Alternative titles; symbols
HGNC Approved Gene Symbol: PLEKHA1
Cytogenetic location: 10q26.13 Genomic coordinates (GRCh38): 10:122,374,708-122,442,600 (from NCBI)
By searching EST databases for proteins containing a putative phosphatidylinositol 3,4,5-trisphosphate-binding motif (PPBM), Dowler et al. (2000) identified PLEKHA1, which they designated TAPP1. The deduced 404-amino acid protein contains 2 pleckstrin homology (PH) domains, the second of which contains the PPBM. The last 3 C-terminal amino acids of TAPP1 are predicted to interact with PDZ domain-containing proteins. TAPP1 and TAPP2 (607773) share 58% identity over the first 300 amino acids, which encompass both PH domains. There is little homology in the C termini. Northern blot analysis detected a 4.0-kb transcript expressed in all tissues examined, with highest levels in skeletal muscle, spleen, lung, thymus, and placenta.
Dowler et al. (2000) determined that full-length TAPP1 and the isolated C-terminal PH domain of TAPP1 interacted with phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2), but not with any other phosphoinositides tested. TAPP1 possessed a 5-fold higher affinity for PtdIns(3,4)P2 than TAPP2. Mutation of the conserved arg212 to leucine within the PPBM of the second PH domain of TAPP1 reduced or eliminated PtdIns(3,4)P2 binding. The N-terminal PH domain contributed to the affinity with which the C-terminal PH domain bound to PtdIns(3,4)P2.
By genomic sequence analysis, Dowler et al. (2000) mapped the PLEKHA1 gene to chromosome 10q25.3-q26.2.
Jakobsdottir et al. (2005) genotyped all nonsynonymous single-nucleotide polymorphisms (SNPs) in the critical region on 10q26 identified by Weeks et al. (2004) and found a highly significant association (P less than 0.00001) between age-related macular degeneration (ARMD: 603075) and PLEKHA1. They concluded that this gene is primarily responsible for the evidence of linkage of age-related maculopathy to 10q26 and a major contributor to susceptibility to this disorder. The association of either a single or a double copy of the high-risk allele within the PLEKHA1 locus accounted for an odds ratio of 5.0 for ARMD and a population-attributable risk as high as 57%.
Conley et al. (2006) investigated the association of the PLEKHA1 and LOC387715 (611313) genes with ARMD in 2 independent cohorts collected using different ascertainment schemes: the Cardiovascular Health Study (CHS) and the Age-Related Eye Disease Study (AREDS). LOC387715 was significantly associated with ARM in both cohorts (P less than 0.00001) and a metaanalysis confirmed that the risk allele (A69S; 611313.0001) in the heterozygous and homozygous state (odds ratio = 2.5 and 7.3, respectively) conferred susceptibility. The A320T variant in PLEKHA1, which is located on the same haplotype block as LOC387715, was significantly associated with ARMD status in the AREDS cohort (P = 0.00004), but not in the CHS cohort (p = 0.08). Haplotype analysis indicated that the LOC387715 gene more likely harbors the true ARMD-predisposing variant.
Conley, Y. P., Jakobsdottir, J., Mah, T., Weeks, D. E., Klein, R., Kuller, L., Ferrell, R. E., Gorin, M. B. CFH, ELOVL4, PLEKHA1 and LOC387715 genes and susceptibility to age-related maculopathy: AREDS and CHS cohorts and meta-analyses. Hum. Molec. Genet. 15: 3206-3218, 2006. [PubMed: 17000705] [Full Text: https://doi.org/10.1093/hmg/ddl396]
Dowler, S., Currie, R. A., Campbell, D. G., Deak, M., Kular, G., Downes, C. P., Alessi, D. R. Identification of pleckstrin-homology-domain-containing proteins with novel phosphoinositide-binding specificities. Biochem. J. 351: 19-31, 2000. [PubMed: 11001876] [Full Text: https://doi.org/10.1042/0264-6021:3510019]
Jakobsdottir, J., Conley, Y. P., Weeks, D. E., Mah, T. S., Ferrell, R. E., Gorin, M. B. Susceptibility genes for age-related maculopathy on chromosome 10q26. Am. J. Hum. Genet. 77: 389-407, 2005. [PubMed: 16080115] [Full Text: https://doi.org/10.1086/444437]
Weeks, D. E., Conley, Y. P., Tsai, H.-J., Mah, T. S., Schmidt, S., Postel, E. A., Agarwal, A., Haines, J. L., Pericak-Vance, M. A., Rosenfeld, P. J., Paul, T. O., Eller, A. W., Morse, L. S., Dailey, J. P., Ferrell, R. E., Gorin, M. B. Age-related maculopathy: a genomewide scan with continued evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions. Am. J. Hum. Genet. 75: 174-189, 2004. [PubMed: 15168325] [Full Text: https://doi.org/10.1086/422476]