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

Pseudohypoaldosteronism type 1 (PHA1, OMIM 264350) is a rare Mendeliandisorder characterised by end-organ unresponsiveness to mineralocorticoids.Most steroid hormone insensitivity syndromes arise from mutations in thecorresponding receptor, but available genetic evidence is againstinvolvement of the mineralocorticoid receptor gene, MLR, in PHA1. Acomplete genome scan for PHA1 genes was undertaken using homozygositymapping in 11 consanguineous families. Conclusive evidence of linkage withheterogeneity was obtained with a maximum two- locus admixture lod score of9.9. The disease locus mapped to chromosome 16p12.2-13.11 in six familiesand to 12p13.1-pter in the other five families. The two chromosomal regionsharbour genes for subunits of the amiloride-sensitive epithelial sodiumchannel: SCNN1B and SCNN1G on 16p and SCNN1A on 12p. Liddle's syndrome ofhypertension and pseudoaldosteronism has been shown to arise from mutationsin SCNN1B and SCNN1G. These results strongly suggest that PHA1 and Liddle'ssyndrome are allelic variants caused by mutations in genes encodingsubunits of this sodium channel. These genes are of broad biologicalinterest both in relation to sodium and water homeostasis in mammals and byvirtue of their homology to the mec genes of Caenorhabditis elegansinvolved in mechanosensitivity and neuronal degeneration.