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Liddle’s Syndrome Caused by a Novel Mutation in the Proline-Rich PY Motif of the Epithelial Sodium Channel ß-Subunit

Second Department of Internal Medicine, Sapporo Medical University School of Medicine (M.F., N.U., Y.Shin., K.S.), Sapporo, Japan; Second Department of Internal Medicine, Obihiro Kosei General Hospital (M.F., Y.Shik., K.-i.S., M.H., N.S., T.N.), Obihiro, Japan; and Department of Nephrology, Kumamoto University Graduate School of Medical Sciences (K.K., M.A., T.M., N.W., K.T.), Kumamoto, Japan

Address all correspondence and requests for reprints to: Dr. Masato Furuhashi, Second Department of Internal Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Japan. E-mail: furuhasi{at}sapmed.ac.jp.

Liddle’s syndrome is an autosomal dominant form of salt-sensitive hypertension and has been shown to be caused by missense or frameshift mutations in the amiloride-sensitive epithelial sodium channel (ENaC), which is composed of three subunits: , ß, and . All disease mutations either remove or alter amino acids of the target proline-rich PPPxY sequence (PY motif) of ß- or -ENaC and result in increased channel activity. In this report, we present a family with Liddle’s syndrome whose abnormality is caused by a novel missense mutation, P616R, in the PY motif of the ßENaC. Functional studies using the P616R mutant expressed in Xenopus oocytes showed an approximately 6-fold increase in the amiloride-sensitive sodium channel activity compared with that of the wild type. These findings provide additional clinical evidence that a conserved PY motif is critically important for the regulation of ENaC activity.

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