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Autosomal Dominant Pseudohypoaldosteronism Type 1: Mechanisms, Evidence for Neonatal Lethality, and Phenotypic Expression in Adults

David S. Geller^*, Junhui Zhang^*, Maria-Christina Zennaro, Alberto Vallo-Boado, Juan Rodriguez-Soriano, Laszlo Furu^*, Robert Haws, Daniel Metzger^||, Barbara Botelho^¶, Lefkothea Karaviti^#, Andrea M. Haqq^**, Howard Corey, Sandra Janssens, Pierre Corvol and Richard P. Lifton

^* Section of Nephrology and Department of Genetics, Yale University School of Medicine, New Haven, Connecticut; INSERM, U36, Collège de France, Paris, France; Division of Pediatric Nephrology, Department of Pediatrics, Hospital de Cruces and Basque University School of Medicine, Bilbao, Spain; Division of Pediatric Nephrology, Marshfield Clinic, Marshfield, Wisconsin; ^|| Division of Pediatric Endocrinology, University of British Columbia, Vancouver, British Columbia, Canada; ^¶ Division of Pediatric Nephrology, Oakland Children’s Hospital, Oakland, California; ^# Division of Pediatric Endocrinology, Baylor College of Medicine, Houston, Texas; ^** Division of Pediatric Endocrinology and Diabetes, Duke University Medical Center, Durham, North Carolina; Division of Pediatric Nephrology, Morristown Memorial Hospital, Morristown, New Jersey; and Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium

Address correspondence to: Dr. David S. Geller, Section of Nephrology, Yale University School of Medicine, PO Box 208029, New Haven, CT 06520-8029. Phone: 203-737-5298; Fax: 203-785-4904; david.geller{at}yale.edu

Received for publication November 15, 2005. Accepted for publication March 6, 2006.

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.

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