Clinical and molecular characterization of a novel INS mutation identified in patients with MODY phenotype
Clinical and molecular characterization of a novel INS mutation identified in patients with MODY phenotype
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DOI：
10.1016/j.ejmg.2016.09.016
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发表时间：
2016-11-01
影响因子：
1.9
通讯作者：
Toni, Sonia
中科院分区：
文献类型：
--
作者：
Piccini, Barbara;Artuso, Rosangela;Toni, Sonia
正确诊断成熟型糖尿病的年轻人（MODY）是基于基因测试需要适当的受试者选择的临床医生。胰岛素（INS）基因突变在MODY患者中很少发生。本研究旨在确定疑似MODY患者的遗传背景和临床表型。采用下一代测序（NGS）技术筛选GCK、HNF1 α、HNF4 α、HNF1b β和PDX1基因突变阴性的34例疑似MODY患者。在同一家族的4个成员中发现了一个杂合的INS突变。首先进行的基因检测发现MODY3/HNF1 α基因中存在两个杂合沉默核苷酸替换。一个无效的尝试暂停胰岛素治疗，给予瑞格列奈和磺脲类，作出。通过NGS对102个基因进行了DNA重测序。选择了与胰腺β细胞通路相关的基因、2型糖尿病的候选基因和小鼠糖尿病的致病基因。在受影响的家族成员中发现了一种新的人胰岛素前原INS基因（C . 125t > C）杂合变异。新的INS突变拓宽了可能的INS表型谱。筛查INS突变不仅适用于新生儿糖尿病，也适用于MODYx患者和自身抗体阴性的1型糖尿病患者。由于Sanger测序在检测罕见变异时效率低下且耗时，因此对于没有特定表型的复杂疾病患者应采用NGS进行研究。(C) 2016 Elsevier Masson SAS。版权所有。
Correct diagnosis of Maturity-Onset Diabetes of the Young (MODY) is based on genetic tests requiring an appropriate subject selection by clinicians. Mutations in the insulin (INS) gene rarely occur in patients with MODY. This study is aimed at determining the genetic background and clinical phenotype in patients with suspected MODY. 34 patients with suspected MODY, negative for mutations in the GCK, HNF1 alpha, HNF4 alpha, HNF1b beta and PDX1 genes, were screened by next generation sequencing (NGS). A heterozygous INS mutation was identified in 4 members of the same family. First genetic tests performed identified two heterozygous silent nucleotide substitutions in MODY3/HNF1 alpha gene. An ineffective attempt to suspend insulin therapy, administering repaglinide and sulphonylureas, was made. DNA was re-sequenced by NGS investigating a set of 102 genes. Genes implicated in the pathway of pancreatic beta-cells, candidate genes for type 2 diabetes mellitus and genes causative of diabetes in mice were selected. A novel heterozygous variant in human preproinsulin INS gene (c.125T > C) was found in the affected family members. The new INS mutation broadens the spectrum of possible INS phenotypes. Screening for INS mutations is warranted not only in neonatal diabetes but also in MODYx patients and in selected patients with type 1 diabetes mellitus negative for autoantibodies. Subjects with complex diseases without a specific phenotype should be studied by NGS because Sanger sequencing is ineffective and time consuming in detecting rare variants. (C) 2016 Elsevier Masson SAS. All rights reserved.