Liddle's syndrome caused by a novel mutation in the proline-rich PY motif of the epithelial sodium channel beta-subunit.
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: alpha, beta, and gamma. All disease mutations either remove or alter amino acids of the target proline-rich PPPxY sequence (PY motif) of beta- or gamma-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 betaENaC. 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.
Furuhashi
Masato
M
Second Department of Internal Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Japan. furuhasi@sapmed.ac.jp
Kitamura
Kenichiro
K
Adachi
Masataka
M
Miyoshi
Taku
T
Wakida
Naoki
N
Ura
Nobuyuki
N
Shikano
Yasukuni
Y
Shinshi
Yasuyuki
Y
Sakamoto
Ken-ichi
K
Hayashi
Manabu
M
Satoh
Naotoshi
N
Nishitani
Takahiro
T
Tomita
Kimio
K
Shimamoto
Kazuaki
K
D000328:Adult; D000368:Aged; D020816:Amino Acid Motifs; D000818:Animals; D002648:Child; D053503:Epithelial Sodium Channels; D005260:Female; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D020125:Mutation, Missense; D011392:Proline; D021122:Protein Subunits; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D013577:Syndrome; D014981:Xenopus
D053503:Epithelial Sodium Channels; D021122:Protein Subunits; D015222:Sodium Channels; D011392:Proline