2010/05/27 by Vikas Bansal, Bernhard R. Winkelmann, Johannes W. Dietrich +2 · 1 voice
Medicine · Social Sciences · #Cardiac electrophysiology and arrhythmias #Cardiomyopathy and Myosin Studies #French Urban and Social Studies #Human Rights and Immigration #Pancreatic function and diabetes
paper · pdf · doi:10.3389/fendo.2024.1258982
openalex publication_date 2010/05/27 · openalex created_date 2016/06/24 · openalex updated_date 2026/07/23
Genome-wide association studies have identified several hundred loci associated with type 2 diabetes mellitus (T2DM). Additionally, pathogenic variants in several genes are known to cause monogenic diabetes that overlaps clinically with T2DM. Whole-exome sequencing of related individuals with T2DM is a powerful approach to identify novel high-penetrance disease variants in coding regions of the genome. We performed whole-exome sequencing on four related individuals with T2DM - including one individual diagnosed at the age of 33 years. The individuals were negative for mutations in monogenic diabetes genes, had a strong family history of T2DM, and presented with several characteristics of metabolic syndrome. A missense variant (p.N2291D) in the type 2 ryanodine receptor (<i>RyR2)</i> gene was one of eight rare coding variants shared by all individuals. The variant was absent in large population databases and affects a highly conserved amino acid located in a mutational hotspot for pathogenic variants in Catecholaminergic polymorphic ventricular tachycardia (CPVT). Electrocardiogram data did not reveal any cardiac abnormalities except a lower-than-normal resting heart rate (< 60 bpm) in two individuals - a phenotype observed in CPVT individuals with <i>RyR2</i> mutations. RyR2-mediated Ca<sup>2+</sup> release contributes to glucose-mediated insulin secretion and pathogenic <i>RyR2</i> mutations cause glucose intolerance in humans and mice. Analysis of glucose tolerance testing data revealed that missense mutations in a CPVT mutation hotspot region - overlapping the p.N2291D variant - are associated with complete penetrance for glucose intolerance. In conclusion, we have identified an atypical missense variant in the <i>RyR2</i> gene that co-segregates with diabetes in the absence of overt CPVT.