KCNJ10 – Pendred Syndrome

The KCNJ10 gene encodes the Kir4.1 inward-rectifying potassium channel and has been investigated as a potential modifier in Pendred syndrome. In two unrelated probands, each carrying a single heterozygous KCNJ10 mutation (c.1042C>T (p.Arg348Cys) or c.581C>A (p.Pro194His)) in combination with a SLC26A4 allele, affected individuals presented with sensorineural hearing loss and enlarged vestibular aqueduct consistent with Pendred syndrome ([PMID:19426954]). However, a larger study of 68 Chinese patients with monoallelic SLC26A4 mutations found KCNJ10 variants p.Arg271Cys and p.Arg18Gln at polymorphic frequencies and no significant enrichment in cases versus controls, arguing against a major role for KCNJ10 in Pendred syndrome ([PMID:23965030]).

Functional analyses of KCNJ10 c.1042C>T (p.Arg348Cys) and c.581C>A (p.Pro194His) demonstrate markedly reduced K+ conductance in heterologous expression systems, and Slc26a4(+/–) mice exhibit decreased Kcnj10 protein expression in the stria vascularis, supporting a mechanistic interaction between pendrin and Kir4.1 ([PMID:19426954]). Despite this functional concordance, the limited number of digenic cases and lack of robust familial segregation yield only limited genetic validity. Key Take-home: KCNJ10 variants may modify Pendred syndrome phenotypes but are unlikely to be primary drivers of disease.

References

• American Journal of Human Genetics • 2009 • Mutations of KCNJ10 together with mutations of SLC26A4 cause digenic nonsyndromic hearing loss associated with enlarged vestibular aqueduct syndrome. PMID:19426954
• BMC Medical Genetics • 2013 • Lack of significant association between mutations of KCNJ10 or FOXI1 and SLC26A4 mutations in Pendred syndrome/enlarged vestibular aqueducts. PMID:23965030

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