligodendrocyte, p < 1.31 × 10-09). CONCLUSION Among the ASD genes enriched with pathogenic de novo LOF variants (i.e. KANK1, PLXNB1), a subgroup has restricted transcriptional regulation in non-neuronal cell types that are evolutionarily conserved. This association strongly suggests the involvement of subtype of non-neuronal glial cells in the pathogenesis of ASD and the need to explore other biological pathways for this disorder.
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Affiliation(s)
- Nasna Nassir
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE
| | - Asma Bankapur
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE
| | - Bisan Samara
- Biomedical Engineering Department, McGill University, Montréal, QC, Canada
| | - Abdulrahman Ali
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE
| | - Awab Ahmed
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE
| | - Ibrahim M Inuwa
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE
| | - Mehdi Zarrei
- The Centre for Applied Genomics (TCAG), The Hospital for Sick Children, Toronto, ON, Canada.,Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
| | | | - Ammar AlBanna
- Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE.,The Mental Health Center of Excellence, Al Jalila Children's Speciality Hospital, Dubai, UAE
| | - Jennifer L Howe
- The Centre for Applied Genomics (TCAG), The Hospital for Sick Children, Toronto, ON, Canada.,Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Bakhrom K Berdiev
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE
| | - Stephen W Scherer
- The Centre for Applied Genomics (TCAG), The Hospital for Sick Children, Toronto, ON, Canada.,Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.,Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Marc Woodbury-Smith
- The Centre for Applied Genomics (TCAG), The Hospital for Sick Children, Toronto, ON, Canada.,Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Mohammed Uddin
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE. .,Cellular Intelligence (Ci) Lab, GenomeArc Inc., Toronto, ON, Canada.
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23
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Akter S, Hossain S, Ali MA, Hosen MI, Shekhar HU. Comprehensive Characterization of the Coding and Non-Coding Single Nucleotide Polymorphisms in the Tumor Protein p63 (TP63) Gene Using In Silico Tools. Biomolecules 2021; 11:1733. [PMID: 34827731 PMCID: PMC8637305 DOI: 10.3390/biom11111733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/08/2021] [Accepted: 11/18/2021] [Indexed: 11/16/2022] Open
Abstract
Single nucleotide polymorphisms (SNPs) help to understand the phenotypic variations in humans. Genome-wide association studies (GWAS) have identified SNPs located in the tumor protein 63 (TP63) locus to be associated with the genetic susceptibility of cancers. However, there is a lack of in-depth characterization of the structural and functional impacts of the SNPs located at the TP63 gene. The current study was designed for the comprehensive characterization of the coding and non-coding SNPs in the human TP63 gene for their functional and structural significance. The functional and structural effects of the SNPs were investigated using a wide variety of computational tools and approaches, including molecular dynamics (MD) simulation. The deleterious impact of eight nonsynonymous SNPs (nsSNPs) affecting protein stability, structure, and functions was measured by using 13 bioinformatics tools. These eight nsSNPs are in highly conserved positions in protein and were predicted to decrease protein stability and have a deleterious impact on the TP63 protein function. Molecular docking analysis showed five nsSNPs to reduce the binding affinity of TP63 protein to DNA with significant results for three SNPs (R319H, G349E, and C347F). Further, MD simulations revealed the possible disruption of TP63 and DNA binding, hampering the essential protein function. PolymiRTS study found five non-coding SNPs in miRNA binding sites, and the GTEx portal recognized five eQTLs SNPs in single tissue of the lung, heart (LV), and cerebral hemisphere (brain). Characterized nsSNPs and non-coding SNPs will help researchers to focus on TP63 gene loci and ascertain their association with certain diseases.
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Affiliation(s)
- Shamima Akter
- Department of Bioinformatics and Computational Biology, George Mason University, Fairfax, VA 22030, USA;
| | - Shafaat Hossain
- Clinical Biochemistry and Translational Medicine Laboratory, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh; (S.H.); (M.I.H.)
| | - Md. Ackas Ali
- Division of Computer Aided Drug-Design, The Red-Green Research Center, 16, Tejkunipara, Tejgaon, Dhaka 1215, Bangladesh;
| | - Md. Ismail Hosen
- Clinical Biochemistry and Translational Medicine Laboratory, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh; (S.H.); (M.I.H.)
| | - Hossain Uddin Shekhar
- Clinical Biochemistry and Translational Medicine Laboratory, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh; (S.H.); (M.I.H.)
