|Coordinate||20,030,796 bp (GRCm38)|
|Base Change||A ⇒ C (forward strand)|
|Gene Name||HPS3, biogenesis of lysosomal organelles complex 2 subunit 1|
|Chromosomal Location||19,995,945-20,035,315 bp (-)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a protein containing a potential clathrin-binding motif, consensus dileucine signals, and tyrosine-based sorting signals for targeting to vesicles of lysosomal lineage. The encoded protein may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 3. [provided by RefSeq, Apr 2015]
PHENOTYPE: Homozygotes for spontaneous null mutations exhibit hypopigmentation and prolonged bleeding associated with a platelet defect. [provided by MGI curators]
|Amino Acid Change||Leucine changed to Arginine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000012580] [ENSMUSP00000103957]|
AA Change: L76R
|Predicted Effect||probably damaging
PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|Predicted Effect||probably benign|
|Meta Mutation Damage Score||0.6467|
|Is this an essential gene?||Probably nonessential (E-score: 0.172)|
|Candidate Explorer Status||CE: failed initial filter|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Unknown|
|Local Stock||Live Mice|
|Last Updated||2019-10-23 1:57 PM by Anne Murray|
|Record Created||2012-12-27 12:31 PM by Adam Dismang|
Blue was initially identified among N-ethyl-N-nitrosourea (ENU)-induced G3 animals as a hypopigmentation mutant (Figure 1). The blue homozygous mice have a gray coat.
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 72 mutations. Three G3 mice with the blue phenotype were genotyped at all 72 mutation sites and three mutations on chromosome 3 (in Hps3, Gm5538, and Zfhx4) were homozygous in two of the three blue mice and heterozygous in one of the three blue mice. Blue phenocopies the pam gray phenotype attributed to Hps3. Therefore, the blue phenotype was ascribed to the Hps3 mutation. The mutation in Hps3 is a T to G transversion at base pair 20030796 (v38) on chromosome 3, or base pair 4515 in the GenBank genomic region NC_000069. The mutation corresponds to residue 272 in the mRNA sequence NM_080634 within exon 2 of 17 total exons.
The mutated nucleotide is indicated in red. The mutation results in a leucine (L) to arginine (R) substitution at residue 76 in the HