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A Review of Functional Characterization of Single Amino Acid Change Mutations in HNF Transcription Factors in MODY Pathogenesis. Protein J 2021; 40:348-360. [PMID: 33950347 DOI: 10.1007/s10930-021-09991-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/22/2021] [Indexed: 12/15/2022]
Abstract
Mutations in HNF transcription factor genes cause the most common subtypes of maturity-onset of diabetes of youth (MODY), a monogenic form of diabetes mellitus. Mutations in the HNF1-α, HNF4-α, and HNF1-β genes are primarily considered as the cause of MODY3, MODY1, and MODY5 subtypes, respectively. Although patients with different subtypes display similar symptoms, they may develop distinct diabetes-related complications and require different treatments depending on the type of the mutation. Genetic analysis of MODY patients revealed more than 400 missense/nonsense mutations in HNF1-α, HNF4-α, and HNF1-β genes, however only a small portion of them are functionally characterized. Evaluation of nonsense mutations are more direct as they lead to premature stop codons and mostly in mRNA decay or nonfunctional truncated proteins. However, interpretation of the single amino acid change (missense) mutation is not such definite, as effect of the variant may vary depending on the location and also the substituted amino acid. Mutations with benign effect on the protein function may not be the pathologic variant and further genetic testing may be required. Here, we discuss the functional characterization analysis of single amino acid change mutations identified in HNF1-α, HNF4-α, and HNF1-β genes and evaluate their roles in MODY pathogenesis. This review will contribute to comprehend HNF nuclear family-related molecular mechanisms and to develop more accurate diagnosis and treatment based on correct evaluation of pathologic effects of the variants.
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Charoensuk C, Thamtarana PJ, Chanprasert C, Tangjittipokin W, Shirakawa J, Togashi Y, Orime K, Songprakhon P, Chaichana C, Abubakar Z, Ouying P, Sujjitjoon J, Doria A, Plengvidhya N, Yenchitsomanus PT. Autosomal dominant diabetes associated with a novel ZYG11A mutation resulting in cell cycle arrest in beta-cells. Mol Cell Endocrinol 2021; 522:111126. [PMID: 33321115 DOI: 10.1016/j.mce.2020.111126] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 12/09/2020] [Accepted: 12/11/2020] [Indexed: 01/20/2023]
Abstract
Diabetes is a genetically heterogeneous disease, for which we are aiming to identify causative genes. Here, we report a missense mutation (c.T1424C:p.L475P) in ZYG11A identified by exome sequencing as segregating with hyperglycemia in a Thai family with autosomal dominant diabetes. ZYG11A functions as a target recruitment subunit of an E3 ubiquitin ligase complex that plays an important role in the regulation of cell cycle. We demonstrate an increase in cells arrested at G2/mitotic phase among beta-cells deficient for ZYG11A or overexpressing L475P-ZYG11A, which is associated with a decreased growth rate. This is the first evidence linking a ZYG11A mutation to hyperglycemia, and suggesting ZYG11A as a cell cycle regulator required for beta-cell growth. Since most family members were either overweight or obese, but only mutation carriers developed hyperglycemia, our data also suggests the ZYG11A mutation as a genetic factor predisposing obese individuals to beta-cell failure in maintenance of glucose homeostasis.
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Affiliation(s)
- Chutima Charoensuk
- Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Cellular and Molecular Biology of Diabetes Research Group, Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Prapaporn Jungtrakoon Thamtarana
- Cellular and Molecular Biology of Diabetes Research Group, Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
| | - Chutima Chanprasert
- Cellular and Molecular Biology of Diabetes Research Group, Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Watip Tangjittipokin
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Jun Shirakawa
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, 371-8512, Japan; Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Yu Togashi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Kazuki Orime
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Pucharee Songprakhon
- Cellular and Molecular Biology of Diabetes Research Group, Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Chartchai Chaichana
- Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Zuroida Abubakar
- Cellular and Molecular Biology of Diabetes Research Group, Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Paweena Ouying
- Cellular and Molecular Biology of Diabetes Research Group, Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Jatuporn Sujjitjoon
- Cellular and Molecular Biology of Diabetes Research Group, Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Alessandro Doria
- Section on Genetics and Epidemiology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Nattachet Plengvidhya
- Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Pa-Thai Yenchitsomanus
- Cellular and Molecular Biology of Diabetes Research Group, Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
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Aarthy R, Aston-Mourney K, Mikocka-Walus A, Radha V, Amutha A, Anjana RM, Unnikrishnan R, Mohan V. Clinical features, complications and treatment of rarer forms of maturity-onset diabetes of the young (MODY) - A review. J Diabetes Complications 2021; 35:107640. [PMID: 32763092 DOI: 10.1016/j.jdiacomp.2020.107640] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/21/2020] [Accepted: 05/21/2020] [Indexed: 12/15/2022]
Abstract
Maturity onset diabetes of the young (MODY) is the most common form of monogenic diabetes and is currently believed to have 14 subtypes. While much is known about the common subtypes of MODY (MODY-1, 2, 3 and 5) little is known about its rare subtypes (MODY4, 6-14). With the advent of next-generation sequencing (NGS) there are several reports of the rarer subtypes of MODY emerging from across the world. Therefore, a greater understanding on these rarer subtypes is needed. A search strategy was created, and common databases were searched, and 51 articles finally selected. INS-(MODY10) and ABCC8-(MODY12) mutations were reported in relatively large numbers compared to the other rare subtypes. The clinical characteristics of the rare MODY subtypes exhibited heterogeneity between families reported with the same mutation. Obesity and diabetic ketoacidosis (DKA) were also reported among rarer MODY subtypes which presents as a challenge as these are not part of the original description of MODY by Tattersal and Fajans. The treatment modalities of the rarer subtypes included oral drugs, predominantly sulfonylureas, insulin but also diet alone. Newer drugs like DPP-4 and SGLT2 inhibitors have also been tried as new modes of treatment. The microvascular and macrovascular complications among the patients with various MODY subtypes are less commonly reported. Recently, there is a view that not all the 14 forms of 'MODY' are true MODY and the very existence of some of these rarer subtypes as MODY has been questioned. This scoping review aims to report on the clinical characteristics, treatment and complications of the rarer MODY subtypes published in the literature.