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24
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Magen-Molho H, Weisskopf MG, Nevo D, Shtein A, Chen S, Broday D, Kloog I, Levine H, Pinto O, Raz R. Air Pollution and Autism Spectrum Disorder in Israel: A Negative Control Analysis. Epidemiology 2021; 32:773-780. [PMID: 34347685 PMCID: PMC8478838 DOI: 10.1097/ede.0000000000001407] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Residual confounding is a major concern for causal inference in observational studies on air pollution-autism spectrum disorder (ASD) associations. This study is aimed at assessing confounding in these associations using negative control exposures. METHODS This nested case-control study included all children diagnosed with ASD (detected through 31 December 2016) born during 2007-2012 in Israel and residing in the study area (N = 3,843), and matched controls of the same age (N = 38,430). We assigned individual house-level exposure estimates for each child. We estimated associations using logistic regression models, mutually adjusted for all relevant exposure periods (prepregnancy, pregnancy, and postnatal). We assessed residual confounding using postoutcome negative control exposure at age 28-36 months. RESULTS In mutually adjusted models, we observed positive associations with ASD for postnatal exposures to NOx (odds ratio per interquartile range, 95% confidence interval: 1.19, 1.02-1.38) and NO2 (1.20, 1.00-1.43), and gestational exposure to PM2.5-10 (1.08, 1.01-1.15). The result for the negative control period was 1.04, 0.99-1.10 for PM2.5, suggesting some residual confounding, but no associations for PM2.5-10 (0.98, 0.81-1.18), NOx (1.02, 0.84-1.25), or NO2 (0.98, 0.81-1.18), suggesting no residual confounding. CONCLUSIONS Our results further support a hypothesized causal link with ASD that is specific to postnatal exposures to traffic-related pollution.
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Affiliation(s)
- Hadas Magen-Molho
- Braun School of Public Health and Community Medicine, The Hebrew University - Hadassah, Jerusalem, Israel
- The Advanced School for Environmental Studies, The Hebrew University, Jerusalem, Israel
| | - Marc G Weisskopf
- Department of Epidemiology and Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Daniel Nevo
- Department of Statistics and Operations Research, Tel Aviv University, Israel
| | - Alexandra Shtein
- Department of Geography and Environmental Development, Ben-Gurion University of the Negev, Israel
| | - Shimon Chen
- Department of Civil and Environmental Engineering, and Technion Center of Excellence in Exposure Science and Environmental Health (TCEEH), Technion, Israel Institute of Technology, Haifa, Israel
| | - David Broday
- Department of Civil and Environmental Engineering, and Technion Center of Excellence in Exposure Science and Environmental Health (TCEEH), Technion, Israel Institute of Technology, Haifa, Israel
| | - Itai Kloog
- Department of Geography and Environmental Development, Ben-Gurion University of the Negev, Israel
| | - Hagai Levine
- Braun School of Public Health and Community Medicine, The Hebrew University - Hadassah, Jerusalem, Israel
| | - Ofir Pinto
- The National Insurance Institute of Israel
| | - Raanan Raz
- Braun School of Public Health and Community Medicine, The Hebrew University - Hadassah, Jerusalem, Israel
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25
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Wang CW, Chang TH, Chuang NC, Au HK, Chen CH, Tseng SH. Association between intracytoplasmic sperm injection and neurodevelopmental outcomes among offspring. PLoS One 2021; 16:e0257268. [PMID: 34506583 PMCID: PMC8432870 DOI: 10.1371/journal.pone.0257268] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 08/31/2021] [Indexed: 12/14/2022] Open
Abstract
PURPOSE To compare the risk of neurodevelopmental disorders in children conceived via intracytoplasmic sperm injection (ICSI) and those conceived naturally. MATERIALS AND METHODS A population-based cohort study using data retrieved from the Taipei Medical University Research Database (TMURD) from January, 2004 to August, 2016. The data included maternal pregnancy history, perinatal history and developmental follow up of their babies up to 5 years of age. The study included 23885 children, of whom 23148 were naturally conceived and 737 were conceived via ICSI. Neurodevelopmental disorders defined by 21 ICD-9-CM codes. RESULTS Of the 23885 children enrolled for analysis, 2778 children were included for further subgrouping analysis after propensity matching to reduce bias from maternal factors. The single-birth group included 1752 naturally conceived (NC) children and 438 ICSI children. The multiple-birth group included 294 NC and 294 ICSI children. The risk of neurodevelopmental disorders was not increased for ICSI children in both groups (single birth: adjusted hazard ratio aHR = 0.70, 95% CI = 0.39-1.27, p = 0.243; multiple-birth group aHR = 0.77, 95% CI = 0.43-1.35, p = 0.853). In the single-birth group, multivariate analyses showed that male sex (aHR = 1.81, 95% CI = 1.29-2.54, p < 0.001), and intensive care unit (ICU) admission (aHR = 3.10, 95% CI = 1.64-5.86, p < 0.001) were risk factors for neurodevelopmental disorders. In the multiple-birth group, multivariate analyses demonstrated that ICU admission (aHR = 3.58, 95% CI = 1.82-7.04, p < 0.001), was risk factor for neurodevelopmental disorders. CONCLUSION Our study indicated that the use of ICSI does not associated with higher risk of neurodevelopmental disorders in the offspring. But male sex, and ICU admission do have increased risk of neurodevelopmental disorders. However, long term follow up of this cohort on health outcomes in adolescence and adulthood will strengthen the conclusions that ICSI is safe regarding offspring long term outcome.
