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

Summary 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.