Different inactivating mutations of the mineralocorticoid receptor in fourteen families affected by type I pseudohypoaldosteronism.
We have analyzed the human mineralocorticoid receptor (hMR) gene in 14 families with autosomal dominant or sporadic pseudohypoaldosteronism (PHA1), a rare form of mineralocorticoid resistance characterized by neonatal renal salt wasting and failure to thrive. Six heterozygous mutations were detected. Two frameshift mutations in exon 2 (insT1354, del8bp537) and one nonsense mutation in exon 4 (C2157A, Cys645stop) generate truncated proteins due to premature stop codons. Three missense mutations (G633R, Q776R, L979P) differently affect hMR function. The DNA binding domain mutant R633 exhibits reduced maximal transactivation, although its binding characteristics and ED(50) of transactivation are comparable with wild-type hMR. Ligand binding domain mutants R776 and P979 present reduced or absent aldosterone binding, respectively, which is associated with reduced or absent ligand-dependent transactivation capacity. Finally, P979 possesses a transdominant negative effect on wild-type hMR activity, whereas mutations G633R and Q776R probably result in haploinsufficiency in PHA1 patients. We conclude that hMR mutations are a common feature of autosomal dominant PHA1, being found in 70% of our familial cases. Their absence in some families underscores the importance of an extensive investigation of the hMR gene and the role of precise diagnostic procedures to allow for identification of other genes potentially involved in the disease.
Sartorato
Paola
P
Institut National de la Santé et de la Recherche Médicale, Unité 478, Faculté de Médecine Xavier Bichat, 75018 Paris, France.
Lapeyraque
Anne-Laure
AL
Armanini
Decio
D
Kuhnle
Ursula
U
Khaldi
Yasmina
Y
Salomon
Rémi
R
Abadie
Véronique
V
Di Battista
Eliana
E
Naselli
Arturo
A
Racine
Alain
A
Bosio
Maurizio
M
Caprio
Massimiliano
M
Poulet-Young
Véronique
V
Chabrolle
Jean-Pierre
JP
Niaudet
Patrick
P
De Gennes
Christiane
C
Lecornec
Marie-Hélène
MH
Poisson
Elodie
E
Fusco
Anna Maria
AM
Loli
Paola
P
Lombès
Marc
M
Zennaro
Maria-Christina
MC
D015331:Cohort Studies; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D011546:Pseudohypoaldosteronism / Q000145:classification / Q000235:genetics*; D018161:Receptors, Mineralocorticoid / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
D018161:Receptors, Mineralocorticoid