Evidence for genetic heterogeneity of pseudohypoaldosteronism type 1: identification of a novel mutation in the human mineralocorticoid receptor in one sporadic case and no mutations in two autosomal dominant kindreds.
Pseudohypoaldosteronism type 1 (PHA1) is characterized by neonatal salt wasting resistant to mineralocorticoids. There are 2 forms of PHA1: the autosomal recessive form with symptoms persisting into adulthood, caused by mutations in the amiloride-sensitive luminal sodium channel, and the autosomal dominant or sporadic form, which shows milder symptoms that remit with age. Mutations in the gene encoding the human mineralocorticoid receptor (hMR) are, at least in some patients, responsible for the latter form of PHA1. We here report the results of a genetic study in a sporadic case and in 5 affected patients from 2 families with autosomal dominant PHA1. In the sporadic case we identified a new frameshift mutation, Ins2871C, in exon 9 of the hMR gene. Family members were asymptomatic and had no mutation. This mutation is the first described in exon 9 and impairs the last 27 amino acids of the hormone-binding domain. In 2 kindreds with autosomal dominant PHA1 we found no mutation of the hMR gene. Our results confirm the hypothesis that autosomal dominant or sporadic PHA1 is a genetically heterogeneous disease involving other, as yet unidentified, genes.
T10 T11 T1 T2 T3 T4 T5 T6 T7 T8 T9
GENE-Y GENE-Y CHEMICAL CHEMICAL CHEMICAL GENE-N GENE-Y GENE-Y GENE-N GENE-Y GENE-N
hMR human mineralocorticoid receptor amiloride sodium amino acids amiloride-sensitive luminal sodium channel human mineralocorticoid receptor hMR Ins2871C hMR hormone-binding domain