Novel mutations in epithelial sodium channel (ENaC) subunit genes and phenotypic expression of multisystem pseudohypoaldosteronism

Objectives: Multisystem pseudohypoaldosteronism (PHA) is a rare autosomal recessive aldosterone unresponsiveness syndrome that results from mutations in the genes encoding epithelial sodium channel (ENaC) subunits α, β and γ. In this study we examined three PHA patients to identify mutations responsible for PHA with different clinical presentations. Patients: 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 α, β and γ 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 αENaC 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 αENaC gene and a splice site mutation in intron 12 of the βENaC gene. Most of the PHA-causing mutations appear in the αENaC gene located on chromosome 12 rather than in the β and γENaC 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 α, β or γENaC, while a mild case has been found to be associated with a missense mutation in αENaC. The predominance of PHA-causing mutations in the αENaC gene may be related to the function of this subunit.