Alternative titles; symbols
HGNC Approved Gene Symbol: APBA1
Cytogenetic location: 9q21.12 Genomic coordinates (GRCh38): 9:69,427,532-69,673,013 (from NCBI)
In the course of the search for the gene mutant in Friedreich ataxia (FRDA; 229300), Fujita et al. (1991) described evolutionarily conserved sequences around the D9S5 marker locus that was shown to be linked to Friedreich ataxia. This was considered to be a candidate gene for FRDA. Duclos et al. (1993) identified a transcript containing these conserved sequences. The 7-kb transcript corresponded to a gene designated X11 that extended at least 80 kb in the direction opposite D9S15. The gene was expressed in the brain, including the cerebellum, but was not detectable in several nonneuronal tissues and cell lines. In situ hybridization of adult mouse brain sections showed prominent expression in the granular layer of the cerebellum. Expression was also found in the spinal cord. The cDNA, which is a partial sequence (Okamoto and Sudhof, 1997), contains an open reading frame encoding a 708-amino acid sequence that showed no significant similarity to other proteins but contained a unique, 24-residue, putative transmembrane segment. On the basis of these findings, Duclos et al. (1993) suggested that this 'pioneer' gene represents the FRDA gene. Further studies by Rodius et al. (1994) excluded X11 as a candidate for the Friedreich ataxia gene. Duclos and Koenig (1995) compared the primary structure of X11 between human and mouse. Okamoto and Sudhof (1997) determined that mouse X11 is an ortholog of human MINT2 (602712) and not of human X11 (MINT1). Another gene, designated X25 according to the same system as that used for X11, proved to be the gene mutant in Friedreich ataxia.
By searching for proteins that bind to Munc18-1 (602926), Okamoto and Sudhof (1997) isolated rat cDNAs encoding Mint1 and Mint2. They determined the full-length human MINT1 cDNA sequence (GenBank AF029106) using human MINT1 ESTs. The deduced 837-amino acid MINT1 protein contains an N-terminal domain that binds to Munc18-1, a middle phosphotyrosine-binding (PTB) domain that binds to phosphatidylinositol phosphates, and 2 C-terminal PDZ domains. The rat Mint1 protein is largely membrane-bound and copurifies with synaptic plasma membranes, but it is not a component of synaptic vesicles. The authors suggested that in the brain Mint1 is part of a multimeric complex containing Munc18-1 and syntaxin-1 (186590) that likely functions as an intermediate in synaptic vesicle docking/fusion.
Using immunostaining analysis, Stricker and Huganir (2003) showed that endogenous Apba1 and Apba2 were present in dendrites and spines of rat brain. In cultured hippocampal neurons, Apba1 and Apba2 localized to the trans-Golgi network.
Hartz (2010) mapped the APBA1 gene to chromosome 9q21.11-q21.12 based on an alignment of the APBA1 sequence (GenBank AF029106) with the genomic sequence (GRCh37).
Abnormal processing of the membrane-spanning amyloid precursor protein (APP; 104760), resulting in the production of increased amounts of fibrillogenic beta-amyloid peptide (A-beta), is considered to be one of the key metabolic events underlying Alzheimer disease (104300). One pathway for A-beta production involves the reinternalization of membrane-bound APP into lysosomes where APP containing intact A-beta are generated. In common with a number of cell surface receptors, the C-terminal cytoplasmic domain of APP contains an asn-pro-thr-tyr (NPTY) motif that mediates re-internalization via clathrin-coated pits (Chen et al., 1990). This motif has also been demonstrated to be a consensus sequence for binding to phosphotyrosine-binding/-interacting domain (PTB)-bearing proteins (van der Geer and Pawson, 1995). Several groups demonstrated that the cytoplasmic domain of APP binds to 4 human PTB proteins: X11, X11-like (APBA2; 602712), Fe65 (APBB1; 602709), and Fe65-like (APBB2; 602710). PTB-domain proteins are believed to be involved in signal transduction processes, and the interaction of APP with the 4 human PTB proteins suggest a role for APP in such signal transaction mechanisms. Furthermore, as the 4 proteins interact with the YENPTY motif in APP, these PTB proteins may modulate processing of APP and hence formation of A-beta.
