Mohammadi Aliasgar, Eskandari Ameneh, Sarmadi Akram, Rahimi Mehrali, Iraj Bijan, Hashemipour Mahin, Chaleshtori Morteza Hashmezadeh, Tabatabaiefar Mohammad Amin
Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
Cellular And Molecular Research Center, Institute of Basic Health Sciences, Shahrekord University of Medical Sciences, Shahrekord, Iran.
Adv Biomed Res. 2019 Sep 23;8:55. doi: 10.4103/abr.abr_54_19. eCollection 2019.
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 () 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 mutations in Iranian diabetic families fulfilling MODY criteria.
Polymerase chain reaction and Sanger sequencing were performed. All the ten exons of the gene were sequenced in ten families, followed by cosegregation analysis and evaluation. Computational protein modeling was accomplished for the identified mutation.
MODY3 was confirmed in two large families by detecting a mutation (p.G253E) in coding regions of . Compound heterozygous state for two common variants in (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 .
It seems that 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.
青年发病的成年型糖尿病（MODY）是一组临床和遗传异质性的糖尿病，其特征为非胰岛素依赖型、常染色体显性疾病，具有强烈的家族病史、发病年龄早以及胰腺β细胞功能障碍。至少14种不同基因的突变导致了各种MODY亚型。肝细胞核因子1α（HNF1α）基因的杂合突变导致MODY3亚型，这是不同研究人群中MODY的常见亚型。迄今为止，该基因已报道超过450种不同的变异可导致MODY3。本研究旨在评估符合MODY标准的伊朗糖尿病家族中的HNF1α突变。
进行聚合酶链反应和桑格测序。对10个家族的HNF1α基因的所有10个外显子进行测序，随后进行共分离分析和突变评估。对鉴定出的突变进行计算蛋白质建模。
通过检测HNF1α编码区的一个突变（p.G253E），在两个大家系中确诊为MODY3。在5个家族的患病成员中检测到HNF1α的两个常见变异（p.I27L和p.S487N）处于复合杂合状态，并且在一个家族中，在 Kozak 序列的编码序列中检测到一个罕见的良性变异。在HNF1α的非编码区发现了两个新的非致病变异。
HNF1α突变似乎是伊朗糖尿病患者MODY的常见病因。杂合状态下鉴定出的常见变异可导致更早年龄段的2型糖尿病。罕见变异rs3455720的作用尚不清楚，需要更多研究来揭示该变异的功能。
