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A Missense Mutation in the Extracellular Domain of ?ENaC Causes Liddle Syndrome.

ABSTRACT: Liddle syndrome is an autosomal dominant form of hypokalemic hypertension due to mutations in the ?- or ?-subunit of the epithelial sodium channel (ENaC). Here, we describe a family with Liddle syndrome due to a mutation in ?ENaC. The proband was referred because of resistant hypokalemic hypertension, suppressed renin and aldosterone, and no mutations in the genes encoding ?- or ?ENaC. Exome sequencing revealed a heterozygous, nonconservative T>C single-nucleotide mutation in ?ENaC that substituted Cys479 with Arg (C479R). C479 is a highly conserved residue in the extracellular domain of ENaC and likely involved in a disulfide bridge with the partner cysteine C394. In oocytes, the C479R and C394S mutations resulted in similar twofold increases in amiloride-sensitive ENaC current. Quantification of mature cleaved ?ENaC in membrane fractions showed that the number of channels did not increase with these mutations. Trypsin, which increases open probability of the channel by proteolytic cleavage, resulted in significantly higher currents in the wild type than in C479R or C394S mutants. In summary, a mutation in the extracellular domain of ?ENaC causes Liddle syndrome by increasing intrinsic channel activity. This mechanism differs from that of the ?- and ?-mutations, which result in an increase in channel density at the cell surface. This mutation may explain other cases of patients with resistant hypertension and also provides novel insight into ENaC activation, which is relevant for kidney sodium reabsorption and salt-sensitive hypertension.

SUBMITTER: Salih M

PROVIDER: S-EPMC5661275 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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A Missense Mutation in the Extracellular Domain of αENaC Causes Liddle Syndrome.

Salih Mahdi M Gautschi Ivan I van Bemmelen Miguel X MX Di Benedetto Michael M Brooks Alice S AS Lugtenberg Dorien D Schild Laurent L Hoorn Ewout J EJ

Journal of the American Society of Nephrology : JASN 20170714 11

Liddle syndrome is an autosomal dominant form of hypokalemic hypertension due to mutations in the β- or γ-subunit of the epithelial sodium channel (ENaC). Here, we describe a family with Liddle syndrome due to a mutation in αENaC. The proband was referred because of resistant hypokalemic hypertension, suppressed renin and aldosterone, and no mutations in the genes encoding β- or γENaC. Exome sequencing revealed a heterozygous, nonconservative T>C single-nucleot ...[more]

PMID: 28710092

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Project description:BackgroundSurveillance for bovine genetic diseases in Denmark identified a hitherto unreported congenital syndrome occurring among progeny of a Holstein sire used for artificial breeding. A genetic aetiology due to a dominant inheritance with incomplete penetrance or a mosaic germline mutation was suspected as all recorded cases were progeny of the same sire. Detailed investigations were performed to characterize the syndrome and to reveal its cause.ResultsSeven malformed calves were submitted examination. All cases shared a common morphology with the most striking lesions being severe facial dysplasia and complete prolapse of the eyes. Consequently the syndrome was named facial dysplasia syndrome (FDS). Furthermore, extensive brain malformations, including microencephaly, hydrocephalus, lobation of the cerebral hemispheres and compression of the brain were present. Subsequent data analysis of progeny of the sire revealed that around 0.5% of his offspring suffered from FDS. High density single nucleotide polymorphism (SNP) genotyping data of the seven cases and their parents were used to map the defect in the bovine genome. Significant genetic linkage was obtained for three regions, including chromosome 26 where whole genome sequencing of a case-parent trio revealed two de novo variants perfectly associated with the disease: an intronic SNP in the DMBT1 gene and a single non-synonymous variant in the FGFR2 gene. This FGFR2 missense variant (c.927G>T) affects a gene encoding a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and across species. It is predicted to change an evolutionary conserved tryptophan into a cysteine residue (p.Trp309Cys). Both variant alleles were proven to result from de novo mutation events in the germline of the sire.ConclusionsFDS is a novel genetic disorder of Holstein cattle. Mutations in the human FGFR2 gene are associated with various dominant inherited craniofacial dysostosis syndromes. Given the phenotypic similarities in FDS affected calves, the genetic mapping and absence of further high impact variants in the critical genome regions, it is highly likely that the missense mutation in the FGFR2 gene caused the FDS phenotype in a dominant mode of inheritance.

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A Missense Mutation in the Extracellular Domain of ?ENaC Causes Liddle Syndrome.

Publications

A Missense Mutation in the Extracellular Domain of <i>α</i>ENaC Causes Liddle Syndrome.

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