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Leonardi E, Aspromonte MC, Drongitis D, Bettella E, Verrillo L, Polli R, McEntagart M, Licchetta L, Dilena R, D'Arrigo S, Ciaccio C, Esposito S, Leuzzi V, Torella A, Baldo D, Lonardo F, Bonato G, Pellegrin S, Stanzial F, Posmyk R, Kaczorowska E, Carecchio M, Gos M, Rzońca-Niewczas S, Miano MG, Murgia A. Expanding the genetics and phenotypic spectrum of Lysine-specific demethylase 5C (KDM5C): a report of 13 novel variants. Eur J Hum Genet 2023; 31:202-215. [PMID: 36434256 PMCID: PMC9905063 DOI: 10.1038/s41431-022-01233-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 10/14/2022] [Accepted: 10/31/2022] [Indexed: 11/27/2022] Open
Abstract
Lysine-specific demethylase 5C (KDM5C) has been identified as an important chromatin remodeling gene, contributing to X-linked neurodevelopmental disorders (NDDs). The KDM5C gene, located in the Xp22 chromosomal region, encodes the H3K4me3-me2 eraser involved in neuronal plasticity and dendritic growth. Here we report 30 individuals carrying 13 novel and one previously identified KDM5C variants. Our cohort includes the first reported case of somatic mosaicism in a male carrying a KDM5C nucleotide substitution, and a dual molecular finding in a female carrying a homozygous truncating FUCA1 alteration together with a de novo KDM5C variant. With the use of next generation sequencing strategies, we detected 1 frameshift, 1 stop codon, 2 splice-site and 10 missense variants, which pathogenic role was carefully investigated by a thorough bioinformatic analysis. The pattern of X-chromosome inactivation was found to have an impact on KDM5C phenotypic expression in females of our cohort. The affected individuals of our case series manifested a neurodevelopmental condition characterized by psychomotor delay, intellectual disability with speech disorders, and behavioral features with particular disturbed sleep pattern; other observed clinical manifestations were short stature, obesity and hypertrichosis. Collectively, these findings expand the current knowledge about the pathogenic mechanisms leading to dysfunction of this important chromatin remodeling gene and contribute to a refinement of the KDM5C phenotypic spectrum.
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Affiliation(s)
- Emanuela Leonardi
- Department of Women's and Children's Health, University of Padova, Padova, Italy
- Pediatric Research Institute, Città della Speranza, Padova, Italy
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Maria Cristina Aspromonte
- Department of Women's and Children's Health, University of Padova, Padova, Italy
- Pediatric Research Institute, Città della Speranza, Padova, Italy
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Denise Drongitis
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", CNR, Naples, Italy
| | - Elisa Bettella
- Department of Women's and Children's Health, University of Padova, Padova, Italy
- Pediatric Research Institute, Città della Speranza, Padova, Italy
| | - Lucia Verrillo
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", CNR, Naples, Italy
| | - Roberta Polli
- Department of Women's and Children's Health, University of Padova, Padova, Italy
- Pediatric Research Institute, Città della Speranza, Padova, Italy
| | - Meriel McEntagart
- Medical Genetics Unit, St. George's University Hospitals, London, UK
| | - Laura Licchetta
- IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Robertino Dilena
- Neurophysiopathology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Stefano D'Arrigo
- Department of Pediatric Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Claudia Ciaccio
- Department of Pediatric Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Silvia Esposito
- Department of Pediatric Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Vincenzo Leuzzi
- Unit of Child Neurology and Psychiatry, Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
| | - Annalaura Torella
- University of Campania "Luigi Vanvitelli", Caserta, Italy
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Demetrio Baldo
- Unit of medical genetics, ULSS 2 Treviso Hospital, Treviso, Italy
| | | | - Giulia Bonato
- Movement Disorders Unit, Department of Neuroscience, University of Padova, Padova, Italy
| | - Serena Pellegrin
- Child Neurology and Neurorehabilitation Unit, Department of Pediatrics, Regional Hospital of Bolzano, Bolzano, Italy
| | - Franco Stanzial
- Genetic Counseling Service, Department of Pediatrics, Regional Hospital of Bolzano, Bolzano, Italy
| | - Renata Posmyk
- Department of Clinical Genetics, Medical University in Bialystok, Bialystok, Poland
| | - Ewa Kaczorowska
- Department of Biology and Medical Genetics, Medical University of Gdansk, Gdansk, Poland
| | - Miryam Carecchio
- Movement Disorders Unit, Department of Neuroscience, University of Padova, Padova, Italy
| | - Monika Gos
- Development Genetics Laboratory, Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland
| | - Sylwia Rzońca-Niewczas
- Development Genetics Laboratory, Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland
| | | | - Alessandra Murgia
- Department of Women's and Children's Health, University of Padova, Padova, Italy.
