J Hypertens 2002 Dec 01;2012:2383-90. doi: 10.1097/00004872-200212000-00017.

Liddle's syndrome associated with a point mutation in the extracellular domain of the epithelial sodium channel gamma subunit.

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OBJECTIVE: To characterize novel type of mutations of the epithelial sodium channel (ENaC) or subunits in patients with Liddle's syndrome, an autosomal dominant form of hypertension. PATIENTS AND METHODS: DNA samples from two probands with early-onset, treatment-resistant hypertension and suppressed plasma renin activity were initially screened for mutations in the C-terminal exons of the ENaC or subunit genes, using amplification by polymerase chain reaction and direct DNA sequencing. RESULTS: Two novel mutations causing Liddle's syndrome were identified. One mutation due to a single nucleotide insertion in the exon 13 of ENaC results in a frameshift at codon 601 and abrogates the PY motif similar to all the previously described ENaC mutations causing Liddle's syndrome. The other mutation, substituting serine for asparagine at codon 530 (Asn530Ser) of the extracellular loop of ENaC subunit, was found in a 25-year-old man with hypertension, hypokalemia, low plasma renin activity and low serum aldosterone levels. Hypertension and hypokalemia favorably responded to amiloride or triamterene administration both in the proband and his affected mother. Expression of the mutant Asn530Ser ENaC subunit in oocytes demonstrated a two-fold increase in ENaC activity, compared with the wild-type, without a significant change in cell surface expression of ENaC. This suggests that the gammaENaC Asn530Ser mutation increases the channel open probability, and is consistent with an abnormally high sodium reabsorption in the distal nephron. CONCLUSIONS: This study describes the first mutation located in the extracellular domain of an ENaC subunit associated with an increased ENaC activity and Liddle's syndrome.

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