Genotype–phenotype analysis of a newly discovered family with Liddleʼs syndrome

Abstract

To investigate the clinical, biologic, and molecular abnormalities in a family with Liddle's syndrome and analyze the short- and long-term efficacies of amiloride treatment. The pedigree consisted of one affected mother and four children, of whom three suffered from earlyonset and moderate-to-severe hypertension. In addition to the biochemical and hormonal measurements, genetic analysis of the carboxy terminus of the β subunit of the epithelial sodium channel (βENaC) was conducted through single-strand conformation analysis and direct sequencing. The functional properties of the mutation were analyzed using the Xenopus expression system and compared with one mutation affecting the proline-rich sequence of the βENaC. Mild hypokalemia and suppressed levels of plasma renin and aldosterone were observed in all affected subjects. Administration of 10mg/day amiloride for 2 months normalized the blood pressure and plasma potassium levels of all of the affected subjects, whereas their plasma and urinary aldosterone levels remained surprisingly low. A similar pattern was observed after 11 years of follow-up, but a fivefold increase in plasma aldosterone was observed under treatment with 20mg/day amiloride for 2 weeks. Genetic analysis of the βENaC revealed a deletion of 32 nucleotides that had modified the open reading frame and introduced a stop codon at position 582. Expression of this β579del32 mutant caused a 3.7 ± 0.3-fold increase in the amiloridesensitive sodium current, without modification of the unitary properties of the channel. A similar increase was elicited by one mutation affecting the carboxy terminus of the βENaC. This new mutation leading to Liddle's syndrome highlights the importance of the carboxy terminus of the βENaC in the activity of the epithelial sodium channel. Small doses of amiloride are able to control the blood pressure on a long-term basis in this monogenic from of hypertension.