- Pediatric Research Institute, Città della Speranza, Padova, Italy.
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Kawatake-Kuno A, Murai T, Uchida S. The Molecular Basis of Depression: Implications of Sex-Related Differences in Epigenetic Regulation. Front Mol Neurosci 2021; 14:708004. [PMID: 34276306 PMCID: PMC8282210 DOI: 10.3389/fnmol.2021.708004] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 06/14/2021] [Indexed: 12/22/2022] Open
Abstract
Major depressive disorder (MDD) is a leading cause of disability worldwide. Although the etiology and pathophysiology of MDD remain poorly understood, aberrant neuroplasticity mediated by the epigenetic dysregulation of gene expression within the brain, which may occur due to genetic and environmental factors, may increase the risk of this disorder. Evidence has also been reported for sex-related differences in the pathophysiology of MDD, with female patients showing a greater severity of symptoms, higher degree of functional impairment, and more atypical depressive symptoms. Males and females also differ in their responsiveness to antidepressants. These clinical findings suggest that sex-dependent molecular and neural mechanisms may underlie the development of depression and the actions of antidepressant medications. This review discusses recent advances regarding the role of epigenetics in stress and depression. The first section presents a brief introduction of the basic mechanisms of epigenetic regulation, including histone modifications, DNA methylation, and non-coding RNAs. The second section reviews their contributions to neural plasticity, the risk of depression, and resilience against depression, with a particular focus on epigenetic modulators that have causal relationships with stress and depression in both clinical and animal studies. The third section highlights studies exploring sex-dependent epigenetic alterations associated with susceptibility to stress and depression. Finally, we discuss future directions to understand the etiology and pathophysiology of MDD, which would contribute to optimized and personalized therapy.
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Affiliation(s)
- Ayako Kawatake-Kuno
- SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Toshiya Murai
- SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Department of Psychiatry, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Shusaku Uchida
- SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Xue XJ, Li FR, Yu J. Mitochondrial pathway of the lysine demethylase 5C inhibitor CPI-455 in the Eca-109 esophageal squamous cell carcinoma cell line. World J Gastroenterol 2021; 27:1805-1815. [PMID: 33967558 PMCID: PMC8072195 DOI: 10.3748/wjg.v27.i16.1805] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/14/2021] [Accepted: 03/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Esophageal cancer is a malignant tumor of the digestive tract that is difficult to diagnose early. CPI-455 has been reported to inhibit various cancers, but its role in esophageal squamous cell carcinoma (ESCC) is unknown.
AIM To investigate the effects and mechanism of the lysine demethylase 5C inhibitor, CPI-455, on ESCC cells.
METHODS A methyl tetrazolium assay was used to detect the inhibitory effect of CPI-455 on the proliferation of Eca-109 cells. Apoptosis, reactive oxygen species (ROS), and mitochondrial membrane potential were assessed by flow cytometry. Laser confocal scanning and transmission electron microscopy were used to observe changes in Eca-109 cell morphology. The protein expression of P53, Bax, lysine-specific demethylase 5C (KDM5C), cleaved Caspase-9, and cleaved Caspase-3 were assayed by western blotting.
