title: Mineralocorticoid receptor mutations and a severe recessive pseudohypoaldosteronism type 1.
abstract: Pseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease of mineralocorticoid resistance characterized by salt wasting and failure to thrive in infancy. Here we describe the first case of a newborn with severe recessive PHA1 caused by two heterozygous mutations in NR3C2, gene coding for the mineralocorticoid receptor (MR). Independent segregation of the mutations occurred in the family, with p.Ser166X being transmitted from the affected father and p.Trp806X from the asymptomatic mother Whereas the truncated MR(166X) protein was degraded, MR(806X) was expressed both at the mRNA and protein level. Functional studies demonstrated that despite its inability to bind aldosterone, MR(806X) had partial ligand-independent transcriptional activity. Partial nuclear localization of MR(806X) in the absence of hormone was identified as a prerequisite to initiate transcription. This exceptional case broadens the spectrum of clinical phenotypes of PHA1 and demonstrates that minimal residual activity of MR is compatible with life. It also suggests that rare hypomorphic NR3C2 alleles may be more common than expected from the prevalence of detected PHA1 cases. This might prove relevant for patient's care in neonatal salt losing disorders and may affect renal salt handling and blood pressure in the general population.
authors: INSERM, U970, Paris Cardiovascular Research Center - PARCC, 56, rue Leblanc, 75015 Paris, France.
authors: Edwige-Ludiwyne
authors: EL
authors: Hubert
authors: Raphaël
authors: R
authors: Teissier
authors: Fábio L
authors: FL
authors: Fernandes-Rosa
authors: Michel
authors: M
authors: Fay
authors: Marie-Edith
authors: ME
authors: Rafestin-Oblin
authors: Xavier
authors: X
authors: Jeunemaitre
authors: Chantal
authors: C
authors: Metz
authors: Brigitte
authors: B
authors: Escoubet
authors: Maria-Christina
authors: MC
authors: Zennaro
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D018389:Codon, Nonsense / Q000235:genetics*; D018388:Codon, Terminator / Q000235:genetics; D005183:Failure to Thrive / Q000235:genetics*; D005192:Family Health; D005260:Female; D006801:Humans; D007010:Hyponatremia / Q000235:genetics*; D007231:Infant, Newborn; D008297:Male; D010375:Pedigree; D011485:Protein Binding / Q000235:genetics; D011546:Pseudohypoaldosteronism / Q000235:genetics*; D018161:Receptors, Mineralocorticoid / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index
chemical_list: D018389:Codon, Nonsense; D018388:Codon, Terminator; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone