HGNC Approved Gene Symbol: AP4B1
Cytogenetic location: 1p13.2 Genomic coordinates (GRCh38) : 1:113,894,194-113,905,028 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p13.2 | Spastic paraplegia 47, autosomal recessive | 614066 | Autosomal recessive | 3 |
The AP4B1 gene encodes a subunit of the heterotetrameric adaptor protein (AP) complex, a component of intracellular transport of proteins that is thought to have a unique role in neurons. AP4 is composed of 2 large chains, beta-4 (AP4B1) and epsilon-4 (AP4E1; 607244), a medium chain, mu-4 (AP4M1; 602296), and a small chain, sigma-4 (AP4S1; 607243) (summary by Tuysuz et al., 2014).
By searching an EST database for homologs of the beta subunits of AP complexes, followed by 5-prime RACE of a skeletal muscle cDNA library, Dell'Angelica et al. (1999) obtained a full-length cDNA encoding AP4B1. The deduced 739-amino acid protein has a calculated molecular mass of about 83 kD and contains an N-terminal 'trunk' region, a solvent-accessible random coil 'hinge' region, and a C-terminal 'ear' domain with a high alpha helix content. Homology with other beta subunits is restricted to the N-terminal trunk region, where AP4B1 shares 28% identity with mammalian Ap1b1 (600157) and Ap2b1 (601025) and 21% identity with human AP3B1 (603401) and AP3B2 (602166). Northern blot analysis revealed ubiquitous expression of a 2.5-kb transcript; a minor 6-kb species was detected in some tissues. Western blot analysis of HeLa cell lysates confirmed an apparent molecular mass of 83 kD, and fractionation studies revealed that it can partition as both a cytosolic and a membrane protein. The membrane portion could be partially extracted with high salt, indicating that AP4B1 is a peripheral membrane protein. Gel filtration of human fibroblast cytosol revealed that AP4B1 is part of a 280-kD complex containing other proteins of 140, 50, and 17 kD. Western blot analysis identified these proteins as AP4E1, AP4M1, and AP4S1, respectively. Immunolocalization of AP4B1 in HeLa cells indicated that the AP4 complex associates with the trans-Golgi network or an adjacent structure. This association was sensitive to brefeldin-A treatment, indicating that the membrane localization of AP4 is dependent upon the small GTP-binding protein ARF1 (103180).
By searching an EST database and screening a brain cDNA library, Hirst et al. (1999) isolated a cDNA encoding AP4B1. The predicted AP4B1 protein contains several motifs shared with other AP beta subunits, including a WIIGEY motif at amino acid 500 and a KKLVYLY motif near the N terminus. They noted that AP4B1 is smaller that AP1B1, AP2B1, and AP3B1 and appears to be missing most of the C-terminal hinge and/or ear domain. By coimmunoprecipitation and yeast 2-hybrid analysis, the authors confirmed that AP4B1 interacts with AP4E1 and AP4M1.
Abou Jamra et al. (2011) found ubiquitous AP4B1 expression in all fetal and adult brain structures examined.
Gross (2016) mapped the AP4B1 gene to chromosome 1p13.2 based on an alignment of the AP4B1 sequence (GenBank BC014146) with the genomic sequence (GRCh38).
By linkage analysis followed by candidate gene sequencing of a consanguineous Israeli Arab family with autosomal recessive mental retardation and spasticity (SPG47; 614066), Abou Jamra et al. (2011) identified a homozygous truncating mutation in the AP4B1 gene (607245.0001). The authors concluded that AP4-complex-mediated vesicular trafficking plays a crucial role in brain development and function.
In 2 sibs, born of consanguineous Arab parents, with SPG47, Bauer et al. (2012) identified a homozygous truncating mutation in the AP4B1 gene (607245.0002). The mutation was found by exome sequencing of the candidate region on chromosome 1p13-p12 identified by linkage analysis (Blumkin et al., 2011). Bauer et al. (2012) noted the phenotypic similarities to the patients reported by Abou Jamra et al. (2011).
In 2 sibs, born of unrelated parents, with SPG47, Abdollahpour et al. (2015) identified a homozygous truncating mutation in the AP4B1 gene (607245.0004). Functional studies of the variant and studies on patient cells were not reported.
By linkage analysis followed by candidate gene sequencing of a consanguineous Israeli Arab family with autosomal recessive mental retardation and spasticity (SPG47; 614066), Abou Jamra et al. (2011) identified a homozygous 3-bp insertion (487insTAT) in exon 5 of the AP4B1 gene, resulting in premature protein termination. PCR analysis showed decreased AP4B1 transcripts in patient cells compared to controls, consistent with nonsense-mediated mRNA decay. The mutation was not found in 796 control chromosomes, including 160 Israeli Arab control chromosomes.