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Affiliation(s)
- Ramasamy Aarthy
- School of Medicine, Deakin University, Australia; Madras Diabetes Research Foundation, Chennai, India
| | | | | | | | | | - Ranjit Mohan Anjana
- Dr Mohan's Diabetes Specialities Centre, Madras Diabetes Research Foundation, Chennai, India
| | - Ranjit Unnikrishnan
- Dr Mohan's Diabetes Specialities Centre, Madras Diabetes Research Foundation, Chennai, India
| | - Viswanathan Mohan
- Dr Mohan's Diabetes Specialities Centre, Madras Diabetes Research Foundation, Chennai, India.
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Defective functions of HNF1A variants on BCL2L1 transactivation and beta-cell growth. Biochem Biophys Res Commun 2020; 529:826-833. [PMID: 32684311 DOI: 10.1016/j.bbrc.2020.05.155] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 05/20/2020] [Indexed: 10/23/2022]
Abstract
Maturity-onset diabetes of the young type 3 (MODY3) is caused by mutations in a gene encoding transcription factor hepatocyte nuclear factor 1-alpha (HNF1A). Although the roles of HNF1A in regulation of hepatic and pancreatic genes to maintain glucose homeostasis were investigated, the functions of HNF1A are not completely elucidated. To better understand the functions of HNF1A, we characterized mutations of HNF1A in Thai MODY3 patients and studied the functions of wild-type HNF1A and variant proteins. We demonstrate for the first time that HNF1A upregulates transactivation of an anti-apoptotic gene BCL2 Like 1 (BCL2L1) and that all the identified HNF1A variants including p.D80V, p.R203C, p.P475L, and p.G554fsX556, reduce this ability. The four HNF1A variants impair HNF1A function in promoting INS-1 cell transition from G1 to S phase of cell cycle, which thereby retard cell growth. This finding indicates the role of HNF1A in beta-cell viability by upregulation of anti-apoptotic gene expression and also reaffirms its role in beta-cell growth through cell cycle control.
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Ivanoshchuk DE, Shakhtshneider EV, Ovsyannikova AK, Mikhailova SV, Rymar OD, Oblaukhova VI, Yurchenko AA, Voevoda MI. A rare splice site mutation in the gene encoding glucokinase/hexokinase 4 in a patient with MODY type 2. Vavilovskii Zhurnal Genet Selektsii 2020. [PMID: 33659812 PMCID: PMC7716520 DOI: 10.18699/vj20.41-o] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The article presents a variant of maturity onset diabetes of the young type 2, caused by a rare mutation
in the GCK gene. Maturity onset diabetes of the young (MODY) is a hereditary form of diabetes with an autosomal
dominant type of inheritance, an onset at a young age, and a primary defect in pancreatic β-cell function. This
type of diabetes is different from classical types of diabetes mellitus (DM1 and DM2) in its clinical course, treatment
strategies, and prognosis. Clinical manifestations of MODY are heterogeneous and may vary even among
members of the same family, i. e., carriers of identical mutations. This phenotypic variation is due to the interaction
of mutations with different genetic backgrounds and the influence of environmental factors (e. g., lifestyle). Using
next-generation sequencing technology, the c.580–1G>A substitution (IVS5 –1G>A, rs1554335421) located in an
acceptor splice site of intron 5 of the GCK gene was found in a proband. The identified variant cosegregated with
a pathological phenotype in the examined family members. The GCK gene encodes glucokinase (hexokinase 4),
which catalyzes the first step in a large number of glucose metabolic pathways such as glycolysis. Mutations in this
gene are the cause of MODY2. The illness is characterized by an insignificant increase in the fasting glucose level, is
a well-controlled disease without medication, and has a low prevalence of micro- and macrovascular complications
of diabetes. The presented case of MODY2 reveals the clinical significance of a mutation in the splice site of the
GCK gene. When nonclassical diabetes mellitus is being diagnosed in young people and pregnant women, genetic
testing is needed to verify the diagnosis and to select the optimal treatment method.
Key words: human; maturity onset diabetes of the young; MODY2; glucokinase gene; next-generation sequencing;
genetic analysis; bioinformatics.
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Affiliation(s)
- D. E. Ivanoshchuk
- Research Institute of Internal and Preventive Medicine – Branch of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences; Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences
| | - E. V. Shakhtshneider
- Research Institute of Internal and Preventive Medicine – Branch of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences; Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences
| | - A. K. Ovsyannikova
- Research Institute of Internal and Preventive Medicine – Branch of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences
| | - S. V. Mikhailova
- Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences
| | - O. D. Rymar
- Research Institute of Internal and Preventive Medicine – Branch of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences
| | - V. I. Oblaukhova
- Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences
| | - A. A. Yurchenko
- Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences
| | - M. I. Voevoda
- Research Institute of Internal and Preventive Medicine – Branch of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences; Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences
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Sousa M, Bruges-Armas J. Monogenic Diabetes: Genetics and Relevance on Diabetes Mellitus Personalized Medicine. Curr Diabetes Rev 2020; 16:807-819. [PMID: 31886753 DOI: 10.2174/1573399816666191230114352] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 11/11/2019] [Accepted: 12/12/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Diabetes mellitus (DM) is a complex disease with significant impression in today's world. Aside from the most common types recognized over the years, such as type 1 diabetes (T1DM) and type 2 diabetes (T2DM), recent studies have emphasized the crucial role of genetics in DM, allowing the distinction of monogenic diabetes. METHODS Authors did a literature search with the purpose of highlighting and clarifying the subtypes of monogenic diabetes, as well as the accredited genetic entities responsible for such phenotypes. RESULTS The following subtypes were included in this literature review: maturity-onset diabetes of the young (MODY), neonatal diabetes mellitus (NDM) and maternally inherited diabetes and deafness (MIDD). So far, 14 subtypes of MODY have been identified, while three subtypes have been identified in NDM - transient, permanent, and syndromic. DISCUSSION Despite being estimated to affect approximately 2% of all the T2DM patients in Europe, the exact prevalence of MODY is still unknown, accentuating the need for research focused on biomarkers. Consequently, due to its impact in the course of treatment, follow-up of associated complications, and genetic implications for siblings and offspring of affected individuals, it is imperative to diagnose the monogenic forms of DM accurately. CONCLUSION Currently, advances in the genetics field allowed the recognition of new DM subtypes, which until now, were considered slight variations of the typical forms. Thus, it is imperative to act in the close interaction between genetics and clinical manifestations, to facilitate diagnosis and individualize treatment.
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MESH Headings
- Deafness/classification
- Deafness/diagnosis
- Deafness/genetics
- Diabetes Mellitus, Type 1/diagnosis
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 2/classification
- Diabetes Mellitus, Type 2/diagnosis
- Diabetes Mellitus, Type 2/genetics
- Genetic Testing
- Genotype
- Humans
- Infant
- Infant, Newborn
- Infant, Newborn, Diseases/classification
- Infant, Newborn, Diseases/diagnosis
- Infant, Newborn, Diseases/genetics
- Mitochondrial Diseases/classification
- Mitochondrial Diseases/diagnosis
- Mitochondrial Diseases/genetics
- Mutation
- Phenotype
- Precision Medicine
- Syndrome
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Affiliation(s)
- Madalena Sousa
- Serviço Especializado de Epidemiologia e Biologia Molecular (SEEBMO), Hospital de Santo Espírito da Ilha Terceira (HSEIT), Angra do Heroísmo, Azores, Portugal
| | - Jácome Bruges-Armas
- Serviço Especializado de Epidemiologia e Biologia Molecular (SEEBMO), Hospital de Santo Espírito da Ilha Terceira (HSEIT), Angra do Heroísmo, Azores, Portugal
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Plengvidhya N, Tangjittipokin W, Teerawattanapong N, Narkdontri T, Yenchitsomanus PT. HNF1A mutation in a Thai patient with maturity-onset diabetes of the young: A case report. World J Diabetes 2019; 10:414-420. [PMID: 31363388 PMCID: PMC6656704 DOI: 10.4239/wjd.v10.i7.414] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 05/24/2019] [Accepted: 06/11/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes. The disease is transmitted in autosomal dominant mode and diabetes is usually diagnosed before age 25 year. MODY 3 is caused by mutation of hepatocyte nuclear factor (HNF) 1A genes and is the most common MODY subtype. Diagnosis of MODY 3 is crucial since glycemic control can be accomplished by very low dose of sulfonylurea. In this report we described a Thai MODY 3 patient who had excellence plasma glucose control by treating with glicazide 20 mg per day and insulin therapy can be discontinued.
CASE SUMMARY A 31-year-old woman was diagnosed diabetes mellitus at 14 years old. The disease was transmitted from her grandmother and mother compatible with autosomal dominant inheritance. Sanger sequencing of proband’s DNA identified mutation of HNF1A at codon 203 which changed amino acid from arginine to cysteine (R203C). This mutation was carried only by family members who have diabetes. The patient has been treated effectively with a combination of oral hypoglycemic agents and must include a very low dose of glicazide (20 mg/d). Insulin therapy was successfully discontinued.
