A frameshift mutation in the <em>SCNN1B</em> gene in a family with Liddle syndrome: A case report and systematic review

Lu,Yiting; Liu,Xinchang; Sun,Lin; Zhang,Di; Fan,Peng; Yang,Kunqi; Zhang,Lin; Liu,Yaxin; Zhou,Xianliang

doi:10.3892/mmr.2023.13142

A frameshift mutation in the SCNN1B gene in a family with Liddle syndrome: A case report and systematic review

Authors:
- Yiting Lu
- Xinchang Liu
- Lin Sun
- Di Zhang
- Peng Fan
- Kunqi Yang
- Lin Zhang
- Yaxin Liu
- Xianliang Zhou
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Affiliations: Department of Cardiology, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, P.R. China, Emergency and Critical Care Center, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, P.R. China
Published online on: December 8, 2023 https://doi.org/10.3892/mmr.2023.13142
Article Number: 19
Copyright: © Lu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Liddle syndrome is an autosomal dominant form of monogenic hypertension that is caused by mutations in SCNN1A, SCNN1B or SCNN1G, which respectively encode the α, β and γ subunits of the epithelial sodium channel. In the present study, DNA was extracted from leukocytes in peripheral blood obtained from all members of a family with Liddle syndrome. Whole‑exome sequencing and Sanger sequencing were performed to assess the candidate variant and a co‑segregation analysis was conducted. A frameshift mutation in SCNN1B (NM_ 000336: c.1806dupG, p.Pro603Alafs*5) in the family was identified, characterized by early‑onset hypertension and hypokalemia. The mutation led to the truncation of the β subunit of the epithelial sodium channel and a lack of the conservative PY motif. Furthermore, a systematic review of follow‑up data from patients with Liddle syndrome with SCNN1B mutations was performed. The follow‑up data of 108 patients with pathogenic SCNN1B mutations from 47 families were summarized. Phenotypic heterogeneity was evident in patients with Liddle syndrome and early‑onset hypertension was the most frequent symptom. Patients responded well to targeted amiloride therapy with significant improvements in blood pressure and serum potassium concentration. The present study demonstrates that confirmatory genetic testing and targeted therapy can prevent premature onset of clinical endpoint events in patients with Liddle syndrome.