In 2 sibs, born of consanguineous Arab parents, with autosomal recessive complicated spastic paraplegia-47 (SPG47; 614066), Bauer et al. (2012) identified a homozygous 1-bp deletion (664delC) in exon 5 of the AP4B1 gene, resulting in a frameshift and premature termination. Each unaffected parent was heterozygous for the mutation, which was not found in 316 Caucasian and 200 ethnically matched control chromosomes.
In 2 Turkish sisters (family 3) with autosomal recessive spastic paraplegia-47 (SPG47; 614066), Tuysuz et al. (2014) identified a homozygous 1-bp deletion (869delC) (chr1.114,244,498delC, NCBI36) in the AP4B1 gene, resulting in a frameshift and premature termination (Leu221fs). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 131) or 1000 Genomes Project databases, or in control chromosomes. Functional studies of the variant and studies on patient cells were not reported.
In 2 sibs, born of unrelated parents, with autosomal recessive spastic paraplegia-47 (SPG47; 614066), Abdollahpour et al. (2015) identified a homozygous 2-bp deletion (c.1160_1161delCA, NM_006594.2) in exon 7 of the AP4B1 gene, resulting in a frameshift and premature termination (Thr387ArgfsTer30). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. Although studies on patient cells and functional studies were not performed, the findings were consistent with a complete loss of protein function.
Abdollahpour, H., Alawi, M., Kortum, F., Beckstette, M., Seemanova, E., Komarek, V., Rosenberger, G., Kutsche, K. An AP4B1 frameshift mutation in siblings with intellectual disability and spastic tetraplegia further delineates the AP-4 deficiency syndrome. Europ. J. Hum. Genet. 23: 256-259, 2015. [PubMed: 24781758] [Full Text: https://doi.org/10.1038/ejhg.2014.73]
Abou Jamra, R., Philippe, O., Raas-Rothschild, A., Eck, S. H., Graf, E., Buchert, R., Borck, G., Ekici, A., Brockschmidt, F. F., Nothen, M. M., Munnich, A., Strom, T. M., Reis, A., Colleaux, L. Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. Am. J. Hum. Genet. 88: 788-795, 2011. [PubMed: 21620353] [Full Text: https://doi.org/10.1016/j.ajhg.2011.04.019]
Bauer, P., Leshinsky-Silver, E., Blumkin, L., Schlipf, N., Schroder, C., Schicks, J., Lev, D., Riess, O., Lerman-Sagie, T., Schols, L. Mutation in the AP4B1 gene cause hereditary spastic paraplegia type 47 (SPG47). Neurogenetics 13: 73-76, 2012. [PubMed: 22290197] [Full Text: https://doi.org/10.1007/s10048-012-0314-0]
Blumkin, L., Lerman-Sagie, T., Lev, D., Yosovich, K., Leshinsky-Silver, E. A new locus (SPG47) maps to 1p13.2-1p12 in an Arabic family with complicated autosomal recessive hereditary spastic paraplegia and thin corpus callosum. J. Neurol. Sci. 305: 67-70, 2011. [PubMed: 21440262] [Full Text: https://doi.org/10.1016/j.jns.2011.03.011]
Dell'Angelica, E. C., Mullins, C., Bonifacino, J. S. AP-4, a novel protein complex related to clathrin adaptors. J. Biol. Chem. 274: 7278-7285, 1999. [PubMed: 10066790] [Full Text: https://doi.org/10.1074/jbc.274.11.7278]
Gross, M. B. Personal Communication. Baltimore, Md. 5/23/2016.
Hirst, J., Bright, N. A., Rous, B., Robinson, M. S. Characterization of a fourth adaptor-related protein complex. Molec. Biol. Cell 10: 2787-2802, 1999. [PubMed: 10436028] [Full Text: https://doi.org/10.1091/mbc.10.8.2787]
Tuysuz, B., Bilguvar, K., Kocer, N., Yalcinkaya, C., Caglayan, O., Gul, E., Sahin, S., Comu, S., Gunel, M. Autosomal recessive spastic tetraplegia caused by AP4M1 and AP4B1 gene mutation: expansion of the facial and neuroimaging features. Am. J. Med. Genet. 164A: 1677-1685, 2014. [PubMed: 24700674] [Full Text: https://doi.org/10.1002/ajmg.a.36514]