Butz et al. (1998) identified a complex of 3 proteins in brain that has the potential to couple synaptic vesicle exocytosis to neuronal cell adhesion. The 3 proteins are CASK (300172), a protein related to membrane-associated guanylate kinases (MAGUKs); Mint1 (APBA1), a putative vesicular trafficking protein; and Veli1 (603380), -2, and -3, vertebrate homologs of C. elegans LIN7. CASK, Mint1, and the Velis form a tight, salt-resistant complex. All of these proteins contain PDZ domains in addition to other modules. Butz et al. (1998) proposed that the tripartite complex acts as a nucleation site for the assembly of proteins involved in synaptic vesicle exocytosis and synaptic junctions.
Experiments with vesicles containing NMDA receptor 2B (NR2B subunit; 138252) showed that they are transported along microtubules by KIF17 (605037), a neuron-specific molecular motor in neuronal dendrites. Setou et al. (2000) demonstrated that selective transport is accomplished by direct interaction of the KIF17 tail with a PDZ domain of Lin10, which is a constituent of a large protein complex including Lin2 (CASK), Lin7 (Veli1), and the NR2B subunit. Setou et al. (2000) concluded that this interaction, which is specific for a neurotransmitter receptor critically important for plasticity in the postsynaptic terminal, may be a regulatory point for synaptic plasticity and neuronal morphogenesis.
Using immunoprecipitation and pull-down assays, Stricker and Huganir (2003) showed that rat Apba1 and Apba2 interacted directly with the AMPA receptor subunits Glur1 (GRIA1; 138248) and Glur2 (GRIA2; 138247).
Using yeast 2-hybrid analysis of a human brain cDNA expression library and protein pull-down and coimmunoprecipitation analyses of transfected CHO cells, Lau et al. (2010) showed that the C-terminal region of FSBP (616306) interacted with the 2 C-terminal PDZ domains of X11-alpha, but not with either PDZ domain alone. Endogenous Fsbp and X11-alpha also coimmunoprecipitated from nuclear lysates of primary rat cortical neurons. Coexpression of X11-alpha and FSBP resulted in repression of a GSK3-beta (605004) promoter reporter construct. Mutation of the PDZ domains of X11-alpha eliminated GSK3-beta repression.
Blanco et al. (1998) considered APBA1, APBA2, APBB1, and APBB2 candidate genes for Alzheimer disease.
Jenkins et al. (1987, 1989) used single-stranded beta-amyloid cDNA as a probe for in situ chromosome hybridization in Epstein-Barr virus transformed lymphoblastoid cells from 3 patients with familial Alzheimer disease (from 2 different families). Although a concentration of grains was found on chromosome 21, a significantly increased number of grains were found on chromosome 9 in the region 9q31-qter. The functional significance of the hybridizing sequence was not known; hence, they designated the protein 'amyloid beta A4 precursor protein-like 1.'
