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 LIDDLES-DISEASE

We describe a family with Liddle's disease caused by a novel mutation of the beta subunit of the human epithelial sodium channel (ENaC), A 1 5-year-old Japanese female was referred to our outclinic because of hy pertension. The physical examination showed no abnormal findings excep t mild hypertension, but the laboratory data revealed low levels of pl asma renin activity, plasma aldosterone and serum potassium. A compreh ensive analysis of steroid hormones showed only high levels of urinary free cortisol and 17-hydroxycorticosteroids. During loading tests, bl ood pressure and serum potassium responded well to triamterene and sli ghtly to spironolactone, but did not respond to dexamethasone. In addi tion, the normal ratio of tetrahydrocortisol plus 5 alpha-tetrahydroco rtisol to tetrahydrocortisone in a 24 h urinary excretion test strongl y suggested a diagnosis of Liddle's disease rather than apparent miner alocorticoid excess syndrome. DNA sequence analysis of members of this family revealed a single cytosine base insertion at Arg-597 of the be ta human ENaC in the proband and her mother, leading to a loss of the last 34 amino acids from the normally encoded protein as the result of a frameshift. We conclude that a de novo cytosine insertion into the final exon of the C-terminus of the beta human ENaC is responsible for Liddle's disease in this Japanese family.