title: Novel mutations in epithelial sodium channel (ENaC) subunit genes and phenotypic expression of multisystem pseudohypoaldosteronism.
abstract: OBJECTIVE
  Multisystem pseudohypoaldosteronism (PHA) is a rare autosomal recessive aldosterone unresponsiveness syndrome that results from mutations in the genes encoding epithelial sodium channel (ENaC) subunits alpha, beta and gamma. In this study we examined three PHA patients to identify mutations responsible for PHA with different clinical presentations.
  
  
  METHODS
  All three patients presented uniformly with symptoms of severe salt-loss during the first week of life and were hospitalized for up to a year. Beyond infancy, one of the patients showed mild renal salt loss and had no lower respiratory tract infections until 8 years of age, while the other patients continue with a severe course.
  
  
  RESULTS
  We sequenced the complete coding regions and intron-exon junctions of the genes encoding alpha, beta and gamma subunits of ENaC for all patients. The results revealed that the mild case represents a novel compound heterozygote including a missense (Gly327Cys) mutation in the alphaENaC gene. Sequences of relatives over three generations confirmed that the missense mutation co-segregates with PHA. This mutation was not found in 60 control subjects. The other patients with severe PHA had two homozygous mutations, a novel deletion mutation in exon 8 of the alphaENaC gene and a splice site mutation in intron 12 of the betaENaC gene. Most of the PHA-causing mutations appear in the alphaENaC gene located on chromosome 12 rather than in the beta and gammaENaC genes located tandemly on chromosome 16. However, the frequency of sequence variants in patients and control subjects showed no difference between genes.
  
  
  CONCLUSIONS
  Severe PHA cases are associated with mutations leading to absence of normal-length alpha, beta or gammaENaC, while a mild case has been found to be associated with a missense mutation in alphaENaC. The predominance of PHA-causing mutations in the alphaENaC gene may be related to the function of this subunit.
authors.affiliation: Department of Molecular Biology, College of Judea and Samaria, Ariel, Israel.
authors.forename: Oded
authors.initials: O
authors.lastname: Edelheit
authors.forename: Israel
authors.initials: I
authors.lastname: Hanukoglu
authors.forename: Maria
authors.initials: M
authors.lastname: Gizewska
authors.forename: Nurgun
authors.initials: N
authors.lastname: Kandemir
authors.forename: Yardena
authors.initials: Y
authors.lastname: Tenenbaum-Rakover
authors.forename: Murat
authors.initials: M
authors.lastname: Yurdakök
authors.forename: Stanislaw
authors.initials: S
authors.lastname: Zajaczek
authors.forename: Aaron
authors.initials: A
authors.lastname: Hanukoglu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D053503:Epithelial Sodium Channels; D005091:Exons; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011546:Pseudohypoaldosteronism / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D053503:Epithelial Sodium Channels; D015222:Sodium Channels