Skip to main content
SpringerLink
Log in

Phenotype–genotype analysis in two Chinese families with Liddle syndrome

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

The families with Liddle syndrome show marked phenotypic variation in blood pressure, serum potassium and other clinical manifestations. Here we analyzed the correlation of genotype–phenotype in two Chinese families with Liddle syndrome. The sequence of C-terminus of SCNN1B and SCNN1G were screened in the two families with likely Liddle syndrome. In addition to hypertension and hypokalemia, one of the two pedigrees had sudden death in their family members, so the exons of 428 reported genes-related to cardiovascular diseases were screened as well in the family. A heterozygous βR566X nonsense mutation was found in the proband-1 in the first pedigree, and the proband’s sister and father. They showed mild phenotype with hypertension under control. In contrast, two of the four previous studies report that the mutation causes severe phenotype. A heterozygous βR597PfrX607 frameshift mutation was identified in the proband-2 in the second pedigree, showing malignant phenotype including resistant hypertension, hypokalemia, higher PRA and plasma angiotensin II levels. Both the proband-2 and the proband-2’s father had sudden death in their twenties, but no meaningful mutations were found by screening of the exons in 428 cardiovascular disease-related genes. However, the same mutation has been related to moderate phenotype in previous studies. Our results confirmed that the phenotypes of Liddle syndrome are varied significantly even with the same mutation. The mechanisms why the same mutation causes very different phenotype need to be explored because intervention of these modifiers may change the disease course and prognosis accordingly.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Liddle GW, Bledsoe T, Coppage WS (1963) A familial renal disorder simulating primary aldosteronism but with negligible aldosterone secretion. Trans Assoc Am Physicians 76:199–213

    CAS  Google Scholar 

  2. Canessa CM, Schild L, Buell G, Thorens B, Gautschi I, Horisberger JD, Rossier BC (1994) Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits. Nature 367(6462):463–467. doi:10.1038/367463a0

    Article  CAS  PubMed  Google Scholar 

  3. Kyuma M, Ura N, Torii T, Takeuchi H, Takizawa H, Kitamura K, Tomita K, Sasaki S, Shimamoto K (2001) A family with liddle’s syndrome caused by a mutation in the beta subunit of the epithelial sodium channel. Clin Exp Hypertens 23(6):471–478

    Article  CAS  PubMed  Google Scholar 

  4. Melander O, Orho M, Fagerudd J, Bengtsson K, Groop PH, Mattiasson I, Groop L, Hulthen UL (1998) Mutations and variants of the epithelial sodium channel gene in Liddle’s syndrome and primary hypertension. Hypertension 31(5):1118–1124

    Article  CAS  PubMed  Google Scholar 

  5. Jeunemaitre X, Bassilana F, Persu A, Dumont C, Champigny G, Lazdunski M, Corvol P, Barbry P (1997) Genotype-phenotype analysis of a newly discovered family with Liddle’s syndrome. J Hypertens 15(10):1091–1100

    Article  CAS  PubMed  Google Scholar 

  6. Shimkets RA, Warnock DG, Bositis CM, Nelson-Williams C, Hansson JH, Schambelan M, Gill JR Jr, Ulick S, Milora RV, Findling JW et al (1994) Liddle’s syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell 79(3):407–414

    Article  CAS  PubMed  Google Scholar 

  7. Hansson JH, Schild L, Lu Y, Wilson TA, Gautschi I, Shimkets R, Nelson-Williams C, Rossier BC, Lifton RP (1995) A de novo missense mutation of the beta subunit of the epithelial sodium channel causes hypertension and Liddle syndrome, identifying a proline-rich segment critical for regulation of channel activity. Proc Natl Acad Sci USA 92(25):11495–11499

    Article  CAS  PubMed  Google Scholar 

  8. Hiltunen TP, Hannila-Handelberg T, Petajaniemi N, Kantola I, Tikkanen I, Virtamo J, Gautschi I, Schild L, Kontula K (2002) Liddle’s syndrome associated with a point mutation in the extracellular domain of the epithelial sodium channel gamma subunit. J Hypertens 20(12):2383–2390. doi:10.1097/01.hjh.0000042881.24999.fc

