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A Family with Liddle’s Syndrome Caused by a New Missense Mutation in the ß Subunit of the Epithelial Sodium Channel

From Third Department of Internal Medicine, School of Medicine (J.I., T.I., H.T., S.N., K.Tomita) Department of Biological Science, Faulty of Science (K.Takamune), Gene Technology Center (M.A.), Department of Hygenic Chemistry, Faculty of Pharmaceutical Science (K.Takahama), Kumamoto University, Kumamoto, Japan; First Department of Internal Medicine, Oita Prefectural Hospital, Oita, Japan (K.Y.)

Abstract

Liddle’s syndrome is an autosomal dominant form of salt sensitive hypertension caused by mutations in the ß or subunit of the epithelial sodium channel. Systemic mutagenesis studies revealed that a conserved PPPXY sequence (PY motif) of the C-terminus of the , ß, or subunits might be involved in the regulation of the channel activity. However, only two missense mutations in the PY motif of the ß subunit have been reported to cause Liddle’s syndrome. We sequenced the C-termini of the ß and subunits of the epithelial sodium channel in a Japanese family clinically diagnosed as having Liddle’s syndrome and found a new missense mutation in the PY motif of the ß subunit, P615S. Expression studies with P615S mutant in Xenopus oocytes resulted in an about 3-fold increase in the amiloride-sensitive sodium current compared to the wild type (p = 0.001). These findings provide further clinical evidence for the hypothesis that a conserved PY motif may be critically important for the regulation of the epithelial sodium channel.

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