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Affiliation(s)
- Cheng-Wei Wang
- Division of Reproduction Medicine, Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei, Taiwan
| | - Tzu-Hao Chang
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Clinical Big Data Research Center, Taipei Medical University Hospital, Taipei, Taiwan
| | - Nai-Chen Chuang
- Clinical Data Center, Office of Data Science, Taipei Medical University, Taipei, Taiwan
| | - Heng-Kien Au
- Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chi-Huang Chen
- Division of Reproduction Medicine, Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei, Taiwan
- Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Sung-Hui Tseng
- Department of Physical Medicine and Rehabilitation, Taipei Medical University Hospital, Taipei, Taiwan
- Department of Physical Medicine and Rehabilitation, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- * E-mail:
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26
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Cruz-Martins N, Quispe C, Kırkın C, Şenol E, Zuluğ A, Özçelik B, Ademiluyi AO, Oyeniran OH, Semwal P, Kumar M, Sharopov F, López V, Les F, Bagiu IC, Butnariu M, Sharifi-Rad J, Alshehri MM, Cho WC. Paving Plant-Food-Derived Bioactives as Effective Therapeutic Agents in Autism Spectrum Disorder. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:1131280. [PMID: 34471461 PMCID: PMC8405324 DOI: 10.1155/2021/1131280] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 08/02/2021] [Indexed: 01/03/2023]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder, where social and communication deficits and repetitive behaviors are present. Plant-derived bioactives have shown promising results in the treatment of autism. In this sense, this review is aimed at providing a careful view on the use of plant-derived bioactive molecules for the treatment of autism. Among the plethora of bioactives, curcumin, luteolin, and resveratrol have revealed excellent neuroprotective effects and can be effectively used in the treatment of neuropsychological disorders. However, the number of clinical trials is limited, and none of them have been approved for the treatment of autism or autism-related disorder. Further clinical studies are needed to effectively assess the real potential of such bioactive molecules.
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Affiliation(s)
- Natália Cruz-Martins
- Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal
- Institute of Research and Advanced Training in Health Sciences and Technologies (CESPU), Rua Central de Gandra, 1317, 4585-116, Gandra, PRD, Portugal
| | - Cristina Quispe
- Facultad de Ciencias de la Salud, Universidad Arturo Prat, Avda. Arturo Prat 2120, Iquique 1110939, Chile
| | - Celale Kırkın
- Department of Food Engineering, Faculty of Chemical and Metallurgical Engineering, Istanbul Technical University, Maslak, 34469 Istanbul, Turkey
| | - Ezgi Şenol
- Department Food Engineering, Faculty of Engineering and Natural Sciences, Istanbul Sabahattin Zaim University, Beyoglu, 34427 Istanbul, Turkey
| | - Aslı Zuluğ
- Department of Gastronomy and Culinary Arts, School of Applied Sciences, Ozyegin University, Cekmekoy, 34794 Istanbul, Turkey
| | - Beraat Özçelik
- Department Food Engineering, Faculty of Chemical and Metallurgical Engineering, Istanbul Technical University, Maslak, 34469 Istanbul, Turkey
- BIOACTIVE Research & Innovation Food Manufacturing Industry Trade Ltd. Co., Maslak, Istanbul 34469, Turkey
| | - Adedayo O. Ademiluyi
- Functional Foods, Nutraceuticals, and Phytomedicine Unit, Department of Biochemistry, Federal University of Technology, Akure 340001, Nigeria
| | - Olubukola Helen Oyeniran
- Functional Foods, Nutraceuticals, and Phytomedicine Unit, Department of Biochemistry, Federal University of Technology, Akure 340001, Nigeria
| | - Prabhakar Semwal
- Department of Biotechnology, Graphic Era University, Dehradun, Uttarakhand, India
- Uttarakhand State Council for Science and Technology, Dehradun, Uttarakhand, India
| | - Manoj Kumar
- Chemical and Biochemical Processing Division, ICAR - Central Institute for Research on Cotton Technology, Mumbai 400019, India
| | - Farukh Sharopov
- Department of Pharmaceutical Technology, Avicenna Tajik State Medical University, Rudaki 139, 734003 Dushanbe, Tajikistan
| | - Victor López
- Facultad de Ciencias de la Salud, Universidad San Jorge, Villanueva de Gállego, Zaragoza, Spain
- Instituto Agroalimentario de Aragón (IA2), Universidad de Zaragoza-CITA, Zaragoza, Spain
| | - Francisco Les
- Facultad de Ciencias de la Salud, Universidad San Jorge, Villanueva de Gállego, Zaragoza, Spain
- Instituto Agroalimentario de Aragón (IA2), Universidad de Zaragoza-CITA, Zaragoza, Spain
| | - Iulia-Cristina Bagiu
- Victor Babes University of Medicine and Pharmacy of Timisoara, Department of Microbiology, Timisoara, Romania
