Identification of Maturity-Onset Diabetes of the Young Caused by Mutation in FOXM1 via Whole-Exome Sequencing in Northern China.

Liang Zhong,Yang Li,Qingshan Hu,Nan Li,Jing Zhang,Weili Zhao,Ruijuan Rong,Zifeng Zhang,Zanchao Liu,Yunqiang Xu,Chuang Li,Zengyi Zhao

doi:10.3389/fendo.2020.534362

Abstract

Diabetes mellitus is a highly heterogeneous disorder encompassing different types with particular clinical manifestations, while maturity-onset diabetes of the young (MODY) is an early-onset monogenenic diabetes. Most genetic predisposition of MODY has been identified in European and American populations. A large number of Chinese individuals are misdiagnosed due to defects of unknown genes. In this study, we analyzed the genetic and clinical characteristics of the Northern China. A total of 200 diabetic patients, including 10 suspected MODY subjects, were enrolled, and the mutational analysis of monogenic genes was performed by whole-exome sequencing and confirmed by familial information and Sanger sequencing. We found that clinical features and genetic characteristics have varied widely between MODY and other diabetic subjects in Northern China. FOXM1, a key molecule in the proliferation of pancreatic β-cells, has a rare mutation rs535471991, which leads to instability within the phosphorylated domain that impairs its function. Our findings indicate that FOXM1 may play a critical role in MODY, which could reduce the misdiagnose rate and provide promising therapy for MODY patients.

Highlights

Maturity-onset diabetes of the young (MODY) is a kind of monogenic diabetes mellitus that is characterized by early-onset, autosomal dominant, non-insulin dependent diabetes
Multiple susceptibility genes involved in diabetes, T1DM or T2DM, presented a distinguishing feature of polygenic inheritance and differed from maturity-onset diabetes of the young (MODY) or neonatal diabetes mellitus (NDM), since whole-exome sequencing (WES) could provide an accurate molecular diagnosis for monogenic disease
We found that BMI, fasting plasma glucose (FPG), C-peptide, and HbA1c had a significant difference between suspected MODY patients and T2DM, while no difference was observed with T1DM

Summary

Introduction

Maturity-onset diabetes of the young (MODY) is a kind of monogenic diabetes mellitus that is characterized by early-onset, autosomal dominant, non-insulin dependent diabetes. Pancreatic bcell dysfunction reduces glucose-stimulated insulin secretion during early age due to monogenic variation [1, 2]. 14 genes (HNF4A, GCK, HNF1A, PDX1, TCF2, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11, and APPL1) have been identified, and their mutations are responsible for the initiation of MODY [3,4,5]. Despite previous intensive linkage analyses for MODY, there are still diagnosed cases. WES Analysis for MODY that remain genetically inexplicable [6]. Different studies suggest that the prevalence of specific mutations of MODY genes differs considerably among various ethnic groups [7]. Without characteristic features and pedigreed awareness, most MODY patients are misdiagnosed with type 1 or type 2 diabetes in Chinese populations, who may potentially receive inappropriate therapy

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