Developmental Endocrinology Branch, NICHD, National Institutes of Health Bethesda, Maryland 20892-1862
Recently, Davies et al. (1) reported that somatic mutations of the coding region of the angiotensin II type 1 receptor (AT1) gene were not found in 17 aldosterone producing adenomas (APA) studied by single strand conformation polymorphism (SSCP) and direct sequencing, although other genetic defects of the 5' and 3' regulatory regions of the gene were not excluded by this study. A previous study showed no abnormalities, on SSCP analysis of the coding region of the AT1 gene, in angiotensin II responsive and angiotensin II unresponsive APAs (2). Recently, we have performed linkage analysis with a polymorphism located within 15kb of the AT1 gene in a 29-member family that included 7 individuals affected with familial hyperaldosteronism type II (FH II). FH II is characterized by primary hyperaldosteronism, dominant transmission, nonsuppressibility of aldosterone by dexamethasone, and absence of the hybrid CYP11B1/CYP11B2 gene known to be the cause of glucocorticoid remediable hyperaldosteronism (or FH I) (3, 4).
Angiotensin II stimulates aldosterone production through activation of
the G-protein coupled 7 transmembrane domain receptor, AT1. Like Davies
et al., we hypothesized that a germ line mutation causing
constitutive activation of the AT1 receptor could be the cause of FH
II. Genomic DNA from 29 family members, including all 7 affected
individuals, was extracted from blood leukocytes, and PCR amplification
of a marker containing a dinucleotide (CA) repeat polymorphism present
in a 0.9 kb EcoRI fragment approximately 15 kb downstream from the 3'
end of the coding sequence of the AT1 gene was performed (5). Linkage
analysis for this marker revealed an LOD score of -2.24 at a
recombination fraction of 0.01 (Table 1),
excluding this gene as a cause of FH II in this family. Figure 1d
emonstrates an informative recombination, where affected individuals 2
and 3 do not share an allele for this gene. Since a LOD score of less
than -2 was achieved with this (Table 1
) and other markers nearby
(data not shown), mutations of AT1 do not appear to be the cause of
familial hyperaldosteronism type II.
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Footnotes
Address correspondence to: David J. Torpy, Section on Pediatric Endocrinology, Developmental Endocrinology, Branch, NICHD, 9000 Rockville Pike, Bethesda, Maryland 20892-1862.
Received August 7, 1997.
References