Digenic HNF1A and ABCC8 variants provide mechanistic insight into early-onset diabetes.
Makie Honda, Ryo Honda, Teiko Komori Nomura et al.
✦ AI-curated · Sources linked
From the abstract
Oligogenic inheritance in maturity-onset diabetes of the young (MODY) remains poorly characterized, and the contribution of multiple candidate variants to disease pathogenesis is incompletely understood. To investigate the pathogenicity and mechanistic contribution of multiple MODY gene variants identified in a MODY-like family and determine their role in early-onset diabetes.
Reported results
Four variants in 3 MODY genes were identified in the proband: novel HNF1A p.Ser551Lysfs*2, HNF1B p.Glu102Ala, and ABCC8 p.Arg298Cys and p.Arg521Gln. Functional analysis showed that HNF1A p.Ser551Lysfs*2 retained approximately 5% of wild-type transactivation activity, consistent with loss-of-function, whereas HNF1B p.Glu102Ala and ABCC8 p.Arg521Gln exhibited wild-type-like function.
Authors' conclusions
Functional characterization distinguishes pathogenic from variants of unknown significance and supports digenic inheritance of HNF1A and ABCC8. Their additive effects, together with intrauterine hyperglycemia, likely accelerated disease onset. This study provides mechanistic evidence for oligogenic contributions to MODY and expands the genetic architecture of early-onset diabetes.