RESULTS Compared with the control group, CPI-455 significantly inhibited Eca-109 cell proliferation. Gemcitabine inhibited Eca-109 cell proliferation in a concentration- and time-dependent manner. CPI-455 caused extensive alteration of the mitochondria, which appeared to have become atrophied. The cell membrane was weakly stained and the cytoplasmic structures were indistinct and disorganized, with serious cavitation when viewed by transmission electron microscopy. The flow cytometry and western blot results showed that, compared with the control group, the mitochondrial membrane potential was decreased and depolarized in Eca-109 cells treated with CPI-455. CPI-455 significantly upregulated the ROS content, P53, Bax, Caspase-9, and Caspase-3 protein expression in Eca-109 cells, whereas KDM5C expression was downregulated.
CONCLUSION CPI-455 inhibited Eca-109 cell proliferation via mitochondrial apoptosis by regulating the expression of related genes.
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Affiliation(s)
- Xiao-Jie Xue
- Department of Clinical Laboratory, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi 435000, Hubei Province, China
- Hubei Key Laboratory of Kidney Disease Pathogenesis and Intervention, Huangshi 435000, Hubei Province, China
- Medical College, Wuhan University of Science and Technology, Wuhan 430081, Hubei Province, China
| | - Fei-Rong Li
- Department of Clinical Laboratory, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi 435000, Hubei Province, China
| | - Jing Yu
- Department of Laboratory Medicine, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430079, Hubei Province, China
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Poeta L, Padula A, Attianese B, Valentino M, Verrillo L, Filosa S, Shoubridge C, Barra A, Schwartz CE, Christensen J, van Bokhoven H, Helin K, Lioi MB, Collombat P, Gecz J, Altucci L, Di Schiavi E, Miano MG. Histone demethylase KDM5C is a SAHA-sensitive central hub at the crossroads of transcriptional axes involved in multiple neurodevelopmental disorders. Hum Mol Genet 2020; 28:4089-4102. [PMID: 31691806 DOI: 10.1093/hmg/ddz254] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 10/17/2019] [Accepted: 10/21/2019] [Indexed: 12/26/2022] Open
Abstract
A disproportional large number of neurodevelopmental disorders (NDDs) is caused by variants in genes encoding transcription factors and chromatin modifiers. However, the functional interactions between the corresponding proteins are only partly known. Here, we show that KDM5C, encoding a H3K4 demethylase, is at the intersection of transcriptional axes under the control of three regulatory proteins ARX, ZNF711 and PHF8. Interestingly, mutations in all four genes (KDM5C, ARX, ZNF711 and PHF8) are associated with X-linked NDDs comprising intellectual disability as a core feature. in vitro analysis of the KDM5C promoter revealed that ARX and ZNF711 function as antagonist transcription factors that activate KDM5C expression and compete for the recruitment of PHF8. Functional analysis of mutations in these genes showed a correlation between phenotype severity and the reduction in KDM5C transcriptional activity. The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice. Aiming to correct the faulty expression of KDM5C, we studied the effect of the FDA-approved histone deacetylase inhibitor suberanilohydroxamic acid (SAHA). In Arx-KO murine ES-derived neurons, SAHA was able to rescue KDM5C depletion, recover H3K4me3 signalling and improve neuronal differentiation. Indeed, in ARX/alr-1-deficient Caenorhabditis elegans animals, SAHA was shown to counteract the defective KDM5C/rbr-2-H3K4me3 signalling, recover abnormal behavioural phenotype and ameliorate neuronal maturation. Overall, our studies indicate that KDM5C is a conserved and druggable effector molecule across a number of NDDs for whom the use of SAHA may be considered a potential therapeutic strategy.
