Novel mutations responsible for autosomal recessive multisystem pseudohypoaldosteronism and sequence variants in epithelial sodium channel α-, β-, and γ-subunit genes

Multisystem pseudohypoaldosteronism (PHA), is a syndrome of unresponsiveness to aldosterone with autosomal recessive inheritance. Previously we showed that mutations in the epithelial sodium channel (ENaC) α-, β-, and γ-subunits are responsible for PHA. In this study we examined four independent probands with multisystem PHA, three of whom were born to consanguineous parents. In our search for mutations we also determined the complete coding sequences of each of the three genes encoding α-, β-, and γ-subunits in individuals representing different ethnic groups. Our analyses revealed the following homozygous mutations in three probands: 1) insertion of a T in exon 8 of the α ENaC gene that causes a frameshift error at Tyr⁴⁴⁷and leads to a premature stop codon at K459 in a Pakistani patient; 2) R508stop mutation in exon 11 of the α ENaC gene in an Indian patient; and 3) a splice site mutation in intron 12 of the β ENaC gene (1669 + I g→a) in a Scottish patient. The parents were heterozygous for the latter two mutations. The second mutation was previously observed in an Iranian Jewish patient. Our sequencing of the α-, β-, and γ-coding sequences revealed some sequence variants, some of which may represent single nucleotide polymorphisms. The γ-sub-unit protein sequence was completely conserved in the six subjects examined. The homozygous mutations identified in the α and β ENaC genes should result in reduced or abolished ENaC activity in PHA patients, explaining the disease symptoms.