A novel gene for MODY?

Abstract

Maturity-onset diabetes of the young (MODY) arises from autosomal dominant mutations in one of 13 established genes affecting beta cell function. Most MODY cases are missed; even when suspected clinically with comprehensive genetic screening, >10% will not have a genetic diagnosis. This suggests as yet unknown genetic causes. Whole exome sequencing (WES) allows simultaneous screening of known MODY genes and gene discovery. We identified a family with clinical features of MODY, through a non-obese proband with antibody-negative diabetes whose identical twin sister, mother, maternal aunt and maternal grandmother also had diabetes. The proband, her maternal aunt, grandmother and unaffected brother underwent WES. After quality control, data were filtered for novel coding variants segregating. Additionally variants were filtered according to conservation (genomic evolutionary rating profile [GERP] score >2) and protein prediction algorithms (predicted to be deleterious/ damaging by SIFT, Mutation Taster and/or Polyphen). No variants were identified in known MODY genes. Two variants were identified, in KCNK16 and USP42. KCNK16 has a known role in insulin secretion; the only known role for USP42 is in spermatogenesis. The KCNK16A variant (c.341T>C, p.Leu114Pro) was novel (not present in ExAC, LOVD, ClinVar, HGMD); affects a highly conserved region (GERP score 5.65); and is predicted to be damaging. KCNK16 encodes a potassium channel on the pancreatic beta cell which creates an outwardly-rectifying potassium current, regulating calcium influx and insulin secretion. A mouse model with a gain-of-function variant (rs1535500, associated with diabetes in multiple type 2 diabetes GWAS) had a similar phenotype to our family. This channel does not respond to the usual stimuli of KATP channels of the islet cell. Thus KNCK16 appears a very strong candidate for a novel MODY gene. If confirmed, this discovery may lead to new therapeutic approaches for this subtype of diabetes.L6190422592017-11-07 <br />