SCNN1G – Liddle Syndrome

Liddle syndrome is an autosomal dominant monogenic hypertension caused by gain-of-function mutations in the epithelial sodium channel γ-subunit (SCNN1G), leading to increased sodium and water reabsorption in the distal nephron and resulting in early-onset salt-sensitive hypertension and hypokalemia ([PMID:28396810]).

Multiple heterozygous SCNN1G variants have been described in at least 86 families (268 patients) with Liddle syndrome, demonstrating consistent segregation of pathogenic alleles in affected relatives and reinforcing a definitive gene–disease relationship ([PMID:38265765]). Notably, a Russian family harbors a novel frameshift mutation c.1769del (p.Gly590AlafsTer9), segregating with hypertension and hypokalemia in the proband, father, and sister ([PMID:31655555]).

Pathogenic variants in SCNN1G predominantly disrupt the C-terminal PPPxY (PY) motif, critical for channel ubiquitination. These include frameshift mutations (e.g., p.Gly590AlafsTer9; p.Arg586ValfsTer598), nonsense variants (p.Gln591Ter; p.Glu571Ter), and missense substitutions (p.Pro625Leu) that all prevent normal channel downregulation ([PMID:31655555]; [PMID:30977777]; [PMID:32161960]).

Clinically, 97% of adult carriers exhibit hypertension responsive to ENaC inhibitors, while hypokalemia and metabolic alkalosis show incomplete penetrance (58% and 45%, respectively). Normokalemic presentations have also been reported, underscoring phenotypic heterogeneity ([PMID:38265765]; [PMID:30977777]).

Functional studies corroborate a gain-of-function mechanism: the Cys479Arg missense mutation increases amiloride-sensitive currents twofold in Xenopus oocytes ([PMID:28710092]), and truncating γ-ENaC variants display elevated channel activity in CHO cell patch-clamp assays (p.Glu571Ter, P<0.05) ([PMID:35685915]).

Targeted therapy with ENaC blockers—amiloride or triamterene—consistently normalizes blood pressure and corrects electrolyte disturbances in adult, pregnant, and pediatric patients, demonstrating clear clinical utility of genetic diagnosis for tailored management ([PMID:28396810]; [PMID:32161960]).

Key Take-home: Definitive SCNN1G gain-of-function variants cause Liddle syndrome, and genetic testing enables precise diagnosis and effective ENaC inhibitor therapy to prevent end-organ damage.

References

• Case reports in obstetrics and gynecology • 2017 • Management of Liddle Syndrome in Pregnancy: A Case Report and Literature Review PMID:28396810
• Journal of the American Society of Nephrology : JASN • 2017 • A Missense Mutation in the Extracellular Domain of γENaC Causes Liddle Syndrome PMID:28710092
• BMC Nephrology • 2019 • Liddle syndrome due to a novel mutation in the γ subunit of the epithelial sodium channel (ENaC) in family from Russia: a case report PMID:31655555
• American Journal of Hypertension • 2019 • A Novel Frameshift Mutation of SCNN1G Causing Liddle Syndrome with Normokalemia PMID:30977777
• American Journal of Hypertension • 2020 • Pediatric Liddle Syndrome Caused by a Novel SCNN1G Variant in a Chinese Family and Characterized by Early-Onset Hypertension PMID:32161960
• Nephron • 2022 • A Family with Liddle Syndrome Caused by a Novel Stop-Gain Mutation in the γ Subunit of Epithelial Sodium Channels PMID:35661050
• Clinical Journal of the American Society of Nephrology : CJASN • 2024 • Reverse Phenotypes of Patients with Genetically Confirmed Liddle Syndrome PMID:38265765

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