Phenotypic Mutation 'bella' (pdf version)
Mutation Type missense
Coordinate94,664,765 bp (GRCm39)
Base Change A ⇒ T (forward strand)
Gene Ap3b1
Gene Name adaptor-related protein complex 3, beta 1 subunit
Synonym(s) AP-3, Hps2, beta3A, rim2, recombination induced mutation 2
Chromosomal Location 94,495,468-94,702,825 bp (+) (GRCm39)
MGI Phenotype 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]
Accession Number

NCBI RefSeq: NM_009680; MGI:1333879

Amino Acid Change Arginine changed to Serine
Institutional SourceBeutler Lab
Gene Model predicted gene model for protein(s): [ENSMUSP00000022196]
AlphaFold Q9Z1T1
SMART Domains Protein: ENSMUSP00000022196
Gene: ENSMUSG00000021686
AA Change: R901S

low complexity region 10 24 N/A INTRINSIC
Pfam:Adaptin_N 39 586 1.2e-170 PFAM
Pfam:SEEEED 672 812 1.3e-27 PFAM
AP3B1_C 822 969 1.58e-78 SMART
Blast:B2 993 1103 2e-27 BLAST
Predicted Effect unknown
Predicted Effect unknown
Meta Mutation Damage Score 0.9138 question?
Is this an essential gene? Possibly nonessential (E-score: 0.320) question?
Phenotypic Category Autosomal Recessive
Candidate Explorer Status loading ...
Single pedigree
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)

Lab Alleles
AlleleSourceChrCoordTypePredicted EffectPPH Score
IGL00660:Ap3b1 APN 13 94527371 missense probably damaging 1.00
IGL00766:Ap3b1 APN 13 94679392 splice site probably benign
IGL01784:Ap3b1 APN 13 94630247 missense probably damaging 1.00
IGL01979:Ap3b1 APN 13 94584971 nonsense probably null
IGL02040:Ap3b1 APN 13 94545353 critical splice donor site probably null
IGL02119:Ap3b1 APN 13 94598911 missense probably benign 0.01
IGL02247:Ap3b1 APN 13 94531303 critical splice donor site probably null
IGL02303:Ap3b1 APN 13 94664827 missense unknown
IGL02493:Ap3b1 APN 13 94540528 missense probably damaging 0.98
IGL02551:Ap3b1 APN 13 94554599 missense probably damaging 0.99
IGL02651:Ap3b1 APN 13 94613529 missense probably damaging 1.00
IGL02832:Ap3b1 APN 13 94664835 missense unknown
IGL03033:Ap3b1 APN 13 94585003 missense probably benign 0.15
IGL03101:Ap3b1 APN 13 94591906 missense probably benign 0.00
bullet_gray UTSW 13 94587594 critical splice donor site probably benign
cuttlefish UTSW 13 94584959 critical splice acceptor site probably null
Gastropod UTSW 13 94679348 missense unknown
razor UTSW 13 94630239 missense unknown
Slime UTSW 13 94540586 missense possibly damaging 0.51
slug UTSW 13 94545353 critical splice donor site probably null
snail UTSW 13 94616393 splice site probably benign
stalk UTSW 13 94609439 critical splice donor site probably null
R0034:Ap3b1 UTSW 13 94616393 splice site probably benign
R0265:Ap3b1 UTSW 13 94630189 missense unknown
R0270:Ap3b1 UTSW 13 94540626 splice site probably benign
R0346:Ap3b1 UTSW 13 94582479 nonsense probably null
R0422:Ap3b1 UTSW 13 94598968 missense probably damaging 0.99
R0496:Ap3b1 UTSW 13 94609446 splice site probably benign
R0508:Ap3b1 UTSW 13 94702222 missense unknown
R0764:Ap3b1 UTSW 13 94616387 splice site probably benign
R1506:Ap3b1 UTSW 13 94582651 splice site probably benign
R1593:Ap3b1 UTSW 13 94638435 missense unknown
R1660:Ap3b1 UTSW 13 94545320 missense probably damaging 0.98
R1735:Ap3b1 UTSW 13 94630225 missense unknown
R1791:Ap3b1 UTSW 13 94545305 missense possibly damaging 0.63
R1818:Ap3b1 UTSW 13 94608212 missense possibly damaging 0.48
R2280:Ap3b1 UTSW 13 94664724 missense unknown
R3031:Ap3b1 UTSW 13 94702151 missense unknown
R3037:Ap3b1 UTSW 13 94582486 critical splice donor site probably null
R4401:Ap3b1 UTSW 13 94554607 missense probably damaging 1.00
R4402:Ap3b1 UTSW 13 94554607 missense probably damaging 1.00
R4403:Ap3b1 UTSW 13 94554607 missense probably damaging 1.00
R4532:Ap3b1 UTSW 13 94702243 missense unknown
R4624:Ap3b1 UTSW 13 94619734 missense unknown
R4626:Ap3b1 UTSW 13 94540586 missense possibly damaging 0.51
R4754:Ap3b1 UTSW 13 94540468 missense probably damaging 1.00
R4788:Ap3b1 UTSW 13 94702149 missense unknown
R4847:Ap3b1 UTSW 13 94608287 missense probably benign 0.15
R4886:Ap3b1 UTSW 13 94609313 missense possibly damaging 0.50
R5096:Ap3b1 UTSW 13 94616357 missense unknown
R5628:Ap3b1 UTSW 13 94613556 missense unknown
R5671:Ap3b1 UTSW 13 94664765 missense unknown
R5677:Ap3b1 UTSW 13 94664704 missense unknown
R5862:Ap3b1 UTSW 13 94684278 missense unknown
R5941:Ap3b1 UTSW 13 94619773 missense probably damaging 0.96
R5941:Ap3b1 UTSW 13 94576781 missense probably benign 0.02
R6043:Ap3b1 UTSW 13 94613501 missense probably benign 0.09
R6212:Ap3b1 UTSW 13 94630207 missense unknown
R6212:Ap3b1 UTSW 13 94587581 missense probably damaging 1.00
R6301:Ap3b1 UTSW 13 94664803 missense unknown
R6765:Ap3b1 UTSW 13 94599017 missense probably benign 0.02
R6812:Ap3b1 UTSW 13 94616369 missense unknown
R6888:Ap3b1 UTSW 13 94545299 missense probably benign 0.42
R6901:Ap3b1 UTSW 13 94554650 missense probably benign 0.00
R7157:Ap3b1 UTSW 13 94668542 nonsense probably null
R7422:Ap3b1 UTSW 13 94664673 missense unknown
R7642:Ap3b1 UTSW 13 94613540 missense probably benign 0.19
R7710:Ap3b1 UTSW 13 94587581 missense probably damaging 1.00
R7757:Ap3b1 UTSW 13 94664666 splice site probably null
R7867:Ap3b1 UTSW 13 94619771 missense unknown
R8492:Ap3b1 UTSW 13 94531294 missense possibly damaging 0.60
R8706:Ap3b1 UTSW 13 94545353 critical splice donor site probably null
R8749:Ap3b1 UTSW 13 94664725 missense unknown
R8876:Ap3b1 UTSW 13 94540586 missense possibly damaging 0.51
R8889:Ap3b1 UTSW 13 94679348 missense unknown
R8892:Ap3b1 UTSW 13 94679348 missense unknown
R9065:Ap3b1 UTSW 13 94608223 missense probably damaging 1.00
R9152:Ap3b1 UTSW 13 94630239 missense unknown
R9152:Ap3b1 UTSW 13 94609439 critical splice donor site probably null
R9166:Ap3b1 UTSW 13 94608236 missense probably damaging 1.00
R9218:Ap3b1 UTSW 13 94584959 critical splice acceptor site probably null
R9269:Ap3b1 UTSW 13 94540570 missense probably damaging 1.00
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
Record Posted 2018-02-22
Phenotypic Description
Figure 1. Bella mice (left) exhibit hypopigmentation. A wild-type (C57BL/6J) littermate is shown for comparison (right). 

