Liddle syndrome misdiagnosed as primary aldosteronism resulting from a novel frameshift mutation of SCNN1B

Fan, Peng; Lu, Chaoxia; Zhang, Di; Yang, Kun; Lu, Peipei; Zhang, Ying; Meng, Xu; Hao, Sufang; Luo, Fang; Liu, Yaxin; Zhang, Huimin; Song, Lingyun; Cai, Jun; Zhang, Xue; Zhou, Xin

doi:10.1530/ec-18-0484

Cited by 9 publications

(6 citation statements)

References 29 publications

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“…In our study, all LS patients had hypokalemia and hypoaldosteronism, but renin levels varied greatly. These results are consistent with those of a previous study showing that a low renin concentration is not a necessary presentation in LS patients [25]. Carriers of the Pro617Leu mutation presented normal plasma potassium concentrations and suppression of both renin and aldosterone in a family [26].…”

Section: Discussionsupporting

confidence: 92%

“…In this study, the proband presented a hemorrhagic stroke. Some patients with severe complications were diagnosed with LS when pathogenic mutations were identified in their first-degree relatives [25]. Excluding other causes leading to hypertension, LS should be considered in all cases of early-onset hypertension, irrespectively of hypokalemia, low renin levels, and family history.…”

Section: Discussionmentioning

confidence: 99%

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Premature Stroke Secondary to Severe Hypertension Results from Liddle Syndrome Caused by a Novel SCNN1B Mutation

Fan

Zhang

Pan

et al. 2020

Kidney Blood Press Res

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Introduction: Liddle syndrome (LS), an autosomal dominant and inherited monogenic hypertension syndrome caused by pathogenic mutations in the epithelial sodium channel (ENaC) genes SCNN1A, SCNN1B, and SCNN1G. Objective: This study was designed to identify a novel SCNN1B missense mutation in a Chinese family with a history of stroke, and to confirm that the identified mutation is responsible for LS in this family. Methods: DNA samples were collected from the proband and 11 additional relatives. Next-generation sequencing was performed in the proband to find candidate variants. In order to exclude genetic polymorphism, the candidate variant in SCNN1B was verified in other family members, 100 hypertensives, and 100 healthy controls by Sanger sequencing. Results: Genetic testing revealed a novel and rare heterozygous variant in SCNN1B in the proband. This variant resulted in a substitution of threonine instead of proline at codon 617, altering the PY motif of β-ENaC. The identified mutation was only verified in 5 relatives. In silico analyses indicated that this variant was highly pathogenic. In this family, phenotypic heterogeneity was present among 6 LS patients. Tailored medicine with amiloride was effective in controlling hypertension and improving the

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Premature Stroke Secondary to Severe Hypertension Results from Liddle Syndrome Caused by a Novel SCNN1B Mutation

Fan

Zhang

Pan

et al. 2020

Kidney Blood Press Res

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“…Phenotypic variability is common in the clinical and biochemical characteristics of Liddle syndrome, and this was also observed in this study ( 35 , 36 ). The blood pressure level, degree of hypokalemia, therapeutic effect of amiloride, and targeted organ damage were the key features in the heterogeneity analysis ( 22 , 27 ).…”

Section: Discussionsupporting

confidence: 85%

A Novel Frame-Shift Mutation in SCNN1B Identified in a Chinese Family Characterized by Early-Onset Hypertension

Liu²,

Zhou³

et al. 2022

Front. Cardiovasc. Med.

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BackgroundLiddle syndrome is a form of monogenic hypertension caused by mutations in the three homologous subunits of the epithelial sodium channels (ENaCs), α, β, and γ. It is characterized by early-onset refractory hypertension, hypokalemia, low renin activity, and hypoaldosteronism. In this study, we report a novel frame-shift mutation in SCNN1B responsible for Liddle syndrome in a Chinese family.MethodsDNA samples were collected from all participants. Whole-exome sequencing was performed in the proband to detect possible causative variants. Sanger sequencing was then conducted in the other family members to verify the candidate variant, and in 100 patients with hypertension and 100 normotensive controls to exclude population genetic polymorphism.ResultsWe identified a novel frame-shift mutation (c.1691_1693delinsG) in SCNN1B that was responsible for Liddle syndrome in this family. This mutation leads to the substitution of Arg in place of Gln at codon site 564 and generates a new stop codon at 592, influencing the crucial PY motif and resulting in reduced inactivation of the ENaCs. Aside from the proband, eight family members carried the mutation. Intra-familial phenotypic heterogeneity was observed in the blood pressure and serum potassium levels. Amiloride therapy combined with a low sodium diet is effective to alleviate the symptoms of patients with Liddle syndrome.Conclusionc.1691_1693delinsG, a novel frame-shift mutation in the β subunit of ENaC, was identified in a Chinese family with Liddle syndrome by whole-exome sequencing. Phenotypic heterogeneity can make diagnosis of Liddle syndrome difficult on the basis of clinical or biochemical characteristics alone. Genetic analysis is a useful tool allowing timely and accurate diagnosis of Liddle syndrome and playing a guiding role in precise treatment of the disease.

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“…Genetic sequencing is recommended for LS screening for SCNN1A , SCNN1B , and SCNN1G mutations, especially in families with a history of early-onset hypertension ( 3 ). Through family screening, it often screens for children who carried mutations in family ( 11 , 14 ). Genetic sequencing screened LS patients, but the pathogenicity of most variants has not been verified by functional experiments.…”

Section: Introductionmentioning

confidence: 99%

Pathogenicity and Long-Term Outcomes of Liddle Syndrome Caused by a Nonsense Mutation of SCNN1G in a Chinese Family

Zhang

Dong

et al. 2022

Front. Pediatr.

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ObjectiveLiddle syndrome (LS) is a monogenic hypertension consistent with autosomal dominant inheritance, often with early onset high blood pressure in childhood or adolescence. This study aimed to identify the pathogenicity of a nonsense mutation in SCNN1G in a Chinese family with LS and the long-term outcomes of tailored treatment with amiloride.MethodsTo explore the pathogenicity of candidate variant reported in 2015 by our team, we constructed mutant and wild-type models in vitro and measured amiloride-sensitive current in Chinese Hamster Ovary (CHO) cells using patch clamp technique. Participants were followed up for 7 years after tailored treatment with amiloride.ResultsA nonsense variant was detected in six members, two of whom were pediatric patients. This mutation 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 all patients with normal cardiorenal function, and no adverse events occurred during follow-up.ConclusionWe found the pathogenicity of a nonsense SCNN1G mutation (p.Glu571*) with enhanced amiloride-sensitive currents in a LS family with young patients. Tailored treatment with amiloride may be an effective strategy for the long-term control of blood pressure and protection from target organ damage or cardiovascular events, including children and youth patients with LS.

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Liddle syndrome misdiagnosed as primary aldosteronism resulting from a novel frameshift mutation of SCNN1B

Cited by 9 publications

References 29 publications

Premature Stroke Secondary to Severe Hypertension Results from Liddle Syndrome Caused by a Novel SCNN1B Mutation

Premature Stroke Secondary to Severe Hypertension Results from Liddle Syndrome Caused by a Novel SCNN1B Mutation

A Novel Frame-Shift Mutation in SCNN1B Identified in a Chinese Family Characterized by Early-Onset Hypertension

Pathogenicity and Long-Term Outcomes of Liddle Syndrome Caused by a Nonsense Mutation of SCNN1G in a Chinese Family

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