CONCLUSION We demonstrated a first case of pharmacogenetics in Thai MODY 3 patient. Our findings underscore the essential role of molecular genetics in diagnosis and guidance of appropriate treatment of diabetes mellitus in particular patient.
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Affiliation(s)
- Nattachet Plengvidhya
- Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Watip Tangjittipokin
- Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Nipaporn Teerawattanapong
- Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Research Division, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Tassanee Narkdontri
- Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Research Division, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Pa-thai Yenchitsomanus
- Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Siriraj Center of Research Excellence for Molecular Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
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Abstract
PURPOSE OF REVIEW MODY6 due to mutations in the gene NEUROD1 is very rare, and details on its clinical manifestation and pathogenesis are scarce. In this review, we have summarized all reported cases of MODY6 diagnosed by genetic testing, and examined their clinical features in detail. RECENT FINDINGS MODY6 is a low penetrant MODY, suggesting that development of the disease is affected by genetic modifying factors, environmental factors, and/or the effects of interactions of genetic and environmental factors, as is the case with MODY5. Furthermore, while patients with MODY6 can usually achieve good glycemic control without insulin, when undiagnosed they are prone to become ketotic with chronic hyperglycemia, and microangiopathy can progress. MODY6 may also cause neurological abnormalities such as intellectual disability. MODY6 should be diagnosed early and definitively by genetic testing, so that the correct treatment can be started as soon as possible to prevent chronic hyperglycemia.
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Affiliation(s)
- Yukio Horikawa
- Department of Diabetes and Endocrinology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu city, Gifu, 501-1194, Japan.
| | - Mayumi Enya
- Department of Diabetes and Endocrinology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu city, Gifu, 501-1194, Japan
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Abstract
Although type 2 diabetes is a disease often associated with aging, the global prevalence of early-onset diabetes has been increasing due to man's sedentary lifestyle, low-physical activity, obesity, and some nonmodifiable risk factors. Many studies have found that individuals with early-onset type 2 diabetes were at higher risk of developing vascular complications than those with late-onset diabetes. Individuals with early-onset diabetes are usually unwilling to visit hospital and have more confidence in their health, which results in poor glycemic control and the delayed detection of diabetes-related complications. Few studies have focused on the treatment and prevention of complications in specific population of individuals with early-onset type 2 diabetes. Therefore, focusing on this particular population is critical for the government and academic societies. Screening for T2DM is imminent for young adults with a family history of diabetes, obesity, markers of insulin resistance, or alcohol consumption. More data are definitely required to establish a reasonable risk model to screen for early-onset diabetes.
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Affiliation(s)
- Jiemin Pan
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai, 200233, China
| | - Weiping Jia
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai, 200233, China.
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Kulanuwat S, Tangjittipokin W, Jungtrakoon P, Chanprasert C, Sujjitjoon J, Binnima N, Yenchitsomanus PT, Plengvidhya N. DNAJC3 mutation in Thai familial type 2 diabetes mellitus. Int J Mol Med 2018; 42:1064-1073. [PMID: 29767246 DOI: 10.3892/ijmm.2018.3678] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 05/08/2018] [Indexed: 11/05/2022] Open
Abstract
Type 2 diabetes mellitus (T2D) is a heterogeneous disease, with certain cases presenting an autosomal dominant type. The rare coding variants of disease‑causing genes in T2D remain mostly unclear. The present study aimed to identify the disease‑causing gene conducting whole exome sequencing in a Thai T2D family with an autosomal dominant transmission of T2D with no evidence of mutations in known maturity‑onset diabetes of the young (MODY) genes. Candidate variants were selected according to certain criteria of mutation prediction programs, followed by segregation analysis with diabetes in the family. The results demonstrated that, of the 68,817 variants obtained, 122 were considered as candidate variants subsequent to the filtering processes. Genotyping of these variants revealed that DnaJ homolog subfamily C member 3 (DNAJC3) p.H238N segregated with diabetes in the family. This mutation was also identified in another proband from the autosomal dominant T2D family without mutation in known MODY genes and was segregated with diabetes. This variant was also identified in 14/1,000 older‑onset T2D patients [minor allele frequency (MAF)=0.007], 2/500 non‑diabetic controls (MAF=0.002) and 3 prediabetic individuals who were previously classified as non‑diabetic controls. In silico mutagenesis and protein modeling of p.H238N revealed changes of the polar contacts across the tetratricopeptide repeat (TPR) motif and TPR subdomains, which may affect the protein tertiary structure. Furthermore, the expression of DNAJC3 H238N protein was 0.68±0.08 fold (P<0.05) lower when compared with that of the wild‑type, possibly due to protein instability. Thus, DNAJC3 p.H238N is likely to be a variant causing diabetes.
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Affiliation(s)
- Sirikul Kulanuwat
- Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Watip Tangjittipokin
- Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Prapaporn Jungtrakoon
- Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Chutima Chanprasert
- Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Jatuporn Sujjitjoon
- Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Ninareeman Binnima
- Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Pa-Thai Yenchitsomanus
- Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Nattachet Plengvidhya
- Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
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11
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Haerian BS, Haerian MS, Roohi A, Mehrad-Majd H. ABCA1 genetic polymorphisms and type 2 diabetes mellitus and its complications. Meta Gene 2017. [DOI: 10.1016/j.mgene.2017.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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12
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Sujjitjoon J, Kooptiwut S, Chongjaroen N, Tangjittipokin W, Plengvidhya N, Yenchitsomanus PT. Aberrant mRNA splicing of paired box 4 (PAX4) IVS7-1G>A mutation causing maturity-onset diabetes of the young, type 9. Acta Diabetol 2016; 53:205-16. [PMID: 25951767 DOI: 10.1007/s00592-015-0760-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 04/12/2015] [Indexed: 01/24/2023]
Abstract
AIMS Paired box 4 (PAX4) mutations cause maturity-onset diabetes of the young, type 9 (MODY9). The molecular defect and alteration of PAX4 function associated with the mutation PAX4 IVS7-1G>A in a family with MODY9 and severe diabetic complications were studied. METHODS We investigated the functional consequences of PAX4 IVS7-1G>A on mRNA splicing using minigene assays. Wild-type and mutant PAX4 were expressed in mouse pancreatic β- and α-cell lines, and protein levels and translocation of PAX4 into the nucleus were determined. We also examined transcriptional repression of PAX4 target-gene promoters and β-cell viability under diabetic-like (high-glucose) conditions. RESULTS PAX4 IVS7-1G>A disrupts an acceptor splice site, causing an adjacent cryptic splice site within exon 8 to be used, resulting in a three-nucleotide deletion and glutamine deletion at position 250 (p.Q250del). Wild-type and PAX4 Q250del proteins were expressed at similar levels and could translocate normally into the nucleus in βTC3 and αTC1.9 cells. However, the repressor functions of PAX4 Q250del on human insulin and glucagon promoters in INS-1 832/13 and αTC1.9 cells were significantly decreased, compared with that of wild-type PAX4. Moreover, the rate of apoptosis was increased in INS-1 cells over-expressing PAX4 Q250del when cultured in high-glucose conditions. CONCLUSIONS PAX4 IVS7-1G>A caused aberrant mRNA splicing and PAX4 Q250 deletion. The mutation impaired PAX4 repressor functions on target-gene promoters and increased susceptibility to apoptosis upon high glucose exposure. Thus, PAX4 IVS7-1G>A contributes to the pathogenesis of diabetes in this MODY9 family through β-cell dysfunction.
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Affiliation(s)
- Jatuporn Sujjitjoon
- Division of Molecular Medicine, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
- Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Suwattanee Kooptiwut
- Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Nalinee Chongjaroen
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Watip Tangjittipokin
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Nattachet Plengvidhya
- Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
| | - Pa-Thai Yenchitsomanus
- Division of Molecular Medicine, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
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Khan IA, Vattam KK, Jahan P, Hasan Q, Rao P. Importance of glucokinase -258G/A polymorphism in Asian Indians with post-transplant and type 2 diabetes mellitus. Intractable Rare Dis Res 2016; 5:25-30. [PMID: 26989645 PMCID: PMC4761580 DOI: 10.5582/irdr.2015.01040] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) and post-transplant diabetes mellitus (PTDM) are non-synonymous forms of diabetes. Glucokinase (GCK) plays a key role in glucose metabolism. The relationship between the GCK promoter and specific types of diabetes, such as PTDM and T2DM, in the Asian Indian population is unknown. We examined the occurrence of a specific GCK promoter variant (-258G/A) in patients with T2DM and PTDM. The case-control study enrolled 640 Asian Indian subjects, including controls (n = 250) and T2DM (n = 250), PTDM (n = 42), and non-post-transplant diabetes mellitus (non-PTDM) (n = 98) patients. Purified Deoxyribonucleic acid (DNA) was genotyped with the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. The digested PCR products were analyzed on 12% polyacrylamide gels. The anthropometric, biochemical, and clinical details of each group were documented. GCK -258G/A alleles and genotypes were not associated with T2DM. However, among PTDM subjects, we detected a higher frequency of heterozygotes (52.4%) and a positive association with alleles/genotypes. The results suggest that the promoter region (-258G/A) of GCK plays an important role in PTDM in Asian Indians.
