Editors' ChoiceGenomics

From Polymorphism to Aberrant Signaling

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Science's STKE  15 Apr 2003:
Vol. 2003, Issue 178, pp. tw143
DOI: 10.1126/stke.2003.178.tw143

Can analysis of genetic polymorphisms provide insight into the signaling pathways associated with disease? That is certainly the hope of this postgenomic age. Kammerer et al. analyzed single-nucleotide polymorphisms (SNPs) to find alleles for which the number of polymorphisms decreased with age, which would suggest that those polymorphisms are associated with mortality or disease morbidity. The d-AKAP2 gene, which encodes dual-specific A kinase-anchoring protein 2 (d-AKAP2), showed the strongest correlation with age. The polymorphism in the G allele caused either an A-to-G conversion in the 3′ untranslated region (UTR) or an A-to-G conversion that resulted in an isoleucine to valine (I646V) transversion. Analysis of twins demonstrated that the G allele was associated with altered cardiac function, specifically an increase in the PR interval. Binding assays with fragments of d-AKAP2 containing either the isoleucine or the valine showed that the valine version had a higher affinity for the RIα (regulatory isoform I) than the isoleucine version of d-AKAP2. The effect of this difference was analyzed in transfected cells in which isoleucine d-AKAP2 or valine d-AKAP2 was tethered to the mitochondrial membrane and the abilities of the two regulatory subunits (RIα and RIIα) of protein kinase A were analyzed by microscopy. The isoleucine variant was not able to sequester the RIα, which suggests that this SNP may have an impact on signaling through pathways involving PKA. These results thus direct attention to altered signal compartmentalization as a factor in cardiac disease pathology.

S. Kammerer, L. L. Burns-Hamuro, Y. Ma, S. C. Hamon, J. M. Cànaves, M. M. Shi, M. R. Nelson, C. F. Sing, C. R. Cantor, S. S. Taylor, A. Braun, Amino acid variant in the kinase binding domain of dual-specific A kinase-anchoring protein 2: A disease susceptibility polymorphism. Proc. Natl. Acad. Sci. U.S.A. 100, 4066-4071 (2003). [Abstract] [Full Text]