Human calcitonin receptor-like receptor for adrenomedullin: genomic structure, eight single-nucleotide polymorphisms, and haplotype analysis

Adrenomedullin (ADM), a peptide characterized by persistent hypotensive act ivity, is thought to be involved when the control mechanism of blood pressu re is deranged, because its plasma concentration is upregulated in hyperten sive patients. The receptor for ADM, a molecular complex consisting of calc itonin-receptor-like receptor (CRLR) and receptor-activity-modifying protei n 2 (RAMP2), is activated through a unique intracellular transport mechanis m. By analyzing the nucleotide sequences of bacterial artificial chromosome (BAC) clones, we have established that the gene encoding CRLR is spread ov er a genomic distance of 103,145 bases; it contains 15 exons interrupted by 14 introns, including 1 that spans more than 60 kilobases. Exons 1-3 const itute the 5' noncoding region; exons 4 through 15 are coding elements, of w hich exons 8 to 14 encode seven transmembrane domains. Eight novel single-n ucleotide polymorphisms (SNPs) and their allelic frequencies in the Japanes e population were found by direct sequencing of 32 alleles; two SNPs were i n the 5' flanking region, one in exon 2, and the other five around intron-e xon junctions. Eight haplotypes were constructed using these alleles in our Japanese population sample. The data establish a basis for investigations to detect molecular variants in the ADM receptor that might alter control o f blood pressure and confer on individuals a predisposition to essential hy pertension.