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Affiliation(s)
- Imran Ali Khan
- Department of Genetics and Molecular medicine, Kamineni Hospitals, Hyderabad, India
- Department of Genetics, Vasavi Medical and Research Centre, Khairathabad, Hyderabad, India
- Department of Genetics and Biotechnology, Osmania University, Tarnaka, Hyderabad, India
| | - Kiran Kumar Vattam
- Department of Genetics and Molecular medicine, Kamineni Hospitals, Hyderabad, India
| | - Parveen Jahan
- Department of Genetics and Biotechnology, Osmania University, Tarnaka, Hyderabad, India
| | - Qurratulain Hasan
- Department of Genetics and Molecular medicine, Kamineni Hospitals, Hyderabad, India
- Department of Genetics, Vasavi Medical and Research Centre, Khairathabad, Hyderabad, India
| | - Pragna Rao
- Department of Biochemistry, Kasturba Medical College, Manipal University, Manipal, Karnataka, India
- Address correspondence to: Dr. Pragna Rao, Department of Biochemistry, Kasturba Medical College, Manipal University, Manipal-576104, Karnataka, India. E-mail:
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Yamagata K. Roles of HNF1α and HNF4α in pancreatic β-cells: lessons from a monogenic form of diabetes (MODY). VITAMINS AND HORMONES 2015; 95:407-23. [PMID: 24559927 DOI: 10.1016/b978-0-12-800174-5.00016-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Mutations in the genes encoding hepatocyte nuclear factor (HNF)1α and HNF4α cause a monogenic form of diabetes mellitus known as maturity-onset diabetes of the young (MODY). The primary cause of MODY is an impairment of glucose-stimulated insulin secretion by pancreatic β-cells, indicating the important roles of HNF1α and HNF4α in β-cells. Large-scale genetic studies have clarified that the common variants of HNF1α and HNF4α genes are also associated with type 2 diabetes, suggesting that they are involved in the pathogenesis of both diseases. Recent experimental studies revealed that HNF1α controls both β-cell function and growth by regulating target genes such as glucose transporter 2, pyruvate kinase, collectrin, hepatocyte growth factor activator, and HNF4α. In contrast, HNF4α mainly regulates the function of β-cells. Although direct target genes of HNF4α in β-cells are largely unknown, we recently identified Anks4b as a novel target of HNF4α that regulates β-cell susceptibility to endoplasmic reticulum stress. Studies of MODY have led to a better understanding of the molecular mechanism of glucose-stimulated insulin secretion by pancreatic β-cells.
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Affiliation(s)
- Kazuya Yamagata
- Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
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15
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Liu L, Nagashima K, Yasuda T, Liu Y, Hu HR, He G, Feng B, Zhao M, Zhuang L, Zheng T, Friedman TC, Xiang K. Mutations in KCNJ11 are associated with the development of autosomal dominant, early-onset type 2 diabetes. Diabetologia 2013; 56:2609-18. [PMID: 24018988 PMCID: PMC5333983 DOI: 10.1007/s00125-013-3031-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2013] [Accepted: 08/02/2013] [Indexed: 12/25/2022]
Abstract
AIMS/HYPOTHESIS More than 90% of Chinese familial early-onset type 2 diabetes mellitus is genetically unexplained. To investigate the molecular aetiology, we identified and characterised whether mutations in the KCNJ11 gene are responsible for these families. METHODS KCNJ11 mutations were screened for 96 familial early-onset type 2 diabetic probands and their families. Functional significance of the identified mutations was confirmed by physiological analysis, molecular modelling and population survey. RESULTS Three novel KCNJ11 mutations, R27H, R192H and S116F117del, were identified in three families with early-onset type 2 diabetes mellitus. Mutated KCNJ11 with R27H or R192H markedly reduced ATP sensitivity (E23K>R27H>C42R>R192H>R201H), but no ATP-sensitive potassium channel currents were detected in the loss-of-function S116F117del channel in vitro. Molecular modelling indicated that R192H had a larger effect on the channel ATP-binding pocket than R27H, which may qualitatively explain why the ATP sensitivity of the R192H mutation is seven times less than R27H. The shape of the S116F117del channel may be compressed, which may explain why the mutated channel had no currents. Discontinuation of insulin and implementation of sulfonylureas for R27H or R192H carriers and continuation/switch to insulin therapy for S116F117del carriers resulted in good glycaemic control. CONCLUSIONS/INTERPRETATION Our results suggest that genetic diagnosis for the KCNJ11 mutations in familial early-onset type 2 diabetes mellitus may help in understanding the molecular aetiology and in providing more personalised treatment for these specific forms of diabetes in Chinese and other Asian patients.
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Affiliation(s)
- Limei Liu
- Department of Endocrinology & Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai Diabetes Institute, 600 Yishan Road, Shanghai, 200233, China,
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16
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Mannino GC, Sesti G. Individualized therapy for type 2 diabetes: clinical implications of pharmacogenetic data. Mol Diagn Ther 2013; 16:285-302. [PMID: 23018631 DOI: 10.1007/s40291-012-0002-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance, abnormally elevated hepatic glucose production, and reduced glucose-stimulated insulin secretion. Treatment with antihyperglycemic agents is initially successful in type 2 diabetes, but it is often associated with a high secondary failure rate, and the addition of insulin is eventually necessary for many patients, in order to restore acceptable glycemic control and to reduce the risk of development and progression of disease complications. Notably, even patients who appear to have similar requirements of antidiabetic regimens show great variability in drug disposition, glycemic response, tolerability, and incidence of adverse effects during treatment. Pharmacogenomics is a promising area of investigation and involves the search for genetic polymorphisms that may explain the interindividual variability in antidiabetic therapy response. The initial positive results portend that genomic efforts will be able to shed important light on variability in pharmacologic traits. In this review, we summarize the current understanding of genetic polymorphisms that may affect the responses of subjects with T2DM to antidiabetic treatment. These genes belong to three major classes: genes involved in drug metabolism and transporters that influence pharmacokinetics (including the cytochrome P450 [CYP] superfamily, the organic anion transporting polypeptide [OATP] family, and the polyspecific organic cation transporter [OCT] family); genes encoding drug targets and receptors (including peroxisome proliferator-activated receptor gamma [PPARG], the adenosine triphosphate [ATP]-sensitive potassium channel [K(ATP)], and incretin receptors); and genes involved in the causal pathway of T2DM that are able to modify the effects of drugs (including adipokines, transcription factor 7-like 2 (T cell specific, HMG-box) [TCF7L2], insulin receptor substrate 1 [IRS1], nitric oxide synthase 1 (neuronal) adaptor protein [NOS1AP], and solute carrier family 30 (zinc transporter), member 8 [SLC30A8]). In addition to these three major classes, we also review the available evidence on novel genes (CDK5 regulatory subunit associated protein 1-like 1 [CDKAL1], insulin-like growth factor 2 mRNA binding protein 2 [IGF2BP2], potassium voltage-gated channel, KQT-like subfamily, member 1 [KCNQ1], paired box 4 [PAX4] and neuronal differentiation 1 [NEUROD1] transcription factors, ataxia telangiectasia mutated [ATM], and serine racemase [SRR]) that have recently been proposed as possible modulators of therapeutic response in subjects with T2DM.
