Recurrence of the R947X Mutation in Unrelated Families with Autosomal Dominant Pseudohypoaldosteronism Type 1: Evidence for a Mutational Hot Spot in the Mineralocorticoid Receptor Gene

• Published in: The journal of clinical endocrinology and metabolism Vol. 91; no. 9; pp. 3671 - 3675
• Main Authors: Fernandes-Rosa, Fabio L., de Castro, Margaret, Latronico, Ana Claudia, Sippell, Wolfgang G., Riepe, Felix G., Antonini, Sonir R.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Oxford University Press 01.09.2006; Endocrine Society
• Subjects: 17-alpha-Hydroxyprogesterone - blood; Aldosterone - blood; Biological and medical sciences; Disease hot spots; Disease resistance; DNA - chemistry; DNA - genetics; DNA sequencing; Endocrinopathies; Female; Founder effect; Fundamental and applied biological sciences. Psychology; Genetic markers; Genetic variability; Haplotypes; Humans; Hydrocortisone - blood; Infant; Infant, Newborn; Male; Medical sciences; Microsatellite Repeats; Microsatellites; Mineralocorticoid receptors; Mutation; Mutation hot spots; Pedigree; Point Mutation; Polymerase Chain Reaction; Polymorphism, Genetic; Pseudohypoaldosteronism; Pseudohypoaldosteronism - blood; Pseudohypoaldosteronism - genetics; Pseudohypoaldosteronism - pathology; Receptors, Mineralocorticoid - genetics; Renin - blood; Stop codon; Vertebrates: endocrinology; Relapse; Gene; Mineralocorticoid; Autosomal character; Hot spot; Pseudohypoaldosteronism type 1; Genetics; Mutation; Endocrinology; Genetic disease; Biological receptor
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2006-0605

Background: The renal form of pseudohypoaldosteronism type 1 (PHA1) is a rare disease characterized by congenital mineralocorticoid resistance of the kidney. Twenty-two different loss-of-function mutations in the mineralocorticoid receptor gene have been described in families with PHA1. These mutations were not recurrent and resulted in a large phenotypic variability. Objective: The objective of this study is to analyze the recurrence of an inactivating mutation in the mineralocorticoid receptor gene in unrelated families with autosomal dominant PHA1. Patients: Seventeen members from three unrelated families with autosomal dominant PHA1 were studied, including 11 affected patients with variable clinical manifestations. Fifty healthy subjects were used as controls. Methods: Genomic DNA was extracted, and the entire coding region of the mineralocorticoid receptor gene was submitted to automatic sequencing. Four dinucleotide microsatellite markers spanning a region of 3.2 cM in the human mineralocorticoid receptor gene locus, and two intragenic polymorphisms were used for haplotype analysis. Results: A heterozygous point mutation at codon 947 (c.2839C>T) changing arginine to stop codon (R947X) was found in the three families. Different haplotypes segregated with the R947X mutation in each family, demonstrating the absence of a founder effect for this mutation. Conclusion: Codon 947 of the mineralocorticoid receptor is the first mutational hot spot for autosomal dominant PHA1.