PATHOGENICITY AND LONG-TERM OUTCOMES OF LIDDLE SYNDROME CAUSED BY A NONSENSE MUTATION OF SCNN1G IN A CHINESE FAMILY

Abstract

Objective: Liddle syndrome (LS) is a common monogenic hypertension with continuous activation of epithelial sodium channels (ENaCs) encoded by SCNN1A, SCNN1B, and SCNN1G. This study aimed to identify the pathogenicity of a nonsense mutation in SCNN1G in a Chinese family with LS and the outcomes of tailored treatment with amiloride. Design and method: Clinical data were collected from six family members and this mutation site was reported by our team at 2015. To explore the pathogenicity of candidate variants, we constructed mutant and wild-type models in vitro and measured amiloride-sensitive current in Chinese Hamster Ovary cells using patch clamp technique. Participants were followed up for 6 years to monitor their target organ damage after tailored treatment with amiloride. Results: Four family members presented with severe hypertension and hypokalemia, and two had stroke. This nonsense variant resulted in a termination codon at codon 572, truncating the Pro-Pro-Pro-X-Tyr motif. The mutant epithelial sodium channels displayed higher amiloride-sensitive currents than the wild-type channels (P < 0.05). Tailored treatment with amiloride achieved ideal blood pressure control in the patients, and no adverse events occurred during follow-up. Conclusions: We found the pathogenicity of a nonsense SCNN1G mutation (p.Glu571*) with enhanced amiloride-sensitive currents in a LS family. Tailored treatment with amiloride may be an effective strategy for the long-term control of blood pressure and the prevention of cardiovascular events in these patients.