Phenotypic Mutation 'bella' (pdf version)
Allele | bella |
Mutation Type |
missense
|
Chromosome | 13 |
Coordinate | 94,664,765 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
|
Mapped | Yes |
Amino Acid Change |
Arginine changed to Serine
|
Institutional Source | Beutler Lab |
Gene Model |
predicted gene model for protein(s):
[ENSMUSP00000022196]
|
AlphaFold |
Q9Z1T1 |
SMART Domains |
Protein: ENSMUSP00000022196 Gene: ENSMUSG00000021686 AA Change: R901S
Domain | Start | End | E-Value | Type |
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 |
Is this an essential gene? |
Possibly nonessential (E-score: 0.320) |
Phenotypic Category |
Autosomal Recessive |
Candidate Explorer Status |
loading ... |
Single pedigree Linkage Analysis Data
|
|
Penetrance | |
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 |
Allele | Source | Chr | Coord | Type | Predicted Effect | PPH 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 |
Repository | |
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.
2830 CACTACTGCTTCCCAAGACAGCCCTGCATCTTC
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
bella_pcr_F: ACACATGTCCTGAGTATTGGCTTG
bella_pcr_R: GGGCACTCTCAGTTAGTAAATAATGC
Sequencing Primer
bella_seq_F: CTTGTTTTCTAGAAGCAGTAGTGAC
bella_seq_R: AAACATTTAGGAACCAAGTTTGCAG
|
Genotyping | 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. |
References |
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.
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.
|
Science Writers | Anne Murray |
Illustrators | Diantha La Vine |
Authors | Carlos Reyna, Jamie Russell, and Bruce Beutler |