title: Autosomal dominant pseudohypoaldosteronism type 1: mechanisms, evidence for neonatal lethality, and phenotypic expression in adults.
abstract: Autosomal dominant pseudohypoaldosteronism type 1 (adPHA1) is a rare condition that is characterized by renal resistance to aldosterone, with salt wasting, hyperkalemia, and metabolic acidosis. It is thought of as a mild disorder; affected children's symptoms respond promptly to salt therapy, and treatment is not required after childhood. Mutations in the mineralocorticoid receptor gene (MR) cause adPHA1, but the long-term consequences of MR deficiency in humans are not known. Herein are described six novel adPHA1-causing MR mutations (four de novo) and evidence that haploinsufficiency of MR is sufficient to cause adPHA1. Furthermore, genotype-phenotype correlation is reported in a large adPHA1 kindred. A number of cases of neonatal mortality in infants who were at risk for adPHA1 were identified; coupled with the frequent identification of de novo mutations in affected individuals, this suggests that the seemingly benign adPHA1 may have been a fatal neonatal disorder in previous eras, preventing propagation of disease alleles. In contrast, it is shown that adult patients with adPHA1 are clinically indistinguishable from their wild-type relatives except for presumably lifelong elevation of renin, angiotensin II, and aldosterone levels. These data highlight the critical role of MR in the maintenance of salt homeostasis early in life and illuminate the sodium dependence of pathologic effects of renin and angiotensin II. They furthermore argue that nongenomic effects of aldosterone play no significant role in the long-term development of cardiovascular disease.
authors.affiliation: Section of Nephrology, Yale University School of Medicine, PO Box 208029, New Haven, CT 06520-8029, USA. david.geller@yale.edu
authors.forename: David S
authors.initials: DS
authors.lastname: Geller
authors.forename: Junhui
authors.initials: J
authors.lastname: Zhang
authors.forename: Maria-Christina
authors.initials: MC
authors.lastname: Zennaro
authors.forename: Alberto
authors.initials: A
authors.lastname: Vallo-Boado
authors.forename: Juan
authors.initials: J
authors.lastname: Rodriguez-Soriano
authors.forename: Laszlo
authors.initials: L
authors.lastname: Furu
authors.forename: Robert
authors.initials: R
authors.lastname: Haws
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Barbara
authors.initials: B
authors.lastname: Botelho
authors.forename: Lefkothea
authors.initials: L
authors.lastname: Karaviti
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Haqq
authors.forename: Howard
authors.initials: H
authors.lastname: Corey
authors.forename: Sandra
authors.initials: S
authors.lastname: Janssens
authors.forename: Pierre
authors.initials: P
authors.lastname: Corvol
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D000328:Adult; D019317:Evidence-Based Medicine; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D015994:Incidence; D007223:Infant; D007226:Infant Mortality; D008297:Male; D010641:Phenotype; D011546:Pseudohypoaldosteronism / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics*; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors; D013030:Spain / Q000453:epidemiology
chemical_list: D018161:Receptors, Mineralocorticoid