title: Different inactivating mutations of the mineralocorticoid receptor in fourteen families affected by type I pseudohypoaldosteronism.
abstract: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 478, Faculté de Médecine Xavier Bichat, 75018 Paris, France.
authors.forename: Paola
authors.initials: P
authors.lastname: Sartorato
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Lapeyraque
authors.forename: Decio
authors.initials: D
authors.lastname: Armanini
authors.forename: Ursula
authors.initials: U
authors.lastname: Kuhnle
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Khaldi
authors.forename: Rémi
authors.initials: R
authors.lastname: Salomon
authors.forename: Véronique
authors.initials: V
authors.lastname: Abadie
authors.forename: Eliana
authors.initials: E
authors.lastname: Di Battista
authors.forename: Arturo
authors.initials: A
authors.lastname: Naselli
authors.forename: Alain
authors.initials: A
authors.lastname: Racine
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bosio
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Caprio
authors.forename: Véronique
authors.initials: V
authors.lastname: Poulet-Young
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Chabrolle
authors.forename: Patrick
authors.initials: P
authors.lastname: Niaudet
authors.forename: Christiane
authors.initials: C
authors.lastname: De Gennes
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Lecornec
authors.forename: Elodie
authors.initials: E
authors.lastname: Poisson
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Fusco
authors.forename: Paola
authors.initials: P
authors.lastname: Loli
authors.forename: Marc
authors.initials: M
authors.lastname: Lombès
authors.forename: Maria-Christina
authors.initials: MC
authors.lastname: Zennaro
mesh_terms: 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
chemical_list: D018161:Receptors, Mineralocorticoid