|Coordinate||94,528,257 bp (GRCm38)|
|Base Change||A ⇒ 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||Arginine changed to Serine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000022196]|
AA Change: R901S
|Meta Mutation Damage Score||0.9138|
|Is this an essential gene?||Probably nonessential (E-score: 0.199)|
|Phenotypic Category||Autosomal Recessive|
|Candidate Explorer Status||loading ...|
Linkage Analysis Data
|Alleles Listed at MGI|
All Mutations and Alleles(54) : Chemically induced (ENU)(1) Chemically induced (other)(1) Gene trapped(34) Spontaneous(14) Targeted(4)
|Mode of Inheritance||Autosomal Recessive|
|Local Stock||Live Mice|
|Last Updated||2021-11-22 7:44 AM by Diantha La Vine|
|Record Created||2017-10-03 1:40 PM by Carlos Reyna|
The bella phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R5671, some of which showed brown fur (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 57 mutations. The pigmentation phenotype was linked to a mutation in Ap3b1: an A to T transversion at base pair 94,528,257 (v38) on chromosome 13, or base pair 169,678 in the GenBank genomic region NC_000079 encoding Ap3b1. Linkage was found with a recessive model of inheritance (P = 0.000448), wherein three affected mice were homozygous for the variant allele, and 26 unaffected mice were either heterozygous (N = 17) or homozygous for the reference allele (N = 9) (Figure 2).
The mutation corresponds to residue 2,847 in the mRNA sequence NM_009680 within exon 23 of 27 total exons.
The mutated nucleotide is indicated in red. The mutation results in an arginine to serine substitution at position 901 (R901S) in the AP3B1 protein.
|Illustration of Mutations in
Gene & Protein
AP-3 is one of four different heterotetrameric adaptor protein complexes (AP-1 to AP-4) in mammalian cells that decorate the cytoplasmic surface of membrane-bound vesicles at all levels from the trans-Golgi complex to the plasma membrane and direct subcelluar trafficking of membrane cargo proteins (1). 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 (2-4). 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 (5). 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 bella mutation results in an arginine to serine substitution at position 901 (R901S) in the AP3B1 protein; residue 901 is within the C region.
For more information about Ap3b1, please see the record for bullet_gray.
Mutations in the β3A subunit of the AP-3 complex cause Hermansky-Pudlak syndrome-2 (HPS-2; OMIM #608233) (6-10). 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).
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 (11;12). 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.
1) 94°C 2:00
The following sequence of 426 nucleotides is amplified (chromosome 13, + strand):
1 acacatgtcc tgagtattgg cttgttttct agaagcagta gtgactgaat gtcctcacta
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
1. Schmid, S. L. (1997) Clathrin-coated vesicle formation and protein sorting: an integrated process, Annu. Rev. Biochem. 66, 511-548.
2. Keen, J. H. (1990) Clathrin and associated assembly and disassembly proteins, Annu. Rev. Biochem. 59, 415-438.
3. Robinson, M. S. (1994) The role of clathrin, adaptors and dynamin in endocytosis, Curr. Opin. Cell Biol. 6, 538-544.
4. Heuser, J. E. and Keen, J. (1988) Deep-etch visualization of proteins involved in clathrin assembly, J. Cell Biol. 107, 877-886.
5. Riggleman, B., Wieschaus, E., and Schedl, P. (1989) Molecular analysis of the armadillo locus: uniformly distributed transcripts and a protein with novel internal repeats are associated with a Drosophila segment polarity gene, Genes Dev. 3, 96-113.
6. Oh, J., Bailin, T., Fukai, K., Feng, G. H., Ho, L., Mao, J. I., Frenk, E., Tamura, N., and Spritz, R. A. (1996) Positional cloning of a gene for Hermansky-Pudlak syndrome, a disorder of cytoplasmic organelles, Nat. Genet. 14, 300-306.
7. Martina, J. A., Moriyama, K., and Bonifacino, J. S. (2003) BLOC-3, a protein complex containing the Hermansky-Pudlak syndrome gene products HPS1 and HPS4, J Biol. Chem. 278, 29376-29384.
8. Jung, J., Bohn, G., Allroth, A., Boztug, K., Brandes, G., Sandrock, I., Schaffer, A. A., Rathinam, C., Kollner, I., Beger, C., Schilke, R., Welte, K., Grimbacher, B., and Klein, C. (2006) Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2, Blood 108, 362-369.
9. Huizing, M., Scher, C. D., Strovel, E., Fitzpatrick, D. L., Hartnell, L. M., Anikster, Y., and Gahl, W. A. (2002) Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2, Pediatr. Res. 51, 150-158.
10. Enders, A., Zieger, B., Schwarz, K., Yoshimi, A., Speckmann, C., Knoepfle, E. M., Kontny, U., Muller, C., Nurden, A., Rohr, J., Henschen, M., Pannicke, U., Niemeyer, C., Nurden, P., and Ehl, S. (2006) Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type II, Blood 108, 81-87.
11. Odorizzi, G., Cowles, C. R., and Emr, S. D. (1998) The AP-3 complex: a coat of many colours, Trends Cell Biol. 8, 282-288.
|Science Writers||Anne Murray|
|Illustrators||Diantha La Vine|
|Authors||Carlos Reyna, Jamie Russell, and Bruce Beutler|