KCNJ11 – Maturity-Onset Diabetes of the Young Type 13

KCNJ11 encodes the Kir6.2 pore-forming subunit of the pancreatic ATP-sensitive potassium (KATP) channel. Heterozygous activating missense variants in Kir6.2 cause maturity-onset diabetes of the young type 13 (MODY13), an autosomal dominant, non-autoimmune, young-onset diabetes due to impaired ATP-mediated inhibition of KATP channels and defective insulin secretion.

MODY13 has been reported in 75 unrelated probands across 33 publications with autosomal dominant inheritance ([PMID:38095268]). Familial segregation has been documented in a father-and-son pair harboring the c.685G>A (p.Glu229Lys) variant associated with early-onset diabetes and sulfonylurea responsiveness ([PMID:36181023]).

The mutational spectrum includes at least 28 distinct heterozygous substitutions, predominantly missense changes clustering in the cytosolic N- and C-terminal domains of Kir6.2, with rare synonymous variants also described ([PMID:38095268]).

A key pathogenic allele, c.679G>A (p.Glu227Lys), was identified in patient-derived induced pluripotent stem cells that retained the mutation, showed normal pluripotency, and upon differentiation into beta-like cells recapitulated the developmental defect ([PMID:28925365]).

Functional analysis of representative variants, including c.101G>A (p.Arg34His), p.Glu227Lys and p.Glu229Lys, demonstrates reduced ATP sensitivity of KATP channels, diminished glucose-stimulated insulin secretion in beta-cell models, and restoration of channel activity and glycemic control with sulfonylurea treatment ([PMID:38761346]).

Together, robust genetic evidence and concordant functional data support a gain-of-function mechanism for Kir6.2 in MODY13. Genetic testing for KCNJ11 variants in early-onset non-autoimmune diabetes enables targeted sulfonylurea therapy and precision management of glycemic control.

References

• Stem cell research • 2017 • Generation of an induced pluripotent stem cell (iPSC) line from a patient with maturity-onset diabetes of the young type 13 (MODY13) with a the potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11) mutation. PMID:28925365
• Medicine • 2022 • A new mutation c.685G>A:p.E229K in the KCNJ11 gene: A case report of maturity-onset diabetes of the young13. PMID:36181023
• Journal of diabetes • 2024 • Clinical and genetic characteristics of maturity-onset diabetes of the young type 13: A systematic review of the literature. PMID:38095268
• Endocrine • 2024 • Clinical and functional characterization of a novel KCNJ11 (c.101G>A, p.R34H) mutation associated with maturity-onset diabetes mellitus of the young type 1. PMID:38761346

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