Screening the human bradykinin B2 receptor gene in patients with cardiovascular diseases: Identification of a functional mutation in the promoter and a new coding variant (T21M)

Abstract

To elucidate if genetic variants in the bradykinin B2 receptor (B2) gene occur that could affect receptor expression and function, we screened for mutations in the promoter and in the coding region of the human B2 gene. In our initial study we analyzed 92 consecutive, unrelated subjects (including 25 patients with hypertrophic cardiomyopathy, 18 patients with dilated cardiomyopathy (DCM), 25 patients with hypertension, 18 patients with coronary heart disease, and 6 patients with valvular heart disease) using nonradioactive polymerase chain reaction-single-strand conformation polymorphism analysis as mutation screening method. We detected eight as yet unknown polymorphic sites in the promoter region of the B2 gene (-845 C/T, -704 C/T, -649 insG, -640 T/C, -536 C/T, -412 C/G, -143 C/T and -78 C/T) with allele frequencies between 0.5 and 13%. One of them (-412 C/G) destroys a Sp1 binding site and abolishes protein binding to this Sp1 site in human umbilical vein 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 coding variant (T21M) in extended samples of 69 patients with HCM, 163 patients with DCM, 109 patients with hypertension, and 173 healthy anonymous blood donors. The promoter variant (-412 C/G) was found in one blood donor and the T21M mutation was not found in the control population. Therefore, it appears that these mutations are rare events and the determination of clinical significance will be a demanding task in the future.

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

“…Infusion of the B 2 receptor antag- RFLP, restriction fragment length polymorphism. a Eight additional polymorphisms in the BDKRB2 promoter region as well as one missense mutation (T21M) were found by Erdmann et al (1998); however, these polymorphisms appear to be present at too low a frequency to be of value for association studies. Eight additional polymorphisms in the BDKBR1 coding region, including two coding for substitution and one coding for premature truncation, were described by Hess et al (2002).…”

Genetic Variations and Polymorphisms of G Protein-Coupled Receptors: Functional and Therapeutic Implications

“…One example is the gene for the bradykinin B 2 receptor. Erdmann et al (122) assessed the role of three novel, but rare, promoter variants isolated in individuals with cardiac disease: A −412C/G variant, identified in a patient with dilated cardiomyopathy, destroys a binding site for the transcription factor Sp1, which affects basal gene transcription; a −704C/ T mutation, identified in an individual with hypertrophic cardiomyopathy, destroys the binding site of a nuclear binding protein; and a −78C/ T mutation, also isolated from an individual with dilated cardiomyopathy, reduces protein binding of an unidentified protein. It will be of interest to determine whether these polymorphisms influence efficacy or toxicity of agents such as angiotensin converting enzyme (ACE) inhibitors, which blunt the degradation of bradykinin.…”