- Multidisciplinary Research Center on Antimicrobial Resistance, Timisoara, Romania
| | - Monica Butnariu
- Banat's University of Agricultural Sciences and Veterinary Medicine “King Michael I of Romania” from Timisoara, Timisoara, Romania
| | - Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammed M. Alshehri
- Pharmaceutical Care Department, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
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27
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Freitag CM, Chiocchetti AG, Haslinger D, Yousaf A, Waltes R. [Genetic risk factors and their influence on neural development in autism spectrum disorders]. ZEITSCHRIFT FUR KINDER-UND JUGENDPSYCHIATRIE UND PSYCHOTHERAPIE 2021; 50:187-202. [PMID: 34128703 DOI: 10.1024/1422-4917/a000803] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Genetic risk factors and their influence on neural development in autism spectrum disorders Abstract. Abstract. Autism spectrum disorders are etiologically based on genetic and specific gene x biologically relevant environmental risk factors. They are diagnosed based on behavioral characteristics, such as impaired social communication and stereotyped, repetitive behavior and sensory as well as special interests. The genetic background is heterogeneous, i. e., it comprises diverse genetic risk factors across the disorder and high interindividual differences of specific genetic risk factors. Nevertheless, risk factors converge regarding underlying biological mechanisms and shared pathways, which likely cause the autism-specific behavioral characteristics. The current selective literature review summarizes differential genetic risk factors and focuses particularly on mechanisms and pathways currently being discussed by international research. In conclusion, clinically relevant aspects and open translational research questions are presented.
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Affiliation(s)
- Christine M Freitag
- Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt am Main
| | - Andreas G Chiocchetti
- Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt am Main
| | - Denise Haslinger
- Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt am Main
| | - Afsheen Yousaf
- Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt am Main
| | - Regina Waltes
- Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt am Main
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28
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Agarwala S, Ramachandra NB. Role of CNTNAP2 in autism manifestation outlines the regulation of signaling between neurons at the synapse. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2021. [DOI: 10.1186/s43042-021-00138-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Abstract
Background
Autism is characterized by high heritability and a complex genetic mutational landscape with restricted social behavior and impaired social communication. Whole-exome sequencing is a reliable tool to pinpoint variants for unraveling the disease pathophysiology. The present meta-analysis was performed using 222 whole-exome sequences deposited by Simons Simplex Collection (SSC) at the European Nucleotide Archive. This sample cohort was used to identify causal mutations in autism-specific genes to create a mutational landscape focusing on the CNTNAP2 gene.
Results
The authors account for the identification of 15 high confidence genes with 24 variants for autism with Simons Foundation Autism Research Initiative (SFARI) gene scoring. These genes encompass critical autism pathways such as neuron development, synapse complexity, cytoskeleton, and microtubule activation. Among these 15 genes, overlapping variants were present across multiple samples: KMT2C in 167 cases, CNTNAP2 in 192 samples, CACNA1C in 152 cases, and SHANK3 in 124 cases. Pathway analysis identifies clustering and interplay of autism genes—WDFY3, SHANK2, CNTNAP2, HOMER1, SYNGAP1, and ANK2 with CNTNAP2. These genes coincide across autism-relevant pathways, namely abnormal social behavior and intellectual and cognitive impairment. Based on multiple layers of selection criteria, CNTNAP2 was chosen as the master gene for the study. It is an essential gene for autism with speech-language delays, a typical phenotype in most cases under study. It showcases nine variants across multiple samples with one damaging variant, T589P, with a GERP rank score range of 0.065–0.95. This unique variant was present across 86.5% of the samples impairing the epithelial growth factor (EGF) domain. Established microRNA (miRNA) genes hsa-mir-548aq and hsa-mir-548f were mutated within the CNTNAP2 region, adding to the severity. The mutated protein showed reduced stability by 0.25, increased solvent accessibility by 9%, and reduced depth by 0.2, which rendered the protein non-functional. Secondary physical interactors of CNTNAP2 through CNTN2 proteins were mutated in the samples, further intensifying the severity.
