|Mutation Type||critical splice donor site (1 bp from exon)|
|Coordinate||94,451,087 bp (GRCm38)|
|Base Change||G ⇒ T (forward strand)|
|Gene Name||adaptor-related protein complex 3, beta 1 subunit|
|Synonym(s)||recombination induced mutation 2, rim2, Hps2, beta3A, AP-3|
|Chromosomal Location||94,358,960-94,566,317 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. The encoded protein is part of the heterotetrameric AP-3 protein complex which interacts with the scaffolding protein clathrin. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 2. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2012]
PHENOTYPE: Homozygous mutants exhibit hypopigmentation, elevated kidney levels of lysosomal enzymes, platelet storage pool deficiency, reduced ipsilateral projections from the retina to brain, reduced sensitivity of dark-adapted retina and shortened life span. [provided by MGI curators]
|Amino Acid Change|
|Institutional Source||Beutler Lab|
|Gene Model||not available|
|Predicted Effect||probably benign|
|Meta Mutation Damage Score||Not available|
|Is this an essential gene?||Possibly nonessential (E-score: 0.395)|
|Candidate Explorer Status||CE: no linkage results|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Local Stock||Embryos, Sperm, gDNA|
|Last Updated||2021-11-22 7:46 AM by Diantha La Vine|
The bullet gray phenotype was detected among ENU-induced homozygous mutant G3 mice. Bullet gray mice display light-colored fur, with a mixture of white and gray-brown hairs. The ears, feet and tail have a light pink color, while the eyes are black (Figure 1). As with the souris, sooty, salt and pepper and toffee phenotypes, bullet gray confers enhanced susceptibility to mouse cytomegalovirus (MCMV) infection (MCMV Susceptibility and Resistance Screen). Bullet gray is allelic to pearl (1;2). Bullet gray and pearl mice also display reduced type I interferon (IFN) responses to CpG DNA challenge in vivo (Figure 2A) (3). This screen is designed to identify mutations that specifically affect plasmacytoid dendritic cell (pDC) development and function as pDCs are the primary type I IFN producing cell type in response to Toll-like receptor 9 (TLR9), which senses CpG DNA. Further analysis of Ap3b1pearl/pearl mice revealed that although splenic pDCs are present (Figure 2B) and can be generated in vitro from bone marrow using FLT3 ligand (see the record for warmflash), the cells cannot produce type I IFN and the proinflammatory cytokine tumor necrosis factor (TNF)-α in response to TLR9 stimulation (Figure 2C). Conventional DCs generated in vitro from GM-CSF treated Ap3b1pearl/pearl bone marrow are functionally normal (Figure 2D). Treatment of pDCs at the time of CpG stimulation with an inhibitor of the AP-3 activating GTP binding protein ARF1 also results in inhibition of type I IFN gene induction by pDCs (Figure 2E).
|Nature of Mutation|
The bullet gray mutation is a G to T transversion in the donor splice site of intron 13 (GTGAGT -> TTGAGT) in the Ap3b1 gene on chromosome 13 (position 92056 in Genbank genomic region NC_000079 for linear genomic DNA sequence of Ap3b1). The mutation is predicted to result in skipping of the 133-nucleotide exon 13 (out of 27 total exons), destroying the reading frame in the middle of the encoded β3A polypeptide chain (aberrant amino acids after position 411), and creating a premature stop codon that would truncate the protein after amino acid 412. The effect of the mutation at the cDNA and protein level has not been tested.
<--exon 12 <--exon 13 intron 13--> exon 14--> 89477 GAATTTCAG……AACAGGGATG GTGAGTTCA……………AAATAGTTGTTG 96377 405 -E--F--Q-……-N--R--D-- -Q--* 412 correct deleted aberrant
The donor splice site of intron 13, which is destroyed by the bullet gray mutation, is indicated in blue lettering; the mutated nucleotide is indicated in red lettering.
|Illustration of Mutations in
Gene & Protein
The AP-1 and AP-2 complexes have an overall shape reminiscent of a “head” with two protruding “ears” separated by a hinge region, and it is believed that AP-3 has the same general shape (Figure 3) (6-8). The A (“amino terminal” or "head") region (alternatively, the trunk domain) contains 12-13 Armadillo repeats, known to function in other settings as protein-protein interaction domains (9). The H (“hinge”) region is strongly hydrophilic and rich in serine and acidic residues, and the C (“carboxy terminal”) region corresponds to an “ear” of the holoprotein complex. The native human ortholog (obtained from M1 cells) has been detected in a phosphorylated state, likely reflecting phosphorylation of serine residues found in the H region (5).
Ap3b1 transcript was detected by Northern blot analysis in all human tissues examined, including heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas (5), and is also ubiquitously expressed in the mouse. The distribution of AP-3 complex was examined in NRK and MDBK cells (rat and bovine kidney cell lines, respectively), and found to co-localize with the trans-Golgi network (TGN) (10). AP-3 also decorates budding profiles on tubular endosomal compartments, likely on the way to lysosomes (11). The association of AP-3 with membranes is reportedly promoted by the small GTP-binding protein ARF-1 (ADP ribosylation factor-1) (12), although there has been no genetic confirmation of this interaction.
AP-1 and AP-2 bind clathrin directly, linking clathrin lattices to membranes within cells (4). The human AP-3 complex has been reported to associate with clathrin in vitro and in HeLa cells (11;13;14). However, another report indicated that it was not associated with clathrin, and controversy remains as to whether AP-3 function is clathrin-dependent (10;15). Studies in yeast support a clathrin-independent function for AP-3 [reviewed in (16)].
Hermansky-Pudlak syndromes (HPS; OMIM #203300) are a group of heterogeneous, autosomal recessive disorders caused by alterations at numerous independent loci (17). Oculocutaneous albinism (OCA) and prolonged bleeding due to impaired platelet aggregation are common to all forms of HPS, but additional manifestations characterize specific types of HPS, such as pulmonary fibrosis (HPS-1 and HPS-4), and neutropenia and mild immunodeficiency (HPS-2). At the cellular level, HPS is caused by defects in the biogenesis of lysosome-related organelles, such as melanosomes, platelet dense granules, lamellar bodies of type II alveolar epithelial cells, and lytic granules of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. In particular, the pigmentation and bleeding problems associated with all forms of HPS arise from defects in melanosomes and platelet dense granules.
Mutations in the β3A subunit of the AP-3 complex cause HPS-2 (OMIM #608233) (18;27-30). The AP complexes transport cargo proteins between components of the endocytic pathway, and AP-3 specifically shuttles proteins from the TGN to lysosomes and lysosome-related organelles (16;32). Mutations of β3A are sufficient to dissociate the AP-3 complex and induce degradation of the other subunits (19;31). Cargo recognition by AP-3 occurs through both tyrosine-based and dileucine-based lysosomal targeting motifs. Thus, lysosome-associated membrane protein-1 (LAMP-1), LAMP-2, and CD63, cargo proteins for AP-3 which are sorted via tyrosine-based signals, fail to be recruited to lysosomes and accumulate at the plasma membrane in human fibroblasts with greatly reduced levels of AP-3 due to a mutation in β3A (11;19;20;33). Biochemical experiments demonstrate that AP-3 associates with dileucine-based signals of tyrosinase and lysosomal integral membrane protein-II (LIMP-II), but not other proteins containing dileucine motifs (33;34). Tyrosinase and LIMP-II also accumulate at the cell membrane in AP-3 deficient cells (33).
In addition to albinism and platelet aggregation deficiency, humans with HPS-2 exhibit neutropenia and immunodeficiency due to defects in NK cells and CTLs (28-30;35). In mice, mutations in the β3A subunit result in the pearl phenotype, which is characterized by hypopigmentation, lysosomal secretion abnormalities, and platelet-dense granules containing reduced levels of adenine nucleotides and serotonin (1). Mutations in the mouse δ subunit of the AP-3 complex cause the similar mocha phenotype, with coat and eye color dilution, lysosomal abnormalities, platelet defects, and neurological defects (balance problems, deafness) (36).
Interestingly, a particular mutation of AP3B1 in dogs, an insertion of an A residue within a tract of nine A residues in exon 20, results in canine cyclic neutropenia, also known as gray Collie syndrome because the dogs have a diluted coat color (37). The mutation leads to a frameshift and premature termination, and absent mRNA due to nonsense-mediated decay (38). Humans with cyclic neutropenia display three week oscillations in the circulating neutrophil count, with fluctuations between near zero and near normal levels (39). Monocytes also cycle in the opposite phase to neutrophils. In dogs, neutrophil counts cycle every two weeks, and all other blood cells cycle in opposite phase. No pigmentation defects are observed in humans with cyclic neutropenia. Mutations in ELA2, encoding neutrophil elastase (NE), cause all known cases of human cyclic neutropenia (40). The enzyme NE (also known as leukocyte elastase) is a serine protease of neutrophil and monocyte granules, and cleaves many substrates including extracellular matrix proteins, clotting factors, immunoglobulins, and bacterial components, promoting microbe and tissue destruction (41;42). A yeast two-hybrid assay for testing adaptor protein subunit and cargo protein interactions indicates that the μ3A subunit of AP-3 interacts with NE via a tyrosine-based recognition signal, suggesting that NE is an AP-3 cargo protein (37). The mistrafficking of NE as a result of mutations in either NE (that prevent recognition of the tyrosine-based signal by AP-3) or AP-3 is thought to underlie cyclic neutropenia (43).
The bullet gray mutation creates a premature stop codon early in the Ap3b1 sequence (amino acid 421 out of 1105), possibly resulting in degradation of the protein, and at minimum abrogating most protein function. Thus, the integrity of the AP-3 complex would likely be compromised. In mammals, melanin pigments conferring skin, hair and eye color are tyrosine-derived polymers synthesized in the melanosomes of melanocytes (16). Incorrect targeting of AP-3 protein cargo, such as the melanin-biosynthetic enzyme tyrosinase (mutated in ghost) to melanosomes, would account for the hypopigmentation of bullet gray animals. However, the presence of a significant amount of lysosomal membrane proteins in lysosomes of AP-3-deficient cells suggests the existence of an AP-3-independent pathway (19).
The MCMV susceptibility and lack of response to CpG stimulation suggests that the AP-3 complex is necessary for certain aspects of the immune response likely by affecting the trafficking and biogenesis of lytic granules in NK and/or T cells and an undefined subcellular compartment in pDCs (44). DCs are immune cells, whose main function is to process antigen material and present it on the surface to other cells of the immune system, thus functioning as antigen-presenting cells (APCs). They activate helper T cells, cytotoxic T cells, and B cells, by presenting them with antigens derived from the pathogen, along with non-antigen specific costimulatory signals. pDCs are a rare subtype of circulating DCs found in the blood as well as in peripheral lymphoid organs. They are distinguished from conventional DCs by being derived from lymphoid precursors rather than myeloid precursors, and by differences in cell-surface markers (45). As components of the innate immune system, these cells express endosomally-localized TLR7 and TLR9, which enable the detection of internalized viral and bacterial nucleic acids, such as ssRNA (via TLR7) or CpG DNA (via TLR9). TLR7 and 9 signaling occurs via the adaptor protein myeloid differentiation (MyD) 88 (see pococurante and lackadaisical) resulting in the activation of the NF-κB pathway and production of proinflammatory cytokines such as TNF-α (see panr1), as well as the production of large amounts of type I IFN. Type I IFNs are pleiotropic anti-viral proteins mediating a wide range of effects. Both TNF-α and type I IFN production by pDCs depends on components of the MyD88 signaling pathway including interleukin receptor associated kinase (IRAK)-1 and IRAK-4 (see otiose), interferon response factor (IRF) 5, TNF receptor–associated factor 6 (TRAF6), inhibitor of kappa-B kinase-α (IKKα), osteopontin, and IRF7 (see the record for inept) [reviewed in (46,47)]. The multispanning ER membrane protein UNC93B (mutated in 3d), which is required for trafficking of TLRs 3, 7, and 9 to the endosomal compartment (48), is also necessary for pDCs to sense nucleic acids. pDCs from TLR9-deficient or TLR7-deficient mice (see records for CpG1 and rsq1) fail to produce type I IFN in response to various viral and bacterial pathogens [reviewed by (49)]. An acidic endosomal environment has been shown to be essential for appropriate TLR7 and TLR9 signaling (50-52).
LROs share various characteristics with lysosomes and endolysosomes, such as an acidic intralumenal pH (53), and it is possible that trafficking and biogenesis of the endosomal or similar compartment in pDCs is also dependent on HPS proteins including AP-3. Indeed, analysis of DC generated from pearl homozygous mice suggests that AP-3 is required for the type I IFN response by trafficking TLR9 to a specialized subcellular compartment (44). Interestingly, the pDC-specific phenotypes identified in mice with mutations in Ap3b1 parallel those found in mice homozygous for a mutation in Slc15a4 (see the record for feeble), which encodes PHT1, a proton-dependent oligopeptide transporter (3). PHT1 contains a typical acidic di-leucine motif required for AP-3 transport. PHT1 may regulate endosomal TLR7 and TLR9 signaling either by transporting a critical component into or out of the endosome, or by maintaining the appropriate pH necessary for TLR activation. Thus, AP-3 may be required to transport multiple proteins required for TLR signaling to their appropriate subcellular location. Mice carrying the salt and pepper allele of Dtnbp1, which encodes dysbindin, and the toffee allele of Hps5 also failed to produce type I IFN after in vivo challenge with CpG DNA.
|Primers||Primers cannot be located by automatic search.|
Bullet gray genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide transversion. This protocol has not been tested.
bullet gray(F): 5’- ACCCTGGCTTGAAAATGTCCCTTTG -3’
bullet gray(R): 5’- CGACTTCCACGCATGACTAGGAAAC -3’
1) 95°C 2:00
2) 95°C 0:30
3) 56°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 29X
6) 72°C 7:00
7) 4°C ∞
Primers for sequencing
bullet gray_seq(F): 5’- ACGTTAAGCAATCATTTGGGGC -3’
bullet gray_seq(R): 5’- TATGAAGCAGTGCTTAGTGAATG -3’
The following sequence of 621 nucleotides (from Genbank genomic region NC_000079 for linear genomic sequence of Ap3b1) is amplified:
91806 accct ggcttgaaaa tgtccctttg ccaaagggac attaagttat aagcgatgaa 91861 agacgttaag caatcatttg gggcccctgt taggcttaag agaattctaa attttttgtc 91921 ctgacaaagc tataaaaatg ggctttgatt cacttgataa cgccaatgtt gaaactaatc 91981 aaactgtttt tagacctacg tgagaagcca ggacaaacag tttgcagcag ccactattca 92041 gaccataggc agatgtgcaa ccagcattag cgaggtcacc gacacatgcc tcaacggcct 92101 ggtctgcctg ctgtccaaca gggatggtga gttcataggt tcactttatt tttatatggt 92161 tcataattgt atattctcag taagtcctat agctgtaatc tattatatta tcttttcggg 92221 tttttctata tatcagtatt ttctcagtaa gtagcagctt tattcttgat ttgcaggaaa 92281 atttatttca aaaaataaat gagataatta atagattttg ttttgctccc attaagacaa 92341 tttatcttac tcattcacta agcactgctt catacccttt ctgcaaaggt tctctgtgac 92401 tgtttcctag tcatgcgtgg aagtcg
Primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated G is highlighted in red.
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|Science Writers||Alyson Mack, Eva Marie Y. Moresco|
|Illustrators||Diantha La Vine, Katherine Timer|
|Authors||Sophie Rutschmann, Amanda L. Blasius, Bruce Beutler|