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Genetic Study of Hepatocyte Nuclear Factor 1 Alpha Variants in Development of Early-Onset Diabetes Type 2 and Maturity-Onset Diabetes of the Young 3 in Iran.

ABSTRACT: Background:Maturity-onset diabetes of the young (MODY) is a clinically and genetically heterogeneous group of diabetes characterized by noninsulin-dependent, autosomal-dominant disorder with strong familial history, early age of onset, and pancreatic beta-cell dysfunction. Mutations in at least 14 different genes are responsible for various MODY subtypes. Heterozygous mutations in the hepatocyte nuclear factor 1 alpha (HNF1A) gene are responsible for the MODY3 subtype, which is a common subtype of MODY in different studied populations. To date, more than 450 different variants of this gene have been reported as disease causing for MODY3. This study was carried out to evaluate HNF1A mutations in Iranian diabetic families fulfilling MODY criteria. Materials and Methods:Polymerase chain reaction and Sanger sequencing were performed. All the ten exons of the HNF1A gene were sequenced in ten families, followed by cosegregation analysis and in silico evaluation. Computational protein modeling was accomplished for the identified mutation. Results:MODY3 was confirmed in two large families by detecting a mutation (p.G253E) in coding regions of HNF1A. Compound heterozygous state for two common variants in HNF1A (p.I27 L and p.S487N) was detected in affected members of 5 families, and in one family, a rare benign variant in the coding sequence for Kozak sequence was detected. Two new nonpathogenic variants were found in noncoding regions of HNF1A. Conclusion:It seems that HNF1A mutations are a common cause of MODY in Iranian diabetic patients. Identified common variants in heterozygous state can cause diabetes Type II in earlier ages. The role of rare variant rs3455720 is unknown, and more investigation is needed to uncover the function of this variant.

SUBMITTER: Mohammadi A

PROVIDER: S-EPMC6777141 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Genetic Study of Hepatocyte Nuclear Factor 1 Alpha Variants in Development of Early-Onset Diabetes Type 2 and Maturity-Onset Diabetes of the Young 3 in Iran.

Mohammadi Aliasgar A Eskandari Ameneh A Sarmadi Akram A Rahimi Mehrali M Iraj Bijan B Hashemipour Mahin M Chaleshtori Morteza Hashmezadeh MH Tabatabaiefar Mohammad Amin MA

Advanced biomedical research 20190923

<h4>Background</h4>Maturity-onset diabetes of the young (MODY) is a clinically and genetically heterogeneous group of diabetes characterized by noninsulin-dependent, autosomal-dominant disorder with strong familial history, early age of onset, and pancreatic beta-cell dysfunction. Mutations in at least 14 different genes are responsible for various MODY subtypes. Heterozygous mutations in the hepatocyte nuclear factor 1 alpha (<i>HNF1A</i>) gene are responsible for the MODY3 subtype, which is a ...[more]

PMID: 31673528

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Project description:It is important to identify patients with Maturity-onset diabetes of the young (MODY) as a molecular diagnosis determines both treatment and prognosis. Genetic testing is currently expensive and many patients are therefore not assessed and are misclassified as having either type 1 or type 2 diabetes. Biomarkers could facilitate the prioritisation of patients for genetic testing. We hypothesised that patients with different underlying genetic aetiologies for their diabetes could have distinct metabolic profiles which may uncover novel biomarkers. The aim of this study was to perform metabolic profiling in urine from patients with MODY due to mutations in the genes encoding glucokinase (GCK) or hepatocyte nuclear factor 1 alpha (HNF1A), type 2 diabetes (T2D) and normoglycaemic control subjects. Urinary metabolic profiling by Nuclear Magnetic Resonance (NMR) and ultra performance liquid chromatography hyphenated to Q-TOF mass spectrometry (UPLC-MS) was performed in a Discovery set of subjects with HNF1A-MODY (n = 14), GCK-MODY (n = 17), T2D (n = 14) and normoglycaemic controls (n = 34). Data were used to build a valid partial least squares discriminate analysis (PLS-DA) model where HNF1A-MODY subjects could be separated from the other diabetes subtypes. No single metabolite contributed significantly to the separation of the patient groups. However, betaine, valine, glycine and glucose were elevated in the urine of HNF1A-MODY subjects compared to the other subgroups. Direct measurements of urinary amino acids and betaine in an extended dataset did not support differences between patients groups. Elevated urinary glucose in HNF1A-MODY is consistent with the previously reported low renal threshold for glucose in this genetic subtype. In conclusion, we report the first metabolic profiling study in monogenic diabetes and show that, despite the distinct biochemical pathways affected, there are unlikely to be robust urinary biomarkers which distinguish monogenic subtypes from T2D. Our results have implications for studies investigating metabolic profiles in complex traits including T2D.

Dataset Information

Genetic Study of Hepatocyte Nuclear Factor 1 Alpha Variants in Development of Early-Onset Diabetes Type 2 and Maturity-Onset Diabetes of the Young 3 in Iran.

Publications

Genetic Study of Hepatocyte Nuclear Factor 1 Alpha Variants in Development of Early-Onset Diabetes Type 2 and Maturity-Onset Diabetes of the Young 3 in Iran.

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