Conclusion
CNTNAP2 has been identified as a master gene in autism manifestation responsible for speech-language delay by impairing the EGF protein domain and downstream cascade. The decrease in EGF is correlated with vital autism symptoms, especially language disabilities.
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Stevens SR, Rasband MN. Ankyrins and neurological disease. Curr Opin Neurobiol 2021; 69:51-57. [PMID: 33485190 DOI: 10.1016/j.conb.2021.01.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/06/2021] [Accepted: 01/08/2021] [Indexed: 12/11/2022]
Abstract
Ankyrins are scaffolding proteins widely expressed throughout the nervous system. Ankyrins recruit diverse membrane proteins, including ion channels and cell adhesion molecules, into specialized subcellular membrane domains. These domains are stabilized by ankyrins interacting with the spectrin cytoskeleton. Ankyrin genes are highly associated with a number of neurological disorders, including Alzheimer's disease, schizophrenia, autism spectrum disorders, and bipolar disorder. Here, we discuss ankyrin function and their role in neurological disease. We propose mutations in ankyrins contribute to disease through two primary mechanisms: 1) altered neuronal excitability by disrupting ion channel clustering at key excitable domains, and 2) altered neuronal connectivity via impaired stabilization of membrane proteins.
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Affiliation(s)
- Sharon R Stevens
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA
| | - Matthew N Rasband
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.
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A Bibliometric Insight of Genetic Factors in ASD: Emerging Trends and New Developments. Brain Sci 2020; 11:brainsci11010033. [PMID: 33396229 PMCID: PMC7824688 DOI: 10.3390/brainsci11010033] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 12/18/2020] [Accepted: 12/25/2020] [Indexed: 12/27/2022] Open
Abstract
Autism spectrum disorder (ASD) cases have increased rapidly in recent decades, which is associated with various genetic abnormalities. To provide a better understanding of the genetic factors in ASD, we assessed the global scientific output of the related studies. A total of 2944 studies published between 1997 and 2018 were included by systematic retrieval from the Web of Science (WoS) database, whose scientific landscapes were drawn and the tendencies and research frontiers were explored through bibliometric methods. The United States has been acting as a leading explorer of the field worldwide in recent years. The rapid development of high-throughput technologies and bioinformatics transferred the research method from the traditional classic method to a big data-based pipeline. As a consequence, the focused research area and tendency were also changed, as the contribution of de novo mutations in ASD has been a research hotspot in the past several years and probably will remain one into the near future, which is consistent with the current opinions of the major etiology of ASD. Therefore, more attention and financial support should be paid to the deciphering of the de novo mutations in ASD. Meanwhile, the effective cooperation of multi-research centers and scientists in different fields should be advocated in the next step of scientific research undertaken.
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Bjørklund G, Tinkov AA, Hosnedlová B, Kizek R, Ajsuvakova OP, Chirumbolo S, Skalnaya MG, Peana M, Dadar M, El-Ansary A, Qasem H, Adams JB, Aaseth J, Skalny AV. The role of glutathione redox imbalance in autism spectrum disorder: A review. Free Radic Biol Med 2020; 160:149-162. [PMID: 32745763 DOI: 10.1016/j.freeradbiomed.2020.07.017] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 07/02/2020] [Accepted: 07/13/2020] [Indexed: 12/22/2022]
Abstract
The role of glutathione in autism spectrum disorder (ASD) is emerging as a major topic, due to its role in the maintenance of the intracellular redox balance. Several studies have implicated glutathione redox imbalance as a leading factor in ASD, and both ASD and many other neurodevelopmental disorders involve low levels of reduced glutathione (GSH), high levels of oxidized glutathione (GSSG), and abnormalities in the expressions of glutathione-related enzymes in the blood or brain. Glutathione metabolism, through its impact on redox environment or redox-independent mechanisms, interferes with multiple mechanisms involved in ASD pathogenesis. Glutathione-mediated regulation of glutamate receptors [e.g., N-methyl-d-aspartate (NMDA) receptor], as well as the role of glutamate as a substrate for glutathione synthesis, may be involved in the regulation of glutamate excitotoxicity. However, the interaction between glutathione and glutamate in the pathogenesis of brain diseases may vary from synergism to antagonism. Modulation of glutathione is also associated with regulation of redox-sensitive transcription factors nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1) and downstream signaling (proinflammatory cytokines and inducible enzymes), thus providing a significant impact on neuroinflammation. Mitochondrial dysfunction, as well as neuronal apoptosis, may also provide a significant link between glutathione metabolism and ASD. Furthermore, it has been recently highlighted that glutathione can affect and modulate DNA methylation and epigenetics. Review analysis including research studies meeting the required criteria for analysis showed statistically significant differences between the plasma GSH and GSSG levels as well as GSH:GSSG ratio in autistic patients compared with healthy individuals (P = 0.0145, P = 0.0150 and P = 0.0202, respectively). Therefore, the existing data provide a strong background on the role of the glutathione system in ASD pathogenesis. Future research is necessary to investigate the role of glutathione redox signaling in ASD, which could potentially also lead to promising therapeutics.
