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Molecular scanning of the beta-3-adrenergic receptor gene in Pima Indians and Caucasians

✍ Scribed by Kristi Silver; Jeremy Walston; Yufeng Yang; Richard Pratley; Eric Ravussin; Nina Raben; Alan R. Shuldiner

Publisher
John Wiley and Sons
Year
1999
Tongue
English
Weight
128 KB
Volume
15
Category
Article
ISSN
1520-7552

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✦ Synopsis

Background The beta-3-adrenergic receptor (b3AR) stimulates lipolysis and thermogenesis in adipocytes. The Trp64Arg b3AR variant is associated in some, but not all, studies with an earlier onset of Type 2 diabetes mellitus and features of the insulin resistance syndrome. Functional studies as to the role of the Trp64Arg variant have been inconclusive. Earlier studies screened the b3AR gene in only ten obese, diabetic Pima Indians. Potentially another yet to be identi®ed polymorphism in the b3AR gene in linkage disequilibrium with the Trp64Arg polymorphism could explain the ®ndings in the association and functional studies.

Methods We scanned the b3AR gene in 20 diabetic Pima subjects and 20 Caucasian subjects using single stranded conformational polymorphism (SSCP) analysis. Variants were sequenced using dideoxy sequence analysis and further characterized using allele speci®c oligonucleotide hybridization (ASO) and RNA template speci®c-polymerase chain reaction (RS-PCR) assays.

Results

We found a guanine to thymidine substitution in the ®rst intron, 14 bases from the splice donor site in both groups. In virtually all subjects, only two haplotypes were detected, Trp64/g1856 and Arg64/t1856, indicating that the g1856t polymorphism is in linkage disequilibrium with the Trp64Arg polymorphism. The g1856t substitution introduces a new consensus splice donor site which, if used, would encode a truncated protein. RNA levels of the two b3AR alleles were approximately equal in omental adipose tissue of heterozygotes. No aberrantly spliced b3AR mRNA was detected, indicating that the new consensus splice donor site is not used in vivo.

Conclusion

The g1856t polymorphism is in linkage disequilibrium with the Trp64Arg variant, but does not appear to have a functional role.

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