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

Figure 2. Linkage mapping of the hypopigmenation phenotype using a recessive model of inheritance. Manhattan plot shows -log10 P values (Y-axis) plotted against the chromosome positions of 57 mutations (X-axis) identified in the G1 male of pedigree R5671. Binary data are shown for single locus linkage analysis without consideration of G2 dam identity. Horizontal pink and red lines represent thresholds of P = 0.05, and the threshold for P = 0.05 after applying Bonferroni correction, respectively.

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.

986  -H--Y--C--F--P--R--Q--P--C--I--F-


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
Protein Prediction

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.

Putative Mechanism

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.

Primers PCR Primer

Sequencing Primer

PCR program

1) 94°C 2:00
2) 94°C 0:30
3) 55°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 40x
6) 72°C 10:00
7) 4°C hold

The following sequence of 426 nucleotides is amplified (chromosome 13, + strand):

1   acacatgtcc tgagtattgg cttgttttct agaagcagta gtgactgaat gtcctcacta
61  actcctgtcg tcctcccaca tgcccaggtc agtacgcctg tcttcgtgcc aacaaaaaca
121 catgagctgc ttcaccgaat gcatgggaaa ggactggccg cccactactg cttcccaaga
181 cagccctgca tcttcagtga caagatggtc tctgtacaga tcaccctgac taatacttct
241 gatcgaaaaa tagaaaacat ccacataggg gggaaagggc ttcctgtggg catgcagatg
301 catgcctttc atccaatagg taaaggctaa gtcttactgc aaacttggtt cctaaatgtt
361 ttcactttta aagcagagtt tcagaaaaag ataaaataca gcattattta ctaactgaga
421 gtgccc

Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.

Science Writers Anne Murray
Illustrators Diantha La Vine
AuthorsCarlos Reyna, Jamie Russell, and Bruce Beutler