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Affiliation(s)
- Geir Bjørklund
- Council for Nutritional and Environmental Medicine (CONEM), Mo I Rana, Norway.
| | - Alexey A Tinkov
- IM Sechenov First Moscow State Medical University, Moscow, Russia; Yaroslavl State University, Yaroslavl, Russia; Federal Research Centre of Biological Systems, Agro-technologies of the Russian Academy of Sciences, Orenburg, Russia
| | - Božena Hosnedlová
- Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Brno, Czech Republic; CONEM Metallomics Nanomedicine Research Group (CMNRG), Brno, Czech Republic
| | - Rene Kizek
- Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Brno, Czech Republic; CONEM Metallomics Nanomedicine Research Group (CMNRG), Brno, Czech Republic; Faculty of Pharmacy with Division of Laboratory Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Olga P Ajsuvakova
- IM Sechenov First Moscow State Medical University, Moscow, Russia; Yaroslavl State University, Yaroslavl, Russia; Federal Research Centre of Biological Systems, Agro-technologies of the Russian Academy of Sciences, Orenburg, Russia
| | - Salvatore Chirumbolo
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; CONEM Scientific Secretary, Verona, Italy
| | - Margarita G Skalnaya
- IM Sechenov First Moscow State Medical University, Moscow, Russia; Federal Research Centre of Biological Systems, Agro-technologies of the Russian Academy of Sciences, Orenburg, Russia
| | | | - Maryam Dadar
- Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
| | - Afaf El-Ansary
- Medicinal Chemistry Department, King Saud University, Riyadh, Saudi Arabia; Autism Research and Treatment Center, Riyadh, Saudi Arabia; CONEM Saudi Autism Research Group, King Saud University, Riyadh, Saudi Arabia
| | - Hanan Qasem
- Autism Research and Treatment Center, Riyadh, Saudi Arabia; CONEM Saudi Autism Research Group, King Saud University, Riyadh, Saudi Arabia
| | - James B Adams
- School for Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ, USA
| | - Jan Aaseth
- Research Department, Innlandet Hospital Trust, Brumunddal, Norway
| | - Anatoly V Skalny
- IM Sechenov First Moscow State Medical University, Moscow, Russia; Federal Research Centre of Biological Systems, Agro-technologies of the Russian Academy of Sciences, Orenburg, Russia
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Pensado-López A, Veiga-Rúa S, Carracedo Á, Allegue C, Sánchez L. Experimental Models to Study Autism Spectrum Disorders: hiPSCs, Rodents and Zebrafish. Genes (Basel) 2020; 11:E1376. [PMID: 33233737 PMCID: PMC7699923 DOI: 10.3390/genes11111376] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 10/26/2020] [Accepted: 11/18/2020] [Indexed: 02/07/2023] Open
Abstract
Autism Spectrum Disorders (ASD) affect around 1.5% of the global population, which manifest alterations in communication and socialization, as well as repetitive behaviors or restricted interests. ASD is a complex disorder with known environmental and genetic contributors; however, ASD etiology is far from being clear. In the past decades, many efforts have been put into developing new models to study ASD, both in vitro and in vivo. These models have a lot of potential to help to validate some of the previously associated risk factors to the development of the disorder, and to test new potential therapies that help to alleviate ASD symptoms. The present review is focused on the recent advances towards the generation of models for the study of ASD, which would be a useful tool to decipher the bases of the disorder, as well as to conduct drug screenings that hopefully lead to the identification of useful compounds to help patients deal with the symptoms of ASD.
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Affiliation(s)
- Alba Pensado-López
- Department of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Campus de Lugo, 27002 Lugo, Spain; (A.P.-L.); (S.V.-R.)
- Genomic Medicine Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela, 15706 Santiago de Compostela, Spain;
| | - Sara Veiga-Rúa
- Department of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Campus de Lugo, 27002 Lugo, Spain; (A.P.-L.); (S.V.-R.)
