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

Document Type : Original Article


1 Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

2 Cellular And Molecular Research Center, Institute of Basic Health Sciences, Shahrekord University of Medical Sciences, Shahrekord, Iran

3 Department of Endocrinology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran

4 Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

5 Department of Endocrinology; Department of Pediatrics, Faculty of Medicine, Imam Hossein Hospital; Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Noncommunicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran

6 Department of Genetics and Molecular Biology, School of Medicine; Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Noncommunicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran


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 HNF1AConclusion: 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.


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