A novel splice-site mutation in the gamma subunit of the epithelial sodium channel gene in three pseudohypoaldosteronism type 1 families

Pseudohypoaldosteronism type 1 (PHA1, OMIM 264350) is an uncommon inherited disorder characterized by salt-wasting and end-organ unresponsiveness to mineralocorticoids. A complete genome search using homozygosity mapping in eleven consanguineous families with PHA1 provided conclusive evidence of linkage with heterogeneity. The disease locus mapped to chromosome 16p12.2-13.11 in six families and to 12p13.1-pter in the other five families. These two chromosomal regions harbour the genes encoding the three subunits of the human amiloride sensitive epithelial sodium channel (hENaC): SCNN1B and SCNN1G on 16p and SCNN1A on 12p3,4. Our linkage results have been further supported by the recent report of mutations in the α and β subunit genes in PHA1 patients. We now report the identification of a 3' splice site mutation in SCNN1G (318-1 G→A) in three families showing linkage to 16p. Abnormal splicing results with the production of two messenger RNAs, one arising from activation of an adjacent cryptic splice site and the other from skipping of the downstream exon. The two corresponding mutant γhENaC subunits are predicted to have three highly conserved amino acids in the extracellular domain replaced by a novel amino acid (KYS106-108→N) and truncation from 649 to 134 amino acids respectively. These three families all originate from the Indian sub-continent and the probands have severe generalized PHA. They share a common haplotype which suggests the presence of a founder mutation in this sub-population.