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1	Liddle GW: A familial renal disorder simulating primary aldosteronism but with negligible aldosterone secretion. Trans Assoc Am Phys. 76:199–213. 1963.
2	Schild L, Lu Y, Gautschi I, Schneeberger E, Lifton RP and Rossier BC: Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome. EMBO J. 15:2381–2387. 1996. View Article : Google Scholar : PubMed/NCBI
3	Yang KQ, Xiao Y, Tian T, Gao LG and Zhou XL: Molecular genetics of Liddle's syndrome. Clin Chim Acta. 436:202–206. 2014. View Article : Google Scholar : PubMed/NCBI
4	Tetti M, Monticone S, Burrello J, Matarazzo P, Veglio F, Pasini B, Jeunemaitre X and Mulatero P: Liddle syndrome: review of the literature and description of a new case. Int J Mol Sci. 19:8122018. View Article : Google Scholar : PubMed/NCBI
5	Khandelwal P and Deinum J: Monogenic forms of low-renin hypertension: Clinical and molecular insights. Pediatr Nephrol. 37:1495–1509. 2021. View Article : Google Scholar : PubMed/NCBI
6	Fan P, Pan XC, Zhang D, Yang KQ, Zhang Y, Tian T, Luo F, Ma WJ, Liu YX, Wang LP, et al: Pediatric liddle syndrome caused by a novel SCNN1G variant in a chinese family and characterized by early-onset hypertension. Am J Hypertens. 33:670–675. 2020. View Article : Google Scholar : PubMed/NCBI
7	Jeunemaitre X, Bassilana F, Persu A, Dumont C, Champigny G, Lazdunski M, Corvol P and Barbry P: Genotype-phenotype analysis of a newly discovered family with Liddle's syndrome. J Hypertens. 15:1091–1100. 1997. View Article : Google Scholar : PubMed/NCBI
8	Li H and Durbin R: Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 25:1754–1760. 2009. View Article : Google Scholar : PubMed/NCBI
9	Tarasov A, Vilella AJ, Cuppen E, Nijman IJ and Prins P: Sambamba: Fast processing of NGS alignment formats. Bioinformatics. 31:2032–2034. 2015. View Article : Google Scholar : PubMed/NCBI
10	Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G and Durbin R; 1000 Genome Project Data Processing Subgroup, : The SEquence Alignment/Map format and SAMtools. Bioinformatics. 25:2078–2079. 2009. View Article : Google Scholar : PubMed/NCBI
11	Krumm N, Sudmant PH, Ko A, O'Roak BJ, Malig M and Coe BP; NHLBI Exome Sequencing Project, ; Quinlan AR, Nickerson DA and Eichler EE: Copy number variation detection and genotyping from exome sequence data. Genome Res. 22:1525–1532. 2012. View Article : Google Scholar : PubMed/NCBI
12	Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al: Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med. 17:405–424. 2015. View Article : Google Scholar : PubMed/NCBI
13	Wang LP, Yang KQ, Jiang XJ, Wu HY, Zhang HM, Zou YB, Song L, Bian J, Hui RT, Liu YX and Zhou XL: Prevalence of liddle syndrome among young hypertension patients of undetermined cause in a Chinese population. J Clin Hypertens (Greenwich). 17:902–907. 2015. View Article : Google Scholar : PubMed/NCBI
14	Liu K, Qin F, Sun X, Zhang Y, Wang J, Wu Y, Ma W, Wang W, Wu X, Qin Y, et al: Analysis of the genes involved in Mendelian forms of low-renin hypertension in Chinese early-onset hypertensive patients. J Hypertens. 36:502–509. 2018. View Article : Google Scholar : PubMed/NCBI
15	Cui Y, Tong A, Jiang J, Wang F and Li C: Liddle syndrome: Clinical and genetic profiles. J Clin Hypertens. 19:524–529. 2017. View Article : Google Scholar : PubMed/NCBI
16	Fan P, Lu CX, Yang KQ, Lu PP, Hao SF, Luo F, Zhang HM, Song L, Wu HY, Cai J, et al: Truncated epithelial sodium channel β subunit responsible for liddle syndrome in a Chinese family. Kidney Blood Press Res. 44:942–949. 2019. View Article : Google Scholar : PubMed/NCBI
17	Pitzer AL, Van Beusecum JP, Kleyman TR and Kirabo A: ENaC in salt-sensitive hypertension: Kidney and beyond. Curr Hypertens Rep. 22:692020. View Article : Google Scholar : PubMed/NCBI
18	Hanukoglu I and Hanukoglu A: Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases. Gene. 579:95–132. 2016. View Article : Google Scholar : PubMed/NCBI
19	Snyder PM: Minireview: Regulation of epithelial Na+ channel trafficking. Endocrinology. 146:5079–5085. 2005. View Article : Google Scholar : PubMed/NCBI
