Localisation of pseudohypoaldosteronism genes to chromosome 16p12.2-13.11 and 12p13.1-pter by homozygosity mapping

Abstract

Pseudohypoaldosteronism type 1 (PHA1, OMIM 264350) is a rare Mendelian disorder characterised by end-organ unresponsiveness to mineralocorticoids. Most steroid hormone insensitivity syndromes arise from mutations in the corresponding receptor, but available genetic evidence is against involvement of the mineralocorticoid receptor gene, MLR, in PHA1. A complete genome scan for PHA1 genes was undertaken using homozygosity mapping in 11 consanguineous families. Conclusive evidence of linkage with heterogeneity was obtained with a maximum two-locus admixture lod score of 9.9. The disease locus mapped to chromosome 16p12.2-13.11 in six families and to 12p13.1-pter in the other five families. The two chromosomal regions harbour genes for subunits of the amiloride-sensitive epithelial sodium channel: SCNN1B and SCNN1G on 16p and SCNN1A on 12p. Liddle's syndrome of hypertension and pseudoaldosteronism has been shown to arise from mutations in SCNN1B and SCNN1G. These results strongly suggest that PHA1 and Liddle's syndrome are allelic variants caused by mutations in genes encoding subunits of this sodium channel. These genes are of broad biological interest both in relation to sodium and water homeostasis in mammals and by virtue of their homology to the mec genes of Caenorhabditis elegans involved in mechanosensitivity and neuronal degeneration.