Phenotype–genotype analysis in two Chinese families with Liddle syndrome
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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.
KeywordsLiddle syndrome Genotype Phenotype
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
- 1.Liddle GW, Bledsoe T, Coppage WS (1963) A familial renal disorder simulating primary aldosteronism but with negligible aldosterone secretion. Trans Assoc Am Physicians 76:199–213Google 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):407–414PubMedCrossRefGoogle 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):11495–11499PubMedCrossRefGoogle 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 PubMedCrossRefGoogle 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):691–697PubMedCrossRefGoogle 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 PubMedCrossRefGoogle 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 PubMedCrossRefGoogle 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 PubMedCrossRefGoogle 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 PubMedCrossRefGoogle Scholar