- Genomic Medicine Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela, 15706 Santiago de Compostela, Spain;
| | - Ángel Carracedo
- Genomic Medicine Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela, 15706 Santiago de Compostela, Spain;
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), CIMUS, Universidade de Santiago de Compostela, 15706 Santiago de Compostela, Spain
| | - Catarina Allegue
- Genomic Medicine Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela, 15706 Santiago de Compostela, Spain;
| | - Laura Sánchez
- Department of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Campus de Lugo, 27002 Lugo, Spain; (A.P.-L.); (S.V.-R.)
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Areal LB, Blakely RD. Neurobehavioral changes arising from early life dopamine signaling perturbations. Neurochem Int 2020; 137:104747. [PMID: 32325191 PMCID: PMC7261509 DOI: 10.1016/j.neuint.2020.104747] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 04/11/2020] [Accepted: 04/14/2020] [Indexed: 12/11/2022]
Abstract
Dopamine (DA) signaling is critical to the modulation of multiple brain functions including locomotion, reinforcement, attention and cognition. The literature provides strong evidence that altered DA availability and actions can impact normal neurodevelopment, with both early and enduring consequences on anatomy, physiology and behavior. An appreciation for the developmental contributions of DA signaling to brain development is needed to guide efforts to preclude and remedy neurobehavioral disorders, such as attention-deficit/hyperactivity disorder, addiction, bipolar disorder, schizophrenia and autism spectrum disorder, each of which exhibits links to DA via genetic, cellular and/or pharmacological findings. In this review, we highlight research pursued in preclinical models that use genetic and pharmacological approaches to manipulate DA signaling at sensitive developmental stages, leading to changes at molecular, circuit and/or behavioral levels. We discuss how these alterations can be aligned with traits displayed by neuropsychiatric diseases. Lastly, we review human studies that evaluate contributions of developmental perturbations of DA systems to increased risk for neuropsychiatric disorders.
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Affiliation(s)
- Lorena B Areal
- Department of Biomedical Science, Florida Atlantic University, Jupiter, FL, 33458, USA
| | - Randy D Blakely
- Department of Biomedical Science, Florida Atlantic University, Jupiter, FL, 33458, USA; Brain Institute, Florida Atlantic University, Jupiter, FL, 33458, USA.
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In Silico Elucidation of Deleterious Non-synonymous SNPs in SHANK3, the Autism Spectrum Disorder Gene. J Mol Neurosci 2020; 70:1649-1667. [DOI: 10.1007/s12031-020-01552-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Accepted: 04/13/2020] [Indexed: 12/11/2022]
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Duan W, Wang K, Duan Y, Chu X, Ma R, Hu P, Xiong B. Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism. Autism Res 2019; 13:352-368. [PMID: 31743624 DOI: 10.1002/aur.2240] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 09/25/2019] [Accepted: 10/14/2019] [Indexed: 12/12/2022]
Abstract
Genetic mutations are the major pathogenic factor of Autism Spectrum Disorder (ASD). In recent years, more and more ASD risk genes have been revealed, among which there are a group of transcriptional regulators. Considering the similarity of the core clinical phenotypes, it is possible that these different factors may regulate the expression levels of certain key targets. Identification of these targets could facilitate the understanding of the etiology and developing of novel diagnostic and therapeutic methods. Therefore, we performed integrated transcriptome analyses of RNA-Seq and microarray data in multiple ASD mouse models and identified a number of common downstream genes in various brain regions, many of which are related to the structure and function of the synapse components or drug addiction. We then established protein-protein interaction networks of the overlapped targets and isolated the hub genes by 11 algorithms based on the topological structure of the networks, including Sdc4, Vegfa, and Cp in the Cortex-Adult subgroup, Gria1 in the Cortex-Juvenile subgroup, and Kdr, S1pr1, Ubc, Grm2, Grin2b, Nrxn1, Pdyn, Grin3a, Itgam, Grin2a, Gabra2, and Camk4 in the Hippocampus-Adult subgroup, many of which have been associated with ASD in previous studies. Finally, we cross compared our results with human brain transcriptional data sets and verified several key candidates, which may play important role in the pathology process of ASD, including SDC4, CP, S1PR1, UBC, PDYN, GRIN2A, GABRA2, and CAMK4. In summary, by integrated bioinformatics analysis, we have identified a series of potentially important molecules for future ASD research. Autism Res 2020, 13: 352-368. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Abnormal transcriptional regulation accounts for a significant portion of Autism Spectrum Disorder. In this study, we performed transcriptome analyses of mouse models to identify common downstream targets of transcriptional regulators involved in ASD. We identified several recurrent target genes that are close related to the common pathological process of ASD, including SDC4, CP, S1PR1, UBC, PDYN, GRM2, NRXN1, GRIN3A, ITGAM, GRIN2A, GABRA2, and CAMK4. These results provide potentially important targets for understanding the molecular mechanism of ASD.
