3.3 A Novel Missense Mutation of the Beta Subunit of the Epithelial Sodium Channel (P617l) Identified in a Patient with Liddle Syndrome
Liddle syndrome (LS) is a rare mendelian form of hypertension due to mutations of either the SCNN1B gene or the SCNN1G gene, encoding the beta and gamma subunit, respectively, of the epithelial sodium channel (ENaC), resulting in a constitutive activation of ENaC. We report a case of LS due to a novel point mutation, causing an expected substitution of a leucine residue for the 2nd proline residue of the conserved PPPxY motif of the beta subunit (P617L).
The patient: a 19 year-old male. His father: died at age 29 of an heroin overdose, had been under antihypertensive pharmacological treatment since age 20. His paternal grandmother: died of a stroke at age 40. In the proband, hypertension and hypokalaemic metabolic alkalosis (K+ 2.8 mEq/L, HCO3− 32 mEq/L) and inappropriate potassium excretion (50 mEq/24 h) dated from age 17. 24-h ABPM: daytime BP 156/89 mmHg, night time BP 161/77 mmHg. After being treated with potassium canrenoate 100 mg od, felodipine 5 mg od and potassium supplementations, the patient was referred to our Centre for uncontrolled hypertension (144/86 mmHg) and persistent hypokalaemia (3.1 mEq/L). Laboratory data as follows 6 weeks after withdrawal of the previous treatment: PRA 0.2 ng/ml/h, plasma aldosterone 1.5 ng/dL (standing). AMES e GRA were ruled out by determination of the urinary F/E ratio and long-PCR, respectively. After treatment with amiloride 5 mg od for 15 days: PA 130/75 mmHg, [K+] 3.9 mEq/L, [HCO3−] 24 mEq/L. Both direct sequencing and PCR-RFLP analysis with BsrBI of exon 13 of SCNN1B were performed on genomic DNA obtained from the proband, his mother, his paternal great-aunt and healthy controls.
In the proband, but neither in his mother nor his great-aunt nor in the controls, a mutation was identified in the 617 codon of SCNN1B (CTC in place of CCC), with an expected conversion of the PPPxY motif to PLPxY.
Hallmarks of LS in this case are: a) early onset of hypertension with dominant autosomic transmission; b) pseudohyperaldosteronism; c) response to ENaC inhibitors, but not to MC receptor antagonists. This newly identified mutation adds to other missense mutations of the PPPxY motif, thus confirming its crucial role in the regulation of ENaC. All mutations identified in LS are nonsense, missense, or frameshift mutations of the C-terminal region of either the beta or gamma subunit, causing disappearance or altered sequence of PPPxY; this motif is needed for the binding of the ubiquitin-protein ligase NEDD4, which triggers the internalisation of ENaC. Failure of NEDD4 binding to ENaC decreases internalisation and increases density of ENaC in the distal nephron, resulting in pseudohyperaldosteronism. To our knowledge, this is the first report of an Italian patient with Liddle syndrome in whom molecular genetic analysis was performed with identification of a mutation not previously reported.
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Rossi, E., Farnetti, E., Nicoli, D. et al. 3.3 A Novel Missense Mutation of the Beta Subunit of the Epithelial Sodium Channel (P617l) Identified in a Patient with Liddle Syndrome. High Blood Press Cardiovasc Prev 14, 145 (2007). https://doi.org/10.2165/00151642-200714030-00048