Blanco, G., Irving, N. G., Brown, S. D. M., Miller, C. C. J., McLoughlin, D. M. Mapping of the human and murine X11-like genes (APBA2 and Apba2), the murine Fe65 gene (Apbb1), and the human Fe65-like gene (APBB2): genes encoding phosphotyrosine-binding domain proteins that interact with the Alzheimer's disease amyloid precursor protein. Mammalian Genome 9: 473-475, 1998. [PubMed: 9585438] [Full Text: https://doi.org/10.1007/s003359900800]
Butz, S., Okamoto, M., Sudhof, T. C. A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain. Cell 94: 773-782, 1998. [PubMed: 9753324] [Full Text: https://doi.org/10.1016/s0092-8674(00)81736-5]
Chen, W.-J., Goldstein, J. L., Brown, M. S. NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor. J. Biol. Chem. 265: 3116-3123, 1990. [PubMed: 1968060]
Duclos, F., Boschert, U., Sirugo, G., Mandel, J.-L., Hen, R., Koenig, M. Gene in the region of the Friedreich ataxia locus encodes a putative transmembrane protein expressed in the nervous system. Proc. Nat. Acad. Sci. 90: 109-113, 1993. [PubMed: 7678331] [Full Text: https://doi.org/10.1073/pnas.90.1.109]
Duclos, F., Koenig, M. Comparison of primary structure of a neuron-specific protein, X11, between human and mouse. Mammalian Genome 6: 57-58, 1995. [PubMed: 7719031] [Full Text: https://doi.org/10.1007/BF00350899]
Fujita, R., Hanauer, A., Vincent, A., Mandel, J.-L., Koenig, M. Physical mapping of two loci (D9S5 and D9S15) tightly linked to Friedreich ataxia locus (FRDA) and identification of nearby CpG islands by pulse-field gel electrophoresis. Genomics 10: 915-920, 1991. [PubMed: 1916823] [Full Text: https://doi.org/10.1016/0888-7543(91)90179-i]
Hartz, P. A. Personal Communication. Baltimore, Md. 11/10/2010.
Jenkins, E. C., Devine-Gage, E. A., Yao, X.-L., Houck, G. E., Jr., Brown W. T., Robakis, N. K., Wisniewski, K. E., Silverman, W. P., Reisberg, B., Wisniewski, H. M. Beta-amyloid protein probe hybridized to chromosome 9 in 3 Alzheimer disease individuals. Prog. Clin. Biol. Res. 317: 269-275, 1989. [PubMed: 2690102]
Jenkins, E. C., Devine-Gage, E. A., Yao, X.-L., Houck, G. E., Jr., Brown, W. T., Wisniewski, H. M., Robakis, N. K. In-situ hybridisation of the beta-amyloid protein probe to chromosome 9 in patients with familial Alzheimer's disease. (Letter) Lancet 330: 1155-1156, 1987. Note: Originally Volume II. [PubMed: 2890057] [Full Text: https://doi.org/10.1016/s0140-6736(87)91591-1]
Lau, K.-F., Perkinton, M. S., Rodriguez, L., McLoughlin, D. M., Miller, C. C. J. An X11-alpha/FSBP complex represses transcription of the GSK3-beta gene promoter. NeuroReport 21: 761-766, 2010. [PubMed: 20531236] [Full Text: https://doi.org/10.1097/WNR.0b013e32833bfca0]
Okamoto, M., Sudhof, T. C. Mints, Munc18-interacting proteins in synaptic vesicle exocytosis. J. Biol. Chem. 272: 31459-31464, 1997. [PubMed: 9395480] [Full Text: https://doi.org/10.1074/jbc.272.50.31459]
Rodius, F., Duclos, F., Wrogemann, K., Le Paslier, D., Ougen, P., Billault, A., Belal, S., Musenger, C., Brice, A., Durr, A., Mignard, C., Sirugo, G., Weissenbach, J., Cohen, D., Hentati, F., Ben Hamida, M., Mandel, J.-L., Koenig, M. Recombinations in individuals homozygous by descent localize the Friedreich ataxia locus in a cloned 450-kb interval. Am. J. Hum. Genet. 54: 1050-1059, 1994. [PubMed: 8198128]
Setou, M., Nakagawa, T., Seog, D.-H., Hirokawa, N. Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport. Science 288: 1796-1802, 2000. [PubMed: 10846156] [Full Text: https://doi.org/10.1126/science.288.5472.1796]
Stricker, N. L., Huganir, R. L. The PDZ domains of mLin-10 regulate its trans-Golgi network targeting and the surface expression of AMPA receptors. Neuropharmacology 45: 837-848, 2003. [PubMed: 14529721] [Full Text: https://doi.org/10.1016/s0028-3908(03)00275-2]
van der Geer, P., Pawson, T. The PTB domain: a new protein module implicated in signal transduction. Trends Biochem. Sci. 20: 277-280, 1995. [PubMed: 7545337] [Full Text: https://doi.org/10.1016/s0968-0004(00)89043-x]