A novel epithelial sodium channel gamma-subunit de novo frameshift mutation leads to Liddle syndrome

Liddle syndrome is a rare autosomal-dominant monogenic form of hypertension caused by mutations in the C-termini of the epithelial sodium channel beta- or gamma-subunit encoded by SCNN1B and SCNN1G, respectively, and often presenting with a familial history of hypertension. The purpose of this study was to determine whether mutations of SCNN1B or SCNN1G were present in a patient clinically suspected to have Liddle syndrome with no familial history of hypertension.

We screened the C-terminus of SCNN1B and SCNN1G in the patient, and also screened for the mutation in his parents, 50 hypertensive patients and 50 controls.

In this patient, no mutations were found in the C-terminus of SCNN1B. However, we found a frameshift mutation caused by an 'AGCTC' deletion at the 583 codon in SCNN1G. The frameshift resulted in a new termination site at the 585 codon of the gamma-subunit and the deletion of its PY motif. Neither his parents nor 50 randomly selected patients with hypertension nor 50 controls have the mutation, indicating that this is a de novo mutation and not a common genetic polymorphism.

The de novo mutation is the first reported frameshift of the gamma-subunit causing Liddle syndrome. These data imply that a familial history of hypertension is not an essential criterion for the diagnosis of Liddle syndrome.