20	Rotin D and Staub O: Role of the ubiquitin system in regulating ion transport. Pflugers Arch. 461:1–21. 2011. View Article : Google Scholar : PubMed/NCBI
21	Bhalla V and Hallows KR: Mechanisms of ENaC regulation and clinical implications. J Am Soc Nephrol. 19:1845–1854. 2008. View Article : Google Scholar : PubMed/NCBI
22	Tapolyai M, Uysal A, Dossabhoy NR, Zsom L, Szarvas T, Lengvárszky Z and Fülöp T: High prevalence of liddle syndrome phenotype among hypertensive US Veterans in Northwest Louisiana. J Clin Hypertens (Greenwich). 12:856–860. 2010. View Article : Google Scholar : PubMed/NCBI
23	Ding X, Jia N, Zhao C, Zhong Y, Dai D, Zhao Y, Xu C, Cai J, Wang Q and He Q: A family with Liddle's syndrome caused by a new c.1721 deletion mutation in the epithelial sodium channel β-subunit. Exp Ther Med. 17:2777–2784. 2019.PubMed/NCBI
24	Fan P, Lu CX, Zhang D, Yang KQ, Lu PP, Zhang Y, Meng X, Hao SF, Luo F, Liu YX, et al: Liddle syndrome misdiagnosed as primary aldosteronism resulting from a novel frameshift mutation of SCNN1B. Endocr Connect. 7:1528–1534. 2018. View Article : Google Scholar : PubMed/NCBI
25	Findling JW, Raff H, Hansson JH and Lifton RP: Liddle's syndrome: prospective genetic screening and suppressed aldosterone secretion in an extended kindred. J Clin Endocrinol Metab. 82:1071–1074. 1997. View Article : Google Scholar : PubMed/NCBI
26	Nakano Y, Ishida T, Ozono R, Matsuura H, Yamamoto Y, Kambe M, Chayama K and Oshima T: A frameshift mutation of beta subunit of epithelial sodium channel in a case of isolated Liddle syndrome. J Hypertens. 20:2379–2382. 2002. View Article : Google Scholar : PubMed/NCBI
27	Awadalla M, Patwardhan M, Alsamsam A and Imran N: Management of liddle syndrome in pregnancy: A case report and literature review. Case Rep Obstet Gynecol. 2017:62794602017.PubMed/NCBI
28	Ma X, Tian Y, Gao Y and Guo X: A study of mutation(s) of the epithelial sodium channel gene in a Liddle's syndrome family. Zhonghua Nei Ke Za Zhi. 40:390–393. 2001.(In Chinese). PubMed/NCBI
29	Hiltunen TP, Hannila-Handelberg T, Petäjäniemi N, Kantola I, Tikkanen I, Virtamo J, Gautschi I, Schild L and Kontula K: Liddle's syndrome associated with a point mutation in the extracellular domain of the epithelial sodium channel gamma subunit. J Hypertens. 20:2383–2390. 2002. View Article : Google Scholar : PubMed/NCBI
30	Bogdanović R, Kuburović V, Stajić N, Mughal SS, Hilger A, Ninić S, Prijić S and Ludwig M: Liddle syndrome in a Serbian family and literature review of underlying mutations. Eur J Pediatr. 171:471–478. 2012. View Article : Google Scholar : PubMed/NCBI
31	Gong L, Chen J, Shao L, Song W, Hui R and Wang Y: Phenotype-genotype analysis in two Chinese families with Liddle syndrome. Mol Biol Rep. 41:1569–1575. 2014. View Article : Google Scholar : PubMed/NCBI
32	Rayner BL, Owen EP, King JA, Soule SG, Vreede H, Opie LH, Marais D and Davidson JS: A new mutation, R563Q, of the beta subunit of the epithelial sodium channel associated with low-renin, low-aldosterone hypertension. J Hypertens. 21:921–926. 2003. View Article : Google Scholar : PubMed/NCBI
33	Jones ES, Owen EP, Davidson JS, Van Der Merwe L and Rayner BL: The R563Q mutation of the epithelial sodium channel beta-subunit is associated with hypertension. Cardiovasc J Afr. 22:241–244. 2011. View Article : Google Scholar : PubMed/NCBI
34	Brower RK, Ghlichloo IA, Shabgahi V, Elsholz D, Menon RK and Vyas AK: Liddle syndrome due to a novel c.1713 deletion in the epithelial sodium channel β-subunit in a normotensive adolescent. AACE Clin Case Rep. 7:65–68. 2021. View Article : Google Scholar : PubMed/NCBI
35	Qu Y, Lu Y, Zhang D, Liu X, Fan P, Chen J, Zhang H, Yang K, Tian T, Zhou Y, et al: Identification of a novel frameshift mutation in the SCNN1B causing Liddle syndrome. Sci Bull (Beijing). 68:383–387. 2023. View Article : Google Scholar : PubMed/NCBI
36	Hansson JH, Nelson-Williams C, Suzuki H, Schild L, Shimkets R, Lu Y, Canessa C, Iwasaki T, Rossier B and Lifton RP: Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome. Nat Genet. 11:76–82. 1995. View Article : Google Scholar : PubMed/NCBI