    Article  CAS  PubMed  Google Scholar 

  9. Inoue T, Okauchi Y, Matsuzaki Y, Kuwajima K, Kondo H, Horiuchi N, Nakao K, Iwata M, Yokogoshi Y, Shintani Y, Bando H, Saito S (1998) Identification of a single cytosine base insertion mutation at Arg-597 of the beta subunit of the human epithelial sodium channel in a family with Liddle’s disease. Eur J Endocrinol 138(6):691–697

    Article  CAS  PubMed  Google Scholar 

  10. Nakano Y, Ishida T, Ozono R, Matsuura H, Yamamoto Y, Kambe M, Chayama K, Oshima T (2002) A frameshift mutation of beta subunit of epithelial sodium channel in a case of isolated Liddle syndrome. J Hypertens 20(12):2379–2382

    Article  CAS  PubMed  Google Scholar 

  11. Inoue J, Iwaoka T, Tokunaga H, Takamune K, Naomi S, Araki M, Takahama K, Yamaguchi K, Tomita K (1998) A family with Liddle’s syndrome caused by a new missense mutation in the beta subunit of the epithelial sodium channel. J Clin Endocrinol Metab 83(6):2210–2213

    CAS  PubMed  Google Scholar 

  12. Gao PJ, Zhang KX, Zhu DL, He X, Han ZY, Zhan YM, Yang LW (2001) Diagnosis of Liddle syndrome by genetic analysis of beta and gamma subunits of epithelial sodium channel–a report of five affected family members. J Hypertens 19(5):885–889

    Article  CAS  PubMed  Google Scholar 

  13. Yamashita Y, Koga M, Takeda Y, Enomoto N, Uchida S, Hashimoto K, Yamano S, Dohi K, Marumo F, Sasaki S (2001) Two sporadic cases of Liddle’s syndrome caused by De novo ENaC mutations. Am J Kidney Dis 37(3):499–504

    Article  CAS  PubMed  Google Scholar 

  14. Uehara Y, Sasaguri M, Kinoshita A, Tsuji E, Kiyose H, Taniguchi H, Noda K, Ideishi M, Inoue J, Tomita K, Arakawa K (1998) Genetic analysis of the epithelial sodium channel in Liddle’s syndrome. J Hypertens 16(8):1131–1135

    Article  CAS  PubMed  Google Scholar 

  15. Freundlich M, Ludwig M (2005) A novel epithelial sodium channel beta-subunit mutation associated with hypertensive Liddle syndrome. Pediatr Nephrol 20(4):512–515. doi:10.1007/s00467-004-1751-2

    Article  PubMed  Google Scholar 

  16. Tamura H, Schild L, Enomoto N, Matsui N, Marumo F, Rossier BC (1996) Liddle disease caused by a missense mutation of beta subunit of the epithelial sodium channel gene. J Clin Invest 97(7):1780–1784. doi:10.1172/JCI118606

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Hansson JH, Nelson-Williams C, Suzuki H, Schild L, Shimkets R, Lu Y, Canessa C, Iwasaki T, Rossier B, Lifton RP (1995) Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome. Nat Genet 11(1):76–82. doi:10.1038/ng0995-76

    Article  CAS  PubMed  Google Scholar 

  18. Wang W, Zhou W, Jiang L, Cui B, Ye L, Su T, Wang J, Li X, Ning G (2006) Mutation analysis of SCNN1B in a family with Liddle’s syndrome. Endocrine 29(3):385–390. doi:10.1385/ENDO:29:3:385

    Article  PubMed  Google Scholar 

  19. Ciechanowicz A, Dolezel Z, Placha G, Starha J, Gora J, Gaciong Z, Brodkiewicz A, Adler G (2005) Liddle syndrome caused by P616R mutation of the epithelial sodium channel beta subunit. Pediatr Nephrol 20(6):837–838. doi:10.1007/s00467-004-1793-5

    Article  PubMed  Google Scholar 

  20. Snyder PM, Price MP, McDonald FJ, Adams CM, Volk KA, Zeiher BG, Stokes JB, Welsh MJ (1995) Mechanism by which Liddle’s syndrome mutations increase activity of a human epithelial Na + channel. Cell 83(6):969–978

    Article  CAS  PubMed  Google Scholar 

  21. Schild L, Lu Y, Gautschi I, Schneeberger E, Lifton RP, Rossier BC (1996) 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(10):2381–2387

