SCNN1B – Liddle syndrome

SCNN1B encodes the β-subunit of the renal epithelial sodium channel (ENaC), and pathogenic variants in SCNN1B cause Liddle syndrome, an autosomal dominant form of early-onset hypertension characterized by hypokalemia, metabolic alkalosis, and suppressed plasma renin and aldosterone ([PMID:9100575]). Liddle syndrome results from truncating or missense mutations that delete or alter the conserved PPPxY (PY) motif in the C-terminus of β-ENaC, leading to impaired channel ubiquitination and increased amiloride-sensitive sodium transport.

Inheritance of Liddle syndrome is autosomal dominant. In the original kindred (K176), a frameshift mutation co-segregated with disease in 7 heterozygotes and 2 obligate carriers among 16 tested relatives, all of whom exhibited hypertension and variable hypokalemia ([PMID:9100575]). Follow-up across 86 families and 268 affected individuals has identified over 45 unique PY-motif variants, with consistent segregation in multiple pedigrees ([PMID:38265765]).

The mutation spectrum includes >15 missense changes (e.g., P615S, P616R) and >30 frameshifts (e.g., Arg564Ter, Pro613GlnfsTer675) clustering in exon 13 of SCNN1B ([PMID:9626162], [PMID:15483078], [PMID:25378078]). A recurrent founder allele c.1849C>T (p.Pro617Ser) has been reported in Japanese and Sicilian cohorts ([PMID:9626162], [PMID:21525970]).

Functional assays in Xenopus oocytes demonstrate that PY-motif missense mutants (e.g., c.1849C>T (p.Pro617Ser)) increase amiloride-sensitive sodium current by 3- to 8-fold compared to wild type, confirming a gain-of-function mechanism ([PMID:9626162], [PMID:15483078]). Frameshifts deleting the PY motif similarly abrogate channel inactivation ([PMID:25378078]).

Clinical features show variable expressivity, including left ventricular hypertrophy and premature stroke in a subset ([PMID:32698182]). Population screening of young hypertensive patients (aged 14–40 y) revealed a 1.52% prevalence of SCNN1B PY-motif mutations, underscoring the importance of genetic testing in hypokalemic, low-renin hypertension ([PMID:26075967]).

Early molecular diagnosis of SCNN1B mutations enables tailored therapy with ENaC inhibitors such as amiloride, normalizes blood pressure and serum potassium, and prevents long-term cardiovascular complications. Regional founder effects (e.g., βP617L in Calabria) further support focused screening in high-risk populations ([PMID:29229744]).

References

• The Journal of Clinical Endocrinology and Metabolism • 1997 • Liddle's syndrome: prospective genetic screening and suppressed aldosterone secretion in an extended kindred. PMID:9100575
• The Journal of Clinical Endocrinology and Metabolism • 1998 • A family with Liddle's syndrome caused by a new missense mutation in the beta subunit of the epithelial sodium channel. PMID:9626162
• Clinical Journal of the American Society of Nephrology • 2024 • Reverse Phenotypes of Patients with Genetically Confirmed Liddle Syndrome. PMID:38265765
• The Journal of Clinical Endocrinology and Metabolism • 2005 • Liddle's syndrome caused by a novel mutation in the proline-rich PY motif of the epithelial sodium channel beta-subunit. PMID:15483078
• Journal of Clinical Hypertension • 2015 • Prevalence of Liddle Syndrome Among Young Hypertension Patients of Undetermined Cause in a Chinese Population. PMID:26075967
• Kidney & Blood Pressure Research • 2020 • Premature Stroke Secondary to Severe Hypertension Results from Liddle Syndrome Caused by a Novel SCNN1B Mutation. PMID:32698182
• Hypertension • 2018 • Three Reportedly Unrelated Families With Liddle Syndrome Inherited From a Common Ancestor. PMID:29229744
• Clinical Endocrinology • 2015 • Liddle syndrome misdiagnosed as primary aldosteronism resulting from a novel frameshift mutation of SCNN1B. PMID:25378078

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