Mutations in KCNJ11 are associated with the development of autosomal dominant, early-onset type 2 diabetes

Abstract

Aims/hypothesis More than 90% of Chinese familial early-onset type 2 diabetes mellitus is genetically unexplained. To investigate the molecular aetiology, we identified and characterised whether mutations in the KCNJ11 gene are responsible for these families. Methods KCNJ11 mutations were screened for 96 familial early-onset type 2 diabetic probands and their families. Functional significance of the identified mutations was confirmed by physiological analysis, molecular modelling and population survey. Results Three novel KCNJ11 mutations, R27H, R192H and S116F117del, were identified in three families with early-onset type 2 diabetes mellitus. Mutated KCNJ11 with R27H or R192H markedly reduced ATP sensitivity (E23K>R27H>C42R>R192H>R201H), but no ATP-sensitive potassium channel currents were detected in the loss-of-function S116F117del channel in vitro. Molecular modelling indicated that R192H had a larger effect on the channel ATP-binding pocket than R27H, which may qualitatively explain why the ATP sensitivity of the R192H mutation is seven times less than R27H. The shape of the S116F117del channel may be compressed, which may explain why the mutated channel had no currents. Discontinuation of insulin and implementation of sulfonylureas for R27H or R192H carriers and continuation/switch to insulin therapy for S116F117del carriers resulted in good glycaemic control. Conclusions/interpretation Our results suggest that genetic diagnosis for the KCNJ11 mutations in familial early-onset type 2 diabetes mellitus may help in understanding the molecular aetiology and in providing more personalised treatment for these specific forms of diabetes in Chinese and other Asian patients.

DNA methylation of candidate genes in peripheral blood from patients with type 2 diabetes or the metabolic syndrome

“…For example, methylation of one locus in the KCNJ11 gene was significantly higher in the MetS group than in the T2D group and was tending towards significance compared to the control group. Genetic defects in the KCNJ11 gene have been previously associated with an increased risk of diabetic disorders and heart failure, by inducing changes in the heart's response to stress[34,35]. In line with these reports, we could speculate that the elevated levels of DNA methylation in the MetS patient group for this KCNJ11 CpG locus may mimic the genetic defects in the KCNJ11 gene.…”

Molecular and phenotypic characteristics of maturity‐onset diabetes of the young compared with early onset type 2 diabetes in China

“…Specifically, HNF1α/MODY3 and KCNJ11/MODY13 were the two most frequent polymorphisms, indicating that these two genes seem to be the most possible common MODY genes identified in the Chinese population so far. 6,19,20 It is of note that most of the polymorphisms detected in the present study have been reported to be associated with T2D. The I27L polymorphism is associated with insulin resistance 21 and both the I27L and S486N variations of HNF1α have been associated with multiple cardiovascular risk phenotypes in the general population of European Americans.…”

“…Although no mutations were identified in the patients, different polymorphisms were found, and those polymorphisms affected only five MODY genes: HNF1α /MODY3, CEL/ MODY8, PAX4 /MODY9, ABCC8 /MODY12, and KCNJ11 /MODY13. Specifically, HNF1α /MODY3 and KCNJ11 /MODY13 were the two most frequent polymorphisms, indicating that these two genes seem to be the most possible common MODY genes identified in the Chinese population so far …”

Epidemiology, clinical characteristics, and genetic etiology of neonatal diabetes in Japan

“…They emphasize mutation screening, at least of INS , for Japanese patients diagnosed as autoantibody negative at <5 years of age. We further reported that not only NDM but also early‐ and adult‐onset diabetes might be caused by KCNJ11 mutation . All of these data taken together suggest that onset of monogenic NDM is not limited to the first 6 months of life, and that, as a result of the causal gene mutations, diabetes could occur at any time of life.…”