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Affiliation(s)
- Weicheng Duan
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Kang Wang
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Yijie Duan
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Xufeng Chu
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Ruoyun Ma
- School of Nursing, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Ping Hu
- Key Laboratory of Environment and Health (HUST), Ministry of Education, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Bo Xiong
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
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Ziats CA, Rennert OM, Ziats MN. Toward a Pathway-Driven Clinical-Molecular Framework for Classifying Autism Spectrum Disorders. Pediatr Neurol 2019; 98:46-52. [PMID: 31272785 DOI: 10.1016/j.pediatrneurol.2019.05.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 04/30/2019] [Accepted: 05/06/2019] [Indexed: 10/26/2022]
Abstract
BACKGROUND The current classification system of neurodevelopmental disorders is based on clinical criteria; however, this method alone fails to incorporate what is now known about genomic similarities and differences between closely related clinical neurodevelopmental disorders. Here we present an alternative clinical molecular classification system of neurodevelopmental disorders based on shared molecular and cellular pathways, using syndromes with autistic features as examples. METHODS Using the Online Mendelian Inheritance in Man database, we identified 83 syndromes that had "autism" as a feature of disease, which in combination were associated with 69 autism disease-causing genes. Using annotation terms generated from the DAVID annotation tool, we grouped each gene and its associated autism syndrome into three biological pathways: ion transport, cellular synaptic function, and transcriptional regulation. RESULTS The majority of the autism syndromes we analyzed (54 of 83) enriched for processes related to transcriptional regulation and were associated with more non-neurologic symptoms and co-morbid psychiatric disease when compared with the other two pathways studied. Disorders with disrupted cellular synaptic function had significantly more motor-related symptoms when compared with the other groups of disorders. CONCLUSION Our pathway-based classification system identified unique clinical characteristics within each group that may help guide clinical diagnosis, prognosis, and treatment. These results suggest that shifting current clinical classification of autism disorders toward molecularly driven, pathway-related diagnostic groups such as this may more precisely guide clinical decision making and may be informative for future clinical trial and drug development approaches.
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Affiliation(s)
- Catherine A Ziats
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
| | - Owen M Rennert
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
| | - Mark N Ziats
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
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In silico Identification of potential Drug Target and Analysis of Effective Single Nucleotide Polymorphisms for autism spectrum Disorder. GENE REPORTS 2019. [DOI: 10.1016/j.genrep.2019.100420] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Altay MA. Family Physicians' Awareness of Autism Spectrum Disorder: Results from a Survey Study. Open Access Maced J Med Sci 2019; 7:967-972. [PMID: 30976342 PMCID: PMC6454156 DOI: 10.3889/oamjms.2019.199] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 02/03/2019] [Accepted: 02/22/2019] [Indexed: 01/19/2023] Open
Abstract
AIM: Autism spectrum disorder (ASD) is a common neurodevelopmental disorder in children. Family physicians with the first medical contact of children are among the most frequent physicians with ASD. We aimed to investigate family physicians’ awareness of ASD. METHODS: This study was carried out family physicians in between September 25-October 15, 2018. The questionnaire form on autism awareness prepared by the researcher was delivered to family physicians electronically and in printed form, and it was filled out by volunteers. RESULTS: Forty-eight family physicians with an average professional experience of 16.9 ± 8.8 years participated in the study. A group of 66.7% of the participants had not previously received education on ASD, and 70.8% of them did not refer any child to child psychiatry with suspected ASD in the last 6 months. The participants stated that the most common clinical features in children with ASD were the inability to make eye contact (72.9%) and repetitive movements (47.9%), and 56.3% of them stated one or more features that are not observed in ASD. The compliance of the participants’ answers about the clinical features observed in children with ASD with the DSM-5 criteria was determined to be 54.6 ± 18.4%. Significantly higher compliance rates were observed in the participants with education on autism and those working as a physician below 15 years. CONCLUSION: In our study, family physicians’ awareness of ASD was not found to be adequate. Education programs on autism awareness should be applied to family physicians who are probably the most frequently encountered physicians by children with ASD.
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Affiliation(s)
- Mengühan Araz Altay
- Department of Child and Adolescent Psychiatry, Trakya University School of Medicine, Edirne 22030, Turkey
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