KCNJ11 – KCNJ11-related Maturity-Onset Diabetes of the Young (MODY13)

KCNJ11 encodes the Kir6.2 subunit of the ATP-sensitive potassium (KATP) channel, a key regulator of pancreatic β-cell membrane potential and insulin secretion. Heterozygous gain-of-function variants in KCNJ11 reduce ATP inhibition of the channel, impairing glucose-stimulated insulin release and leading to a dominantly inherited form of maturity-onset diabetes of the young (MODY13). This association has been replicated in multiple unrelated families over >10 years, with concordant in vitro electrophysiology and successful precision therapy.

MODY13 follows an autosomal dominant inheritance pattern with high penetrance. A four-generation French pedigree showed co-segregation of the c.679G>A (p.Glu227Lys) variant with diabetes (LOD 3.68) (PMID:22701567), a father–son pair harbored c.685G>A (p.Glu229Lys) with vertical transmission (PMID:36181023), and a de novo case confirmed pathogenicity in a 24-year-old patient (PMID:39700334). In total, at least four affected relatives have been documented with segregating KCNJ11 variants in MODY13 pedigrees.

Molecular genetic evidence is robust: KCNJ11-MODY variants are heterozygous, gain-of-function missense changes clustered near the ATP-binding site. The prototypic c.679G>A (p.Glu227Lys) variant meets ClinGen genetic criteria, having been identified in three families with co-segregation and reaching the genetic evidence cap. Genetic testing for KCNJ11 should be included in MODY gene panels to capture this rare subtype.

Functional studies in Xenopus oocytes and mammalian cells demonstrate that MODY13 variants reduce ATP sensitivity and increase resting KATP currents. For example, R201C, Q52R and V59G Kir6.2 mutations show diminished ATP inhibition and enhanced MgATP activation, linking channel hyperactivity to β-cell hyperpolarization and diabetes (PMID:15583126; PMID:15579781). This mechanistic concordance underpins the pathogenic classification.

Clinically, KCNJ11-MODY patients often present in adolescence or early adulthood with non-insulin-dependent diabetes and elevated HbA1c. Sulfonylurea therapy (e.g., glibenclamide, gliclazide) effectively closes mutant KATP channels, restoring insulin secretion and permitting insulin withdrawal in most cases. Precision treatment based on KCNJ11 genotype improves glycemic control and quality of life.

In summary, autosomal dominant KCNJ11 gain-of-function variants cause MODY13 through impaired ATP-dependent channel inhibition. Strong genetic segregation across three pedigrees, concordant electrophysiology, and sulfonylurea responsiveness provide a solid basis for diagnosis and targeted therapy. Genetic screening for KCNJ11 in suspected MODY patients enables personalized management and informs familial risk.

References

• PLoS One • 2012 • Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene. PMID:22701567
• 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
• Endocrinology, diabetes & metabolism case reports • 2024 • Challenges in diagnosis and treatment of KCNJ11-MODY. PMID:39700334
• Proceedings of the National Academy of Sciences of the United States of America • 2004 • Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features. PMID:15583126
• The Journal of Clinical Endocrinology and Metabolism • 2004 • Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity. PMID:15579781

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