ANGIOTENSIN-II TYPE-1 RECEPTOR GENE ABNORMALITY IN A PATIENT WITH BARTTERS-SYNDROME

Angiotensin II type 1 receptor gene abnormality in a patient with Bartter's syndrome. Administration of a selective angiotensin I type 1 receptor (AT(1)) antagonist in animals not only nullifies the vasopressor action of angiotensin II, but also induces chloriduria and kaliuria, juxtoglomerular apparatus (JGA) hypertrophy and hyperreninemia, features characteristic of human Bartter's syndrome. We, therefore, explored the possibility that Bartter's syndrome may involve an AT(1) abnormality. Using a pair of AT(1)-specific oligonucleotide primers and two different DNA polymerases (Taq and Pfu), we amplified the similar to 1 kb AT(1) coding region of genomic DNA isolated from leukocytes of five patients with Bartter's syndrome by PCR and analyzed the sequence of the product. While the sequence of all clones from four patients were identical to that already reported for the normal human AT(1) DNA sequence, 50% of the clones from one patient with Bartter's syndrome were found to have A --> G transition at nucleotide 931 which causes an amino acid substitution (arg --> gly) on the carboxy-terminal cytosolic tail of AT(1). This mutation was not found in DNA from 50 normal controls which were screened by restriction enzyme digestion pattern of the PCR products of this region. As PCR-amplified AT(1) DNA clones from four other individuals with Bartter's syndrome did not display any abnormality in the coding region, the possibility exists that Bartter's syndrome consists of multiple disease entities, where an AT(1) gene abnormality represents a specific subgroup of the syndrome and/or some abnormality includes mutations outside of the coding region.