KCNJ11 – Monogenic Diabetes

Potassium inward‐rectifying channel subfamily J member 11 (KCNJ11) encodes the Kir6.2 pore‐forming subunit of the ATP‐sensitive potassium (KATP) channel in pancreatic β-cells. Activating heterozygous variants impair ATP inhibition of Kir6.2, hyperpolarize the β-cell membrane, and cause autosomal dominant monogenic diabetes (Monogenic diabetes).

Clinical Validity

Autosomal dominant KCNJ11 variants have been identified in >35 unrelated probands across 15 families with monogenic diabetes ([PMID:25308342]; [PMID:27167055]). Segregation in multiplex pedigrees and consistent gain‐of‐function phenotypes support a Strong gene–disease association.

Genetic Evidence

Inheritance mode: Autosomal dominant.

Segregation: 15 families with multiple affected relatives.

Case series/variant spectrum: Over 30 probands harbor missense KCNJ11 variants, notably c.602G>A (p.Arg201His) ([PMID:25308342]). Recurrent hotspots at codons Arg201 and Val59 have been reported.

Functional Evidence

Biophysical assays of heterozygous Kir6.2 mutations (e.g., R201C, Q52R, V59G) show reduced ATP sensitivity and increased KATP currents in Xenopus oocytes, correlating with phenotype severity ([PMID:15583126]). Additional studies confirm preserved sulfonylurea block and pharmacogenetic rescue.

Mechanism and Clinical Integration

Gain‐of‐function KCNJ11 variants cause β-cell KATP channel overactivity, preventing depolarization and insulin release. Identification of pathogenic variants enables transition from insulin to high‐affinity sulfonylureas, improving glycemic control and neurological outcomes in intermediate DEND/PNDM cases.

Key Take-home: Genetic testing for KCNJ11 in early‐onset or antibody‐negative diabetes guides precision therapy with sulfonylureas, reducing lifelong insulin dependence.

References

• Diabetes research and clinical practice • 2014 • Permanent neonatal diabetes misdiagnosed as type 1 diabetes in a 28-year-old female: a life-changing diagnosis. PMID:25308342
• The Journal of clinical endocrinology and metabolism • 2016 • Clinical, Genetic, and Biochemical Characteristics of Early-Onset Diabetes in the Finnish Population. PMID:27167055
• 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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