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

Angiotensin II type 1 receptor gene abnormality in a patient with Bart ter's syndrome. Administration of a selective angiotensin I type 1 rec eptor (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, featur es characteristic of human Bartter's syndrome. We, therefore, explored the possibility that Bartter's syndrome may involve an AT(1) abnormal ity. Using a pair of AT(1)-specific oligonucleotide primers and two di fferent DNA polymerases (Taq and Pfu), we amplified the similar to 1 k b AT(1) coding region of genomic DNA isolated from leukocytes of five patients with Bartter's syndrome by PCR and analyzed the sequence of t he product. While the sequence of all clones from four patients were i dentical to that already reported for the normal human AT(1) DNA seque nce, 50% of the clones from one patient with Bartter's syndrome were f ound to have A --> G transition at nucleotide 931 which causes an amin o acid substitution (arg --> gly) on the carboxy-terminal cytosolic ta il of AT(1). This mutation was not found in DNA from 50 normal control s which were screened by restriction enzyme digestion pattern of the P CR products of this region. As PCR-amplified AT(1) DNA clones from fou r other individuals with Bartter's syndrome did not display any abnorm ality in the coding region, the possibility exists that Bartter's synd rome consists of multiple disease entities, where an AT(1) gene abnorm ality represents a specific subgroup of the syndrome and/or some abnor mality includes mutations outside of the coding region.