Mineralocorticoid Receptor Mutations and a Severe Recessive Pseudohypoaldosteronism Type 1
| Autor: | Raphaël Teissier, Edwige-Ludiwyne Hubert, Fabio L. Fernandes-Rosa, Michel Fay, Marie-Edith Rafestin-Oblin, Maria-Christina Zennaro, Xavier Jeunemaitre, Chantal Metz, Brigitte Escoubet |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Male
medicine.medical_specialty medicine.drug_class Pseudohypoaldosteronism Population 030209 endocrinology & metabolism Biology Severity of Illness Index 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Mineralocorticoid receptor Internal medicine Chlorocebus aethiops medicine Animals Humans Allele education Aldosterone Gene 030304 developmental biology Family Health Genetics 0303 health sciences education.field_of_study Infant Newborn General Medicine medicine.disease Failure to Thrive Pedigree Receptors Mineralocorticoid Basic Research Endocrinology chemistry Codon Nonsense Nephrology Mineralocorticoid Child Preschool COS Cells Failure to thrive Codon Terminator Female medicine.symptom Hyponatremia Protein Binding |
| Zdroj: | Journal of the American Society of Nephrology; Vol 22 Journal of the American Society of Nephrology |
| ISSN: | 1046-6673 |
| DOI: | 10.1681/ASN.2011030245 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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