Alternative titles; symbols
HGNC Approved Gene Symbol: AP3D1
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:2,100,988-2,164,616 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | ?Hermansky-Pudlak syndrome 10 | 617050 | Autosomal recessive | 3 |
AP3D1 is a subunit of the AP3 adaptor-like complex, which is not associated with clathrin (Simpson et al., 1997). The AP3D1 subunit is implicated in intracellular biogenesis and trafficking of pigment granules (Ooi et al., 1997) and possibly platelet dense granules and neurotransmitter vesicles (Kantheti et al., 1998). AP3D1 is expressed in the ubiquitous AP3 complex and also in the neuronal form (summary by Ammann et al., 2016).
Using homology with the alpha- (see AP2A1; 601026) and gamma-adaptins (see AP1G1; 603533) of the AP2 and AP1 complexes, respectively, Simpson et al. (1997) identified an EST clone of AP3D1, and they obtained the full-length cDNA by screening a heart cDNA library. The predicted 1,112-amino acid protein has a calculated molecular mass of 125 kD and contains an N-terminal domain, a highly hydrophilic linker or 'hinge' domain, and a C-terminal 'ear' domain. It also has a WIIGEY consensus sequence found in adaptins and in beta-COP (600959). AP3D1 shares only about 15% identity with the alpha- and gamma-adaptins, and the homology is restricted to the extreme N-terminal portion. AP3D1 shares 96% identity with the homologous Drosophila 'garnet' protein across an N-terminal 100-amino acid stretch. Using coimmunoprecipitation of pig brain cytosol, Simpson et al. (1997) determined that AP3D1, beta-3 (see AP3B1; 603401), sigma-3 (see AP3S1; 601507), and mu-3 (see AP3M1; 610366), but not gamma-adaptins, interact in AP3 complexes. Immunofluorescence localization of AP3D1 showed colocalization with AP3B. Endogenous AP3 complexes showed perinuclear staining with punctate labeling extending to the cell periphery. Staining did not colocalize with endosomal or trans-Golgi markers, nor did it colocalize with clathrin.
Ooi et al. (1997) independently cloned AP3D1 based on sequence similarity with the alpha- and gamma-adaptins. The predicted 1,153-amino acid protein has a calculated molecular mass of 130 kD. Ooi et al. (1997) noted that a C-terminal extension results in the hinge/ear domain being about 2-fold larger than those of the alpha- and gamma-adaptins. They also identified 3 variants containing in-frame deletions. Northern blot analysis revealed a 5-kb transcript in all tissues examined, with highest expression in skeletal muscle, heart, pancreas, and testis. A minor 5.5-kb transcript was detected in skeletal muscle and heart, and a minor 4-kb transcript was detected in testis. Coimmunoprecipitations of human fibroblasts confirmed that AP3D1 interacts with the other subunits of the AP3 complex. Western blot analysis of AP3 complex affinity purified from Jurkat cell cytosol showed AP3D1 to have an apparent molecular mass of 160 kD.
Gross (2017) mapped the AP3D1 gene to chromosome 19p13.3 based on an alignment of the AP3D1 sequence (GenBank AF002163) with the genomic sequence (GRCh38).
Kantheti et al. (1998) mapped the mouse Ap3d1 gene to chromosome 10 in a region showing homology of synteny to human chromosome 19p13.3.
Using a yeast 2-hybrid assay, Lefrancois et al. (2004) determined that the ear domain of the AP3 delta subunit (AP3D1) interacts with both isoforms of the sigma-3 subunit, sigma-3A (AP3S1) and sigma-3B (AP3S2; 602416). An extended C-terminal segment of sigma-3 was necessary for the interaction with the delta subunit. The delta-sigma-3 interaction interfered with the binding of AP3 to ARF (see 103180), but not with its binding to dileucine-based sorting signals. As a consequence, the delta subunit ear inhibited the recruitment of AP3 to membranes both in vitro and in vivo and impaired the sorting of lysosomal membrane proteins.
In a boy, born of consanguineous Turkish parents, with Hermansky-Pudlak syndrome-10 (HPS10; 617050), Ammann et al. (2016) identified a homozygous truncating mutation in the AP3D1 gene (607246.0001). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. The mutation was shown to disrupt assembly of the AP3 complex, consistent with a loss of function, and putatively causing a defect in the biogenesis and transport of lysosome-related organelles. Ammann et al. (2016) noted the phenotypic similarities to the 'mocha' mouse, which results from a null mutation in the Ap3d1 gene (see ANIMAL MODEL).
Simpson et al. (1997) and Ooi et al. (1997) showed that the garnet mutation in Drosophila, which causes reduced pigmentation of the eyes and other tissues, results from a mutation in the fly Ap3d1 gene.
The 'mocha' mouse mutant, a model for Hermansky-Pudlak syndrome (see 203300), shows coat and eye color dilution, reduced levels of renal lysosomal enzymes in urine, and prolonged bleeding due to storage pool deficiency in the dense granules of platelets. Mocha mice have balance problems due to otolith defects and eventually become deaf. They are also hyperactive and have a unique hypersynchronized 6- to 7-Hz electrocortigram. By Southern blot analysis of restriction digests of mocha mouse DNA, Kantheti et al. (1998) determined that mocha is a null allele of the Ap3d1 gene. They observed a lack of AP3 in mocha tissues and reduced levels of the zinc transporter Znt3 (SLC30A3; 602878) in brain, resulting in a lack of zinc-associated Timm historeactivity in hippocampal mossy fibers.
In a boy, born of consanguineous Turkish parents, with Hermansky-Pudlak syndrome-10 (HPS10; 617050), Ammann et al. (2016) identified a homozygous 2-bp deletion (c.3565_3566delGT, NM_001261826) in exon 32 of the AP3D1 gene, resulting in a frameshift and premature termination (Val1189LeufsTer8). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family, and was not found in the 1000 Genomes Project or Exome Sequencing Project databases. The mutation affects both isoforms of AP3D1: in isoform 2, the mutation is found in exon 30 (c.3379_3380delGT, NM_003938). Patient T cells showed significantly decreased levels of the AP3D1 protein compared to controls; other proteins in the AP3 complex were also decreased, consistent with an unstable heterotetramer formation. The AP3 assembly defects and defects in patient T-cell degranulation were rescued by expression of wildtype AP3D1.
Ammann, S., Schulz, A., Krageloh-Mann, I., Dieckmann, N. M. G., Niethammer, K., Fuchs, S., Eckl, K. M., Plank, R., Werner, R., Altmuller, J., Thiele, H., Nurnberg, P., and 9 others. Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. Blood 127: 997-1006, 2016. [PubMed: 26744459] [Full Text: https://doi.org/10.1182/blood-2015-09-671636]
Gross, M. B. Personal Communication. Baltimore, Md. 10/30/2017.
Kantheti, P., Qiao, X., Diaz, M. E., Peden, A. A., Meyer, G. E., Carskadon, S. L., Kapfhamer, D., Sufalko, D., Robinson, M. S., Noebels, J. L., Burmeister, M. Mutation in AP-3 delta in the mocha mouse links endosomal transport to storage deficiency in platelets, melanosomes, and synaptic vesicles. Neuron 21: 111-122, 1998. [PubMed: 9697856] [Full Text: https://doi.org/10.1016/s0896-6273(00)80519-x]
Lefrancois, S., Janvier, K., Boehm, M., Ooi, C. E., Bonifacino, J. S. An ear-core interaction regulates the recruitment of the AP-3 complex to membranes. Dev. Cell 7: 619-625, 2004. [PubMed: 15469849] [Full Text: https://doi.org/10.1016/j.devcel.2004.08.009]
Ooi, C. E., Moreira, J. E., Dell'Angelica, E. C., Poy, G., Wassarman, D. A., Bonifacino, J. S. Altered expression of a novel adaptin leads to defective pigment granule biogenesis in the Drosophila eye color mutant garnet. EMBO J. 16: 4508-4518, 1997. [PubMed: 9303295] [Full Text: https://doi.org/10.1093/emboj/16.15.4508]
Simpson, F., Peden, A. A., Christopoulou, L., Robinson, M. S. Characterization of the adaptor-related protein complex, AP-3. J. Cell Biol. 137: 835-845, 1997. [PubMed: 9151686] [Full Text: https://doi.org/10.1083/jcb.137.4.835]