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

Authors

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

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 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.

Keywords

1.
Colclough K, Bellanne-Chantelot C, Saint-Martin C, Flanagan SE, Ellard S. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia. Hum Mutat 2013;34:669-85.  Back to cited text no. 1
    
2.
Vaxillaire M, Froguel P. Maturity-onset Diabetes of the Young: From Genetics to Translational Biology and Personalized Medicine. Diabetes Associated with Single Gene Defects and Chromosomal Abnormalities. Vol. 25. basel: Karger Publishers; 2017. p. 26-48.  Back to cited text no. 2
    
3.
Billings LK, Jablonski KA, Warner AS, Cheng YC, McAteer JB, Tipton L, et al. Variation in maturity-onset diabetes of the young genes influence response to interventions for diabetes prevention. J Clin Endocrinol Metab 2017;102:2678-89.  Back to cited text no. 3
    
4.
Patel KA, Kettunen J, Laakso M, Stančáková A, Laver TW, Colclough K, et al. Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance. Nat Commun 2017;8:888.  Back to cited text no. 4
    
5.
Fanjans SS, Bell GI. (2011). History, genetics, pathophysiology, and clinical decision making. Diabetes Care. Aug; 34 (8): 1878-1884. DOI.org/10.2337/dc11-0035.  Back to cited text no. 5
    
6.
Shields BM, Hicks S, Shepherd MH, Colclough K, Hattersley AT, Ellard S. Maturity-onset diabetes of the young (MODY): How many cases are we missing? Diabetologia 2010;53:2504-8.  Back to cited text no. 6
    
7.
Firdous P, Nissar K, Ali S, Ganai BA, Shabir U, Hassan T, et al. Genetic testing of maturity-onset diabetes of the young current status and future perspectives. Front Endocrinol (Lausanne) 2018;9:253.  Back to cited text no. 7
    
8.
Acar S, Abacı A, Demir K, Özdemir TR, Özyılmaz B, Böber E. A novel de novo missense mutation in HNF4A resulting in sulfonylurea-responsive MODY. J Clin Res Pediatr Endocrinol 2017;9:15.  Back to cited text no. 8
    
9.
Naylor RN, Montgomery JT, Lindauer K, Letourneau L, Bindal A, Sanyoura M, et al. Long Delay in Accurate Diagnosis of HNF1A-Mody in the US Monogenic Diabetes Registry. Biology, Pathogenesis, and Clinical Dilemmas in Diabetes (posters): Endocrine Society; 2016.  Back to cited text no. 9
    
10.
Bellanné-Chantelot C, Carette C, Riveline JP, Valéro R, Gautier JF, Larger E, et al. The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3. Diabetes 2008;57:503-8.  Back to cited text no. 10
    
11.
Yamagata K, Oda N, Kaisaki PJ, Menzel S, Furuta H, Vaxillaire M, et al. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature 1996;384:455-8.  Back to cited text no. 11
    
12.
Karaca E, Onay H, Cetinkalp S, Aykut A, Göksen D, Ozen S, et al. The spectrum of HNF1A gene mutations in patients with MODY 3 phenotype and identification of three novel germline mutations in Turkish population. Diabetes Metab Syndr 2017;11 Suppl 1:S491-6.  Back to cited text no. 12
    
13.
Morita K, Saruwatari J, Tanaka T, Oniki K, Kajiwara A, Miyazaki H, et al. Common variants of HNF1A gene are associated with diabetic retinopathy and poor glycemic control in normal-weight Japanese subjects with type 2 diabetes mellitus. J Diabetes Complications 2017;31:483-8.  Back to cited text no. 13
    
14.
Barzi SA, Ghaderian SM, Noormohammadi Z. A molecular case-control study of association of HNF1A gene polymorphisms (rs2259816 and rs7310409) with risk of coronary artery disease in Iranian patients. Hum Antibodies 2017;25:65-70.  Back to cited text no. 14
    
15.
Tang J, Tang CY, Wang F, Guo Y, Tang HN, Zhou CL, et al. Genetic diagnosis and treatment of a Chinese Ketosis-prone MODY 3 family with depression. Diabetol Metab Syndr 2017;9:5.  Back to cited text no. 15
    
16.
Sneha P, Thirumal Kumar D, Priya Doss CG, Siva R, Zayed H. Determining the role of missense mutations in the POU domain of HNF1A that reduce the DNA-binding affinity: A computational approach. PLoS One 2017;12:e0174953.  Back to cited text no. 16
    
17.
Fajans SS, Bell GI. Phenotypic heterogeneity between different mutations of MODY subtypes and within MODY pedigrees. Diabetologia 2006;49:1106-8.  Back to cited text no. 17
    
18.
Kammenga JE. The background puzzle: How identical mutations in the same gene lead to different disease symptoms. FEBS J 2017;284:3362-73.  Back to cited text no. 18
    
19.
Schober E, Rami B, Grabert M, Thon A, Kapellen T, Reinehr T, et al. Phenotypical aspects of maturity-onset diabetes of the young (MODY diabetes) in comparison with type 2 diabetes mellitus (T2DM) in children and adolescents: Experience from a large multicentre database. Diabet Med 2009;26:466-73.  Back to cited text no. 19
    
20.
Yang Y, Zhou TC, Liu YY, Li X, Wang WX, Irwin DM, et al. Identification of HNF4A mutation p.T130I and HNF1A mutations p.I27L and p.S487N in a Han Chinese family with early-onset maternally inherited type 2 diabetes. J Diabetes Res 2016;2016:3582616.  Back to cited text no. 20
    
21.
Chi YI, Frantz JD, Oh BC, Hansen L, Dhe-Paganon S, Shoelson SE. Diabetes mutations delineate an atypical POU domain in HNF-1alpha. Mol Cell 2002;10:1129-37.  Back to cited text no. 21
    
22.
Liang S, Tippens ND, Zhou Y, Mort M, Stenson PD, Cooper DN, et al. IRegNet3D: Three-dimensional integrated regulatory network for the genomic analysis of coding and non-coding disease mutations. Genome Biol 2017;18:10.  Back to cited text no. 22
    
23.
Kim KA, Kang K, Chi YI, Chang I, Lee MK, Kim KW, et al. Identification and functional characterization of a novel mutation of hepatocyte nuclear factor-1alpha gene in a Korean family with MODY3. Diabetologia 2003;46:721-7.  Back to cited text no. 23
    
24.
Topaloǧlu Ö, Evren B, Şahin İ. Monogenic diabetes case presented with symptomatic hyperglycemia and atypical mutation. J Clin Res Pediatr Endocrinol 2017;9:14.  Back to cited text no. 24