KCNJ6 – Keppen-Lubinsky syndrome

Autosomal dominant mutations in KCNJ6 have been identified in five unrelated individuals presenting with features of Keppen-Lubinsky syndrome, including global developmental delay and intellectual disability (PMID:29852244, PMID:36071510). All cases were sporadic, each harboring a de novo missense variant. Functional studies demonstrate a gain-of-function mechanism for these alleles, consistent with the neurological channelopathy phenotype.

Clinical Validity

The gene–disease association is classified as Strong based on five unrelated probands with de novo KCNJ6 variants and concordant functional data supporting pathogenicity. No familial segregation beyond the probands has been reported. Experimental evidence from both human variant assays and the murine weaver model (Gly156Ser) further corroborates the mechanistic link.

Genetic Evidence

All five reported probands carry heterozygous de novo missense variants in KCNJ6. Two recurrent substitutions have been described: c.512T>G (p.Leu171Arg) and c.460G>T (p.Gly154Cys). Each variant arose de novo in individuals with severe or mild global developmental delay, feeding difficulties, startle responses, compulsive behaviors, and intellectual disability (severe or mild). The absence of LoF, splice, or structural variants suggests a specific gain-of-function spectrum.

Functional Evidence

In vitro electrophysiology of GIRK2(p.Leu171Arg) channels reveals aberrant basal inward currents lacking G protein regulation, loss of K+ selectivity and acquisition of Ca2+ permeability, paralleling the murine weaver Gly156Ser phenotype (PMID:8706831). Molecular dynamics and patch-clamp analyses of GIRK2(p.Gly154Cys) confirm selectivity filter destabilization and altered gating. These data support a dominant gain-of-function mechanism.

Conflicting Evidence

No studies have refuted the pathogenic association of KCNJ6 variants with Keppen-Lubinsky syndrome. All functional assessments consistently demonstrate channel dysregulation in line with patient phenotypes.

Integration & Conclusion

Collectively, genetic and functional data establish a robust autosomal dominant gain-of-function mechanism for KCNJ6 in Keppen-Lubinsky syndrome. The clinical spectrum ranges from severe hyperkinetic movement disorders to milder startle phenotypes, expanding the diagnostic considerations. Future research may explore targeted therapies modulating GIRK2 channel activity.

Key Take-home: De novo gain-of-function KCNJ6 variants cause an autosomal dominant channelopathy underpinning Keppen-Lubinsky syndrome, with clear implications for molecular diagnosis and potential therapeutic targeting.

References

• Neuroscience • 2018 • Gain-of-function KCNJ6 Mutation in a Severe Hyperkinetic Movement Disorder Phenotype PMID:29852244
• Clinical genetics • 2023 • Expanding the spectrum of KCNJ6-related disorders: Milder phenotype with pathological startle responses PMID:36071510
• FEBS letters • 1996 • The weaver mutation changes the ion selectivity of the affected inwardly rectifying potassium channel GIRK2 PMID:8706831

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