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Affiliation(s)
- Gaia Chiara Mannino
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
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Kooptiwut S, Plengvidhya N, Chukijrungroat T, Sujjitjoon J, Semprasert N, Furuta H, Yenchitsomanus PT. Defective PAX4 R192H transcriptional repressor activities associated with maturity onset diabetes of the young and early onset-age of type 2 diabetes. J Diabetes Complications 2012; 26:343-7. [PMID: 22521316 DOI: 10.1016/j.jdiacomp.2012.03.025] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2011] [Revised: 03/21/2012] [Accepted: 03/21/2012] [Indexed: 01/28/2023]
Abstract
AIMS PAX4 R192H polymorphism was reported to be associated with maturity onset diabetes of the young (MODY) and early onset-age of type 2 diabetes (T2D). This study aimed to evaluate transcriptional repression activity of PAX4 R192H polymorphism on its target promoters comparing with wild-type PAX4. METHODS Wild-type PAX4 and PAX4 R192H proteins were expressed in vitro and the cell compartmentalization of each protein was examined after transfection of the plasmid constructs into βTC3 cells followed by Western-blot analysis. The plasmid containing wild-type PAX4 or PAX4 R192H was co-transfected into βTC3 and αTC-1.9 cells with insulin or glucagon promoter-reporter construct. Transcriptional repression activities were then determined by dual-luciferase reporter assay. RESULTS Wild-type PAX4 and PAX4 R192H, which were found to be equally expressed in vitro and transfection systems, were present in the nuclear compartment. Transcriptional repressor activities of PAX4 R192H on human insulin and glucagon promoters were reduced when they were compared with those of wild-type PAX4. CONCLUSIONS These results suggested that PAX4 R192H polymorphism generated a protein with defect in transcriptional repressor activities on its target genes, which may lead to β-cell dysfunction associated with MODY and early onset-age of T2D as reported in our previous study.
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Affiliation(s)
- Suwattanee Kooptiwut
- Department of Physiology, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
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Hellwege JN, Hicks PJ, Palmer ND, Ng MCY, Freedman BI, Bowden DW. Examination of Rare Variants in HNF4 α in European Americans with Type 2 Diabetes. ACTA ACUST UNITED AC 2011; 2. [PMID: 23227446 DOI: 10.4172/2155-6156.1000145] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The hepatocyte nuclear factor 4-α (HNF4α) gene codes for a transcription factor which is responsible for regulating gene transcription in pancreatic beta cells, in addition to its primary role in hepatic gene regulation. Mutations in this gene can lead to maturity-onset diabetes of the young (MODY), an uncommon, autosomal dominant, non-insulin dependent form of diabetes. Mutations in HNF4α have been found in few individuals, and infrequently have they segregated completely with MODY in families. In addition, due to similarity of phenotypes, it is unclear what proportion of type 2 diabetes (T2DM) in the general population is due to MODY or HNF4α mutations specifically. In this study, 27 documented rare and common variants were genotyped in a European American population of 1270 T2DM cases and 1017 controls from review of databases and literature implicating HNF4α variants in MODY and T2DM. Seventeen variants were found to be monomorphic. Two cases and one control subject had one copy of a 6-bp P2 promoter deletion. The intron 1 variant (rs6103716; MAF = 0.31) was not significantly associated with disease status (p>0.8) and the missense variant Thr130Ile (rs1800961; MAF = 0.027) was also not significantly different between cases and controls (p>0.2), but showed a trend consistent with association with T2DM. Four variants were found to be rare as heterozygotes in small numbers of subjects. Since many variants were infrequent, a pooled chi-squared analysis of rare variants was used to assess the overall burden of variants between cases and controls. This analysis revealed no significant difference (P=0.22). We conclude there is little evidence to suggest that HNF4α variants contribute significantly to risk of T2DM in the general population, but a modest contribution cannot be excluded. In addition, the observation of some mutations in controls suggests they are not highly penetrant MODY-causing variants.