    CAS  PubMed  Google Scholar 

  22. Rayner BL, Owen EP, King JA, Soule SG, Vreede H, Opie LH, Marais D, Davidson JS (2003) A new mutation, R563Q, of the beta subunit of the epithelial sodium channel associated with low-renin, low-aldosterone hypertension. J Hypertens 21(5):921–926. doi:10.1097/01.hjh.0000059009.82022.9b

    Article  CAS  PubMed  Google Scholar 

  23. Wang Y, Zheng Y, Chen J, Wu H, Zheng D, Hui R (2007) A novel epithelial sodium channel gamma-subunit de novo frameshift mutation leads to Liddle syndrome. Clin Endocrinol (Oxf) 67(5):801–804. doi:10.1111/j.1365-2265.2007.02967.x

    Article  CAS  Google Scholar 

  24. Rossi E, Farnetti E, Debonneville A, Nicoli D, Grasselli C, Regolisti G, Negro A, Perazzoli F, Casali B, Mantero F, Staub O (2008) Liddle’s syndrome caused by a novel missense mutation (P617L) of the epithelial sodium channel beta subunit. J Hypertens 26(5):921–927. doi:10.1097/HJH.0b013e3282f85dfe

    Article  CAS  PubMed  Google Scholar 

  25. Sawathiparnich P, Sumboonnanonda A, Weerakulwattana P, Limwongse C (2009) A novel mutation in the beta-subunit of the epithelial sodium channel gene (SCNN1B) in a Thai family with Liddle’s syndrome. J Pediatr Endocrinol Metab 22(1):85–89

    Article  CAS  PubMed  Google Scholar 

  26. Shi JY, Chen X, Ren Y, Long Y, Tian HM (2010) Liddle’s syndrome caused by a novel mutation of the gamma-subunit of epithelial sodium channel gene SCNN1G in Chinese. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 27(2):132–135. doi:10.3760/cma.j.issn.1003-9406.2010.02.003

    CAS  PubMed  Google Scholar 

  27. Gao L, Wang L, Liu Y, Zhou X, Hui R, Hu A (2013) A family with Liddle syndrome caused by a novel missense mutation in the PY motif of the beta-subunit of the epithelial sodium channel. J Pediatr 162(1):166–170. doi:10.1016/j.jpeds.2012.06.017

    Article  CAS  PubMed  Google Scholar 

  28. World Medical Association declaration of Helsinki (1997) Recommendations guiding physicians in biomedical research involving human subjects. JAMA 277(11):925–926

    Article  Google Scholar 

  29. Jackson SN, Williams B, Houtman P, Trembath RC (1998) The diagnosis of Liddle syndrome by identification of a mutation in the beta subunit of the epithelial sodium channel. J Med Genet 35(6):510–512

    Article  CAS  PubMed  Google Scholar 

  30. Rossi E, Farnetti E, Nicoli D, Sazzini M, Perazzoli F, Regolisti G, Grasselli C, Santi R, Negro A, Mazzeo V, Mantero F, Luiselli D, Casali B (2011) A clinical phenotype mimicking essential hypertension in a newly discovered family with Liddle’s syndrome. Am J Hypertens 24(8):930–935. doi:10.1038/ajh.2011.76

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The study was supported by the Ministry of Science and Technology of China with grant 973 2012CB517804 to Dr. Wang and grant 2011BAI11B04 to Dr. Hui, and the National Natural Science Foundation of China with grants 81270333 and 81322002 to Dr. Wang.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. State Key Laboratory of Cardiovascular Disease, Sino-German Laboratory for Molecular Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing, 100037, China

    Ling Gong, Jinxing Chen, Liying Shao, Rutai Hui & Yibo Wang

  2. Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing, 100037, China

    Ling Gong, Weihua Song & Rutai Hui

Authors
  1. Ling Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jinxing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liying Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Weihua Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rutai Hui
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yibo Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Rutai Hui or Yibo Wang.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (XLS 50 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gong, L., Chen, J., Shao, L. et al. Phenotype–genotype analysis in two Chinese families with Liddle syndrome. Mol Biol Rep 41, 1569–1575 (2014). https://doi.org/10.1007/s11033-013-3003-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-013-3003-7

Keywords

Search

Navigation