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

Liddle’s syndrome is an autosomal dominant form of salt sensitive hypertension caused by mutations in the β or γ subunit of the epithelial sodium channel. Systemic mutagenesis studies revealed that a conserved PPPXY sequence (PY motif) of the C-terminus of the α, β, or γ subunits might be involved in the regulation of the channel activity. However, only two missense mutations in the PY motif of theβ subunit have been reported to cause Liddle’s syndrome. We sequenced the C-termini of the β and γ 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 β 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.

Download Full-text

A family with Liddle's syndrome caused by a new c.1721 deletion mutation in the epithelial sodium channel β‑subunit

Experimental and Therapeutic Medicine ◽

10.3892/etm.2019.7270 ◽

2019 ◽

Author(s):

Xia Ding ◽

Na Jia ◽

Cong Zhao ◽

You Zhong ◽

Dapeng Dai ◽

...

Keyword(s):

Sodium Channel ◽

Epithelial Sodium Channel ◽

Deletion Mutation ◽

Β Subunit ◽

Liddle’S Syndrome ◽

Liddle's Syndrome

Download Full-text

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

Journal of Hypertension ◽

10.1097/00004872-200212000-00017 ◽

2002 ◽

Vol 20 (12) ◽

pp. 2383-2390 ◽

Cited By ~ 57

Author(s):

Timo P Hiltunen ◽

Tuula Hannila-Handelberg ◽

Noora Petäjäniemi ◽

Ilkka Kantola ◽

Ilkka Tikkanen ◽

...

Keyword(s):

Sodium Channel ◽

Point Mutation ◽

Epithelial Sodium Channel ◽

Extracellular Domain ◽

Γ Subunit ◽

Liddle’S Syndrome ◽

Liddle's Syndrome

Download Full-text

Aldosterone responsiveness of the epithelial sodium channel (ENaC) in colon is increased in a mouse model for Liddle's syndrome

The Journal of Physiology ◽

10.1113/jphysiol.2007.140459 ◽

2008 ◽

Vol 586 (2) ◽

pp. 459-475 ◽

Cited By ~ 36

Author(s):

Marko Bertog ◽

John E. Cuffe ◽

Sylvain Pradervand ◽

Edith Hummler ◽

Andrea Hartner ◽

...

Keyword(s):

Mouse Model ◽

Sodium Channel ◽

Epithelial Sodium Channel ◽

Liddle’S Syndrome ◽

Liddle's Syndrome ◽

Epithelial Sodium Channel Enac

Download Full-text

Conservation of pH sensitivity in the epithelial sodium channel (ENaC) with Liddle's syndrome mutation

Pflügers Archiv - European Journal of Physiology ◽

10.1007/s004240000430 ◽

2000 ◽

Vol 441 (2-3) ◽

pp. 341-350 ◽

Cited By ~ 17

Author(s):

Angelos-Aristeidis Konstas ◽

Dimitrios Mavrelos ◽

Christoph Korbmacher

Keyword(s):

Sodium Channel ◽

Epithelial Sodium Channel ◽

Ph Sensitivity ◽

Liddle’S Syndrome ◽

Liddle's Syndrome ◽

Epithelial Sodium Channel Enac

Download Full-text

Liddle's syndrome: Heritable human hypertension caused by mutations in the β subunit of the epithelial sodium channel

Cell ◽

10.1016/0092-8674(94)90250-x ◽

1994 ◽

Vol 79 (3) ◽

pp. 407-414 ◽

Cited By ~ 900

Author(s):

Richard A. Shimkets ◽

David G. Warnock ◽

Christopher M. Bositis ◽

Carol Nelson-Williams ◽

Joni H. Hansson ◽

...

Keyword(s):

Sodium Channel ◽

Epithelial Sodium Channel ◽

Β Subunit ◽

Human Hypertension ◽

Liddle’S Syndrome ◽

Liddle's Syndrome

Download Full-text

Liddle’s syndrome: Heritable human hypertension caused by mutations in the ß subnit of the epithelial sodium channel

Journal of Endocrinological Investigation ◽

10.1007/bf03349775 ◽

1995 ◽

Vol 18 (7) ◽

pp. 592-594 ◽

Cited By ~ 4

Author(s):

R. A. Shimkets ◽

D. G. Warnock ◽

C. M. Bositis ◽

C. Nelson-Williams ◽

J. H. Hansson ◽

...

Keyword(s):

Sodium Channel ◽

Epithelial Sodium Channel ◽

Human Hypertension ◽

Liddle’S Syndrome ◽

Liddle's Syndrome

Download Full-text

Association of Cystic Fibrosis Transmembrane Conductance Regulator with Epithelial Sodium Channel Subunits Carrying Liddle's Syndrome Mutations

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00298.2020 ◽

2021 ◽

Author(s):

Arun K. Rooj ◽

Estelle Cormet-Boyaka ◽

Edlira B. Clark ◽

Yawar J. Qadri ◽

William Lee ◽

...

Keyword(s):

Cystic Fibrosis ◽

Sodium Channel ◽

Epithelial Sodium Channel ◽

Fluorescence Lifetime Imaging ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

Physical Association ◽

Liddle’S Syndrome ◽

Liddle's Syndrome ◽

Cystic Fibrosis Transmembrane

The association of the cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial sodium channel (ENaC) in the pathophysiology of cystic fibrosis (CF) is controversial. Previously, we demonstrated a close physical association between wild type (WT) CFTR and WT ENaC. We have also shown that the F508del CFTR fails to associate with ENaC unless the mutant protein is rescued pharmacologically or by low temperature. In this study, we present the evidence for a direct physical association between WT CFTR and ENaC subunits carrying Liddle's syndrome mutations. We show that all three ENaC subunits bearing Liddle's syndrome mutations (both point mutations and the complete truncation of the carboxy terminus), could be co-immunoprecipitated with WT CFTR. The biochemical studies were complemented by fluorescence lifetime imaging microscopy (FLIM), a distance-dependent approach that monitors protein-protein interactions between fluorescently labeled molecules. Our measurements revealed significantly increased FRET between CFTR and all tested ENaC combinations as compared to controls (ECFP and EYFP co-transfected cells). Our findings are consistent with the notion that CFTR and ENaC are within reach of each other even in the setting of Liddle's syndrome mutations, suggestive of a direct intermolecular interaction between these two proteins.

Download Full-text