KCNJ11 – DEND Syndrome

Heterozygous activating mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium channel, underlie permanent neonatal diabetes mellitus (PNDM). A subset of patients also display developmental delay and epilepsy, collectively termed DEND syndrome. Although rare, DEND syndrome represents the most severe phenotype spectrum of KCNJ11-associated diabetes and carries significant implications for neurological and metabolic management.

DEND syndrome follows an autosomal dominant pattern with de novo gain-of-function KCNJ11 variants in five unrelated probands (V59Met [PMID:19686306]; V59Ala [PMID:23382304]; 9-month old infant [PMID:28666500]; Arg50Pro [PMID:25678012]; Ile296Leu [PMID:15864298]), without evidence of multigenerational transmission. No additional affected relatives have been documented, underscoring the sporadic nature of these cases and the importance of early genetic testing in infants presenting with neonatal diabetes plus neurological features.

All reported DEND‐associated mutations are missense changes clustering in the slide helix (Val59) or ATP-binding regions (Arg50, Ile296). The recurrent variant c.175G>A (p.Val59Met) exemplifies this class and has been detected across independent cohorts. Phenotypic heterogeneity is evident: e.g., c.155A>G (p.Gln52Leu) affects the same ATP-binding site but causes isolated PNDM without neurological involvement ([PMID:24150202]), highlighting allele-specific effects.

Functional assessment in Xenopus oocytes demonstrates that DEND-associated mutations diminish ATP inhibition and increase baseline KATP currents. Severe phenotypes (e.g., p.Gln52Arg, p.Val59Gly) show larger reductions in ATP sensitivity than mutations causing PNDM alone, linking biophysical impact to clinical severity ([PMID:15583126], [PMID:15864298]). These in vitro data define a gain-of-function mechanism in neuronal and pancreatic contexts.

An nV59M neuronal mouse model recapitulates neurobehavioral alterations, including reduced anxiety and hyperactivity, mirroring human motor and cognitive dysfunction ([PMID:24582665]). Clinically, sulfonylurea therapy restores channel inhibition and has led to durable improvements in glycemic control and neurological function in patients with p.His46Leu ([PMID:17982434]) and p.Arg50Pro ([PMID:25678012]).

Integration of case reports and experimental studies establishes a strong causal relationship between autosomal dominant KCNJ11 gain-of-function variants and DEND syndrome. Early identification enables transition from insulin to sulfonylureas, offering targeted metabolic control and potential neurological benefit. Key Take-home: Extend KCNJ11 mutation screening to all infants with neonatal diabetes and developmental or seizure manifestations to guide precision sulfonylurea therapy.

References

• Pediatric diabetes • 2010 • Medical and developmental impact of transition from subcutaneous insulin to oral glyburide in a 15-yr-old boy with neonatal diabetes mellitus and intermediate DEND syndrome: extending the age of KCNJ11 mutation testing in neonatal DM. PMID:19686306
• Journal of pediatric endocrinology & metabolism • 2013 • DEND syndrome due to V59A mutation in KCNJ11 gene: unresponsive to sulfonylureas. PMID:23382304
• Journal of the College of Physicians and Surgeons--Pakistan • 2016 • Permanent Neonatal Diabetes (DEND Syndrome). PMID:28666500
• Diabetes research and clinical practice • 2015 • Successful transition to sulfonylurea in neonatal diabetes, developmental delay, and seizures (DEND syndrome) due to R50P KCNJ11 mutation. PMID:25678012
• EMBO reports • 2005 • A gating mutation at the internal mouth of the Kir6.2 pore is associated with DEND syndrome. PMID:15864298
• 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
• Nature clinical practice. Neurology • 2007 • Sulfonylurea improves CNS function in a case of intermediate DEND syndrome caused by a mutation in KCNJ11. PMID:17982434
• Physiology & behavior • 2014 • A mutation causing increased KATP channel activity leads to reduced anxiety in mice. PMID:24582665

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