Molecular Genetic Mechanism Research Of Liddle Syndrome Caused By A Novel SCNN1B Missense Mutation

BackgroundLiddle syndrome(LS)is an autosomal dominant inherited monogenic hypertension syndrome,mainly manifests as early-onset refractory hypertension,hypokalemia and metabolic alkalosis,accompanied with lower plasma renin concentration and lower plasma aldosterone concentration.The symptoms of LS are sensitive to blockers of sodium channel such as amiloride.The mechanism of LS is related to mutations of genes which encode three subunits of epithelial sodium channel(ENaC):SCNN1A,SCNN1B and SCNN1G.Due to the long-term hypertension of the patients,the risk of suffering from injury of target organs or sudden death is rising.Therefore,timely diagnosis and tailored treatments are important for patients with Liddle syndrome.Genetic diagnosis contributes for the improvement of diagnosis for Liddle syndrome.AimOur research aimed to discover the mutation in a family diagnosed with Liddle syndrome by gene detection,and to confirm pathogenicity of the mutation,in purpose to accurate diagnosis,targeted therapy and improvement of the prognosis of patients.MethodsThe research involved a family with history of early-onset hypertension,including the proband and 11 additional relatives.We collected medical history of the patients and measured their blood pressure,serum potassium,plasma renin concentration and aldosterone concentration.DNA samples were collected from the patients.Candidate variants were selected in the proband by next-generation sequencing,and then verified in other relatives.The control group consisted of 100 sporadic hypertensives and 100 health in order to exclude genetic polymorphism.Patients were treated with low-sodium diet and amiloride.ResultsGenetic testing was performed to the proband and indicated a novel missense mutation in SCNN1B(c.1849C>A).The mutation of SCNN1B resulted in a substitution of threonine instead of proline at codon 617,which altered the PY motif of the ? subunit of ENaC,obstructed the process of inactivation and degradation of ENaC,and resulted in LS.Excluding the proband,the variant was detected in the other 5 relatives with hypertension.Analyses indicated that this variant was highly pathogenic.Phenotypic heterogeneity was presented among all 6 patients in this family.After tailored treatment of amiloride,their hypertension was controlled effectively.Serum potassium concentration was improving as a consequence of the treatment.ConclusionWe identified a novel missense mutation(c.1849C>A)in SCNN1B in a family affected by LS.Clinical features and genetic evidence are both considerable in diagnosis of LS.For first-degree relatives of patients diagnosed with LS,gene detection is necessary.LS increases the risk of complications such as premature stroke,especially in patients with severe hypertension.Research about molecular genetics mechanisms of LS may contribute to timely diagnosis and tailored treatment,reduce the risk of severe complications,and finally improve the prognosis of the patients.