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Affiliation(s)
- Loredana Poeta
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy
| | - Agnese Padula
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy.,University of Campania Luigi Vanvitelli, Caserta, Italy
| | - Benedetta Attianese
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy
| | - Mariaelena Valentino
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy
| | - Lucia Verrillo
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy.,University of Campania Luigi Vanvitelli, Caserta, Italy
| | - Stefania Filosa
- Institute of Biosciences and BioResources, National Research Council (CNR), Naples, Italy.,Istituto Neurologico Mediterraneo (Neuromed), Pozzilli, Isernia, Italy
| | - Cheryl Shoubridge
- Intellectual Disability Research, Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.,Robinson Research Institute, Department of Paediatrics, University of Adelaide, Adelaide, South Australia, Australia
| | - Adriano Barra
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy
| | | | - Jesper Christensen
- University of Copenhagen, Biotech Research and Innovation Centre (BRIC), Copenhagen, Denmark.,University of Copenhagen, The Novo Nordisk Foundation Center for Stem Cell Biology (Danstem), Copenhagen, Denmark
| | - Hans van Bokhoven
- Department of Human Genetics, Donders Institute for Brain, Behaviour and Cognition, Radboudumc, Nijmegen, The Netherlands
| | - Kristian Helin
- University of Copenhagen, Biotech Research and Innovation Centre (BRIC), Copenhagen, Denmark.,University of Copenhagen, The Novo Nordisk Foundation Center for Stem Cell Biology (Danstem), Copenhagen, Denmark
| | | | | | - Jozef Gecz
- Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia
| | - Lucia Altucci
- University of Campania Luigi Vanvitelli, Caserta, Italy
| | - Elia Di Schiavi
- Institute of Biosciences and BioResources, National Research Council (CNR), Naples, Italy
| | - Maria Giuseppina Miano
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy
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Hu VW, Devlin CA, Debski JJ. ASD Phenotype-Genotype Associations in Concordant and Discordant Monozygotic and Dizygotic Twins Stratified by Severity of Autistic Traits. Int J Mol Sci 2019; 20:ijms20153804. [PMID: 31382655 PMCID: PMC6696087 DOI: 10.3390/ijms20153804] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 07/30/2019] [Accepted: 07/31/2019] [Indexed: 12/19/2022] Open
Abstract
Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder characterized by impaired social communication coupled with stereotyped behaviors and restricted interests. Despite the high concordance rate for diagnosis, there is little information on the magnitude of genetic contributions to specific ASD behaviors. Using behavioral/trait severity scores from the Autism Diagnostic Interview-Revised (ADI-R) diagnostic instrument, we compared the phenotypic profiles of mono- and dizygotic twins where both co-twins were diagnosed with ASD or only one twin had a diagnosis. The trait distribution profiles across the respective twin populations were first used for quantitative trait association analyses using publicly available genome-wide genotyping data. Trait-associated single nucleotide polymorphisms (SNPs) were then used for case-control association analyses, in which cases were defined as individuals in the lowest (Q1) and highest (Q4) quartiles of the severity distribution curves for each trait. While all of the ASD-diagnosed twins exhibited similar trait severity profiles, the non-autistic dizygotic twins exhibited significantly lower ADI-R item scores than the non-autistic monozygotic twins. Case-control association analyses of twins stratified by trait severity revealed statistically significant SNPs with odds ratios that clearly distinguished individuals in Q4 from those in Q1. While the level of shared genomic variation is a strong determinant of the severity of autistic traits in the discordant non-autistic twins, the similarity of trait profiles in the concordantly autistic dizygotic twins also suggests a role for environmental influences. Stratification of cases by trait severity resulted in the identification of statistically significant SNPs located near genes over-represented within autism gene datasets.
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Affiliation(s)
- Valerie W Hu
- Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA.
| | - Christine A Devlin
- Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA
| | - Jessica J Debski
- Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA
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