Clinical and molecular characterization of a novel INS mutation identified in patients with MODY phenotype

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• 作者：Barbara Piccini^a ; ^{b.piccini@meyer.it" class="auth_mail" title="E-mail the corresponding author} ; Rosangela Artuso^b ; Lorenzo Lenzi^a ; Monica Guasti^a ; Giulia Braccesi^a ; Federica Barni^a ; Emilio Casalini^c ; Sabrina Giglio^b ; ^d ; Sonia Toni^a
• 关键词：Monogenic diabetes ; MODY ; Next generation sequencing ; β-Cell ; Children
• 刊名：European Journal of Medical Genetics
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：59
• 期：11
• 页码：590-595
• 全文大小：471 K

文摘

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, HNF1α, HNF4α, HNF1β 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/HNF1α 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 β-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.