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Affiliation(s)
- Jacklyn N Hellwege
- Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA ; Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA ; Program in Molecular Genetics and Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA
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Paulmann N, Grohmann M, Voigt JP, Bert B, Vowinckel J, Bader M, Skelin M, Jevšek M, Fink H, Rupnik M, Walther DJ. Intracellular serotonin modulates insulin secretion from pancreatic beta-cells by protein serotonylation. PLoS Biol 2009; 7:e1000229. [PMID: 19859528 PMCID: PMC2760755 DOI: 10.1371/journal.pbio.1000229] [Citation(s) in RCA: 271] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2009] [Accepted: 09/18/2009] [Indexed: 11/23/2022] Open
Abstract
Non-neuronal, peripheral serotonin deficiency causes diabetes mellitus and identifies an intracellular role for serotonin in the regulation of insulin secretion. While serotonin (5-HT) co-localization with insulin in granules of pancreatic β-cells was demonstrated more than three decades ago, its physiological role in the etiology of diabetes is still unclear. We combined biochemical and electrophysiological analyses of mice selectively deficient in peripheral tryptophan hydroxylase (Tph1−/−) and 5-HT to show that intracellular 5-HT regulates insulin secretion. We found that these mice are diabetic and have an impaired insulin secretion due to the lack of 5-HT in the pancreas. The pharmacological restoration of peripheral 5-HT levels rescued the impaired insulin secretion in vivo. These findings were further evidenced by patch clamp experiments with isolated Tph1−/− β-cells, which clearly showed that the secretory defect is downstream of Ca2+-signaling and can be rescued by direct intracellular application of 5-HT via the clamp pipette. In elucidating the underlying mechanism further, we demonstrate the covalent coupling of 5-HT by transglutaminases during insulin exocytosis to two key players in insulin secretion, the small GTPases Rab3a and Rab27a. This renders them constitutively active in a receptor-independent signaling mechanism we have recently termed serotonylation. Concordantly, an inhibition of such activating serotonylation in β-cells abates insulin secretion. We also observed inactivation of serotonylated Rab3a by enhanced proteasomal degradation, which is in line with the inactivation of other serotonylated GTPases. Our results demonstrate that 5-HT regulates insulin secretion by serotonylation of GTPases within pancreatic β-cells and suggest that intracellular 5-HT functions in various microenvironments via this mechanism in concert with the known receptor-mediated signaling. Diabetes is the most prevalent metabolic disease and one that affects individuals of every social and economic status. The disease can arise as a result of reduced secretion of insulin from pancreatic β-cells or reduced action of insulin on its target organs. Therefore, understanding how to prevent and treat diabetes requires an extensive knowledge of the regulation of insulin secretion. In this study, we identify the hormone serotonin as a new regulator of insulin secretion and thereby attribute a function to the co-localization of serotonin and insulin in pancreatic β-cells that was first observed 30 years ago but until now not understood. We first demonstrate that a lack of serotonin in β-cells of transgenic mice leads to reduced insulin secretion and diabetes mellitus and that pharmacological replenishment of serotonin rescues insulin secretion in these mice. Interestingly, serotonin mainly acts not as an intercellular signaling molecule via its traditional surface receptors but intracellularly via regulation of the activity of target proteins through covalent coupling of serotonin to them. This coupling, called serotonylation, activates specific small GTPases, which in turn promote glucose-mediated insulin secretion. Adding this receptor-independent signaling mechanism to the multifarious regulatory functions of serotonin, we hypothesize that protein serotonylation modulates physiological secretion processes in all serotonin-containing tissues.
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Affiliation(s)
- Nils Paulmann
- Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany
- Department of Biology, Chemistry, and Pharmacy, Free University Berlin, Berlin, Germany
| | - Maik Grohmann
- Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany
- Department of Biology, Chemistry, and Pharmacy, Free University Berlin, Berlin, Germany
| | - Jörg-Peter Voigt
- Institute of Pharmacology and Toxicology of the School of Veterinary Medicine, Free University Berlin, Berlin, Germany
| | - Bettina Bert
- Institute of Pharmacology and Toxicology of the School of Veterinary Medicine, Free University Berlin, Berlin, Germany
| | - Jakob Vowinckel
- Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany
- Department of Biology, Chemistry, and Pharmacy, Free University Berlin, Berlin, Germany
| | - Michael Bader
- Laboratory of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Maša Skelin
- Institute of Physiology of the Medical Faculty, University of Maribor, Maribor, Slovenia
| | - Marko Jevšek
- Institute of Physiology of the Medical Faculty, University of Maribor, Maribor, Slovenia
| | - Heidrun Fink
- Institute of Pharmacology and Toxicology of the School of Veterinary Medicine, Free University Berlin, Berlin, Germany
| | - Marjan Rupnik
- Institute of Physiology of the Medical Faculty, University of Maribor, Maribor, Slovenia
| | - Diego J. Walther
- Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany
- * E-mail:
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Kooptiwut S, Sujjitjoon J, Plengvidhya N, Boonyasrisawat W, Chongjaroen N, Jungtrakoon P, Semprasert N, Furuta H, Nanjo K, Banchuin N, Yenchitsomanus PT. Functional defect of truncated hepatocyte nuclear factor-1α (G554fsX556) associated with maturity-onset diabetes of the young. Biochem Biophys Res Commun 2009; 383:68-72. [DOI: 10.1016/j.bbrc.2009.03.130] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2009] [Accepted: 03/21/2009] [Indexed: 11/17/2022]
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