SCNN1A – Liddle syndrome

Liddle syndrome is an autosomal dominant monogenic hypertension disorder characterized by early-onset hypertension, hypokalemia, and metabolic alkalosis. Pathogenic variants in the SCNN1A gene encoding the α subunit of the epithelial sodium channel have been identified in affected individuals. Two unrelated probands harbor heterozygous missense variants c.1130T>G (p.Ile377Ser) (PMID:36336351) and c.1475G>A (p.Arg492Gln) (PMID:39236685). The c.1130T>G variant co-segregated with disease in a family with two additional affected relatives (the proband’s brother and son) ([PMID:39236685]). Both variants are predicted damaging by multiple in silico tools and structural modeling.

Functional modeling suggests that these amino acid substitutions disrupt key regulatory PY motifs in the extracellular loop of α-ENaC, promoting channel overactivity consistent with a gain-of-function mechanism. Clinical improvement with ENaC inhibitors (amiloride, triamterene) further supports pathogenicity. On the basis of two probands with familial segregation and concordant in silico data, the SCNN1A–Liddle syndrome association is classified as Limited. Routine SCNN1A sequencing is recommended in early-onset hypertension with hypokalemia to enable targeted ENaC-blocker therapy.

References

• Scandinavian journal of clinical and laboratory investigation • 2022 • Clinical and genetic characteristics of the patients with hypertension and hypokalemia carrying a novel SCNN1A mutation. PMID:36336351
• Kidney & blood pressure research • 2024 • Liddle Syndrome with a SCNN1A Mutation: A Case Report and Literature Review. PMID:39236685

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