KCNJ10 – EAST syndrome

EAST syndrome (Epilepsy, Ataxia, Sensorineural deafness, and Tubulopathy) is an autosomal recessive disorder caused by biallelic mutations in KCNJ10, encoding the Kir4.1 inwardly rectifying potassium channel. Clinically, affected individuals present in infancy with tonic–clonic seizures, non-progressive cerebellar ataxia, sensorineural hearing loss, and renal salt-wasting tubulopathy (hypokalemia, metabolic alkalosis) (Seizure, HP:0001250; Ataxia, HP:0001251; Sensorineural hearing impairment, HP:0000407; Intellectual disability, HP:0001249).

Genetic studies have identified over 50 unrelated probands across more than seven families, each harboring homozygous or compound heterozygous loss-of-function variants in KCNJ10 ([PMID:19289823], [PMID:27652280], [PMID:23924083]). Recurrent and founder mutations such as p.Arg65Pro in Pakistani kindreds and diverse truncating alleles, including c.321_322del (p.Val109fs), segregate with disease in large multiplex pedigrees, supporting pathogenicity and autosomal recessive inheritance.

Variant spectrum encompasses missense (e.g., p.Arg199Ter), nonsense, frameshift (c.321_322del (p.Val109fs)), and splice-site changes, with at least 16 distinct pathogenic alleles reported to date ([PMID:29722015]). Founder analysis demonstrates a 500-year origin for p.Arg65Pro in Pakistani patients ([PMID:27652280]).

Functional assays in heterologous systems reveal that disease-associated KCNJ10 mutations markedly reduce K+ currents, disrupt PIP2 binding, and impair Kir4.1 membrane localization. Xenopus oocyte recordings show residual activity of some alleles but complete loss in others ([PMID:20651251], [PMID:21849804]). Knockdown in zebrafish recapitulates epilepsy, ataxia, and renal defects, and rescue with human wild-type—but not mutant—KCNJ10 cRNA confirms pathogenicity ([PMID:23471908]). Mouse glia-specific knockout models exhibit delayed K+ clearance and epileptiform activity, mirroring human seizures ([PMID:21748805]).

No credible conflicting evidence has been reported. The convergence of robust segregation, consistent phenotype across diverse populations, and concordant functional data meets ClinGen criteria for a definitive gene–disease relationship.

Key Take-home: Biallelic KCNJ10 loss-of-function mutations cause EAST syndrome via impaired Kir4.1-mediated K+ buffering; genetic testing for KCNJ10 should be incorporated into diagnostic panels for early-onset epilepsy, ataxia, hearing loss, and tubulopathy.

References

• Proceedings of the National Academy of Sciences of the United States of America • 2009 • Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10 PMID:19289823
• Molecular Genetics & Genomic Medicine • 2016 • Founder mutation in KCNJ10 in Pakistani patients with EAST syndrome PMID:27652280
• Developmental Medicine and Child Neurology • 2013 • Neurological features of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome PMID:23924083
• Disease Models & Mechanisms • 2013 • Generation and validation of a zebrafish model of EAST syndrome PMID:23471908
• Proceedings of the National Academy of Sciences of the United States of America • 2010 • KCNJ10 gene mutations causing EAST syndrome disrupt channel function PMID:20651251
• Journal of the American Society of Nephrology • 2009 • Molecular basis of decreased Kir4.1 function in SeSAME/EAST syndrome PMID:21088294

Evidence Based Scoring (AI generated)