Screening the human bradykinin B-2 receptor gene in patients with cardiovascular diseases: Identification of a functional mutation in the promoter and a new coding variant (T21M)

To elucidate if genetic variants in the bradykinin B-2 receptor (B-2) gene occur that could affect receptor expression and function, we screened for m utations in the promoter and in the coding region of the human B-2 gene. In our initial study we analyzed 92 consecutive, unrelated subjects (includin g 25 patients with hypertrophic cardiomyopathy, 18 patients with dilated ca rdiomyopathy (DCM), 25 patients with hypertension, 18 patients with coronar y heart disease, and 6 patients with valvular heart disease) using nonradio active polymerase chain reaction-single-strand conformation polymorphism an alysis as mutation screening method. We detected eight as yet unknown polym orphic sites in the promoter region of the B-2 gene (-845 C/T, -704C/T, -64 9 insG, -640 T/C, -536 C/T, -412 C/G, -143 CPT and -78 C/T) with allele fre quencies between 0.5 and 13%. One of them (-412 C/G) destroys a Spl binding site and abolishes protein binding to this Spl site in human umbilical vei n endothelial cells and human vascular smooth muscle cells. In the protein- coding region one new coding variant (T21M) with the potential to create a truncated receptor isoform was detected. We determined the frequency of the promoter variant at position -412 (C --> G) and the newly identified codin g variant (T21M) in extended samples of 69 patients with HCM, 163 patients with DCM, 109 patients with hypertension, and 173 healthy anonymous blood d onors. The promoter variant (-412C/G) was found in one blood donor and the T21M mutation was not found in the control population. Therefore, it appear s that these mutations are rare events and the determination of clinical si gnificance will be a demanding task in the future. Am. J. Med. Genet. 80:52 1-525, 1998. (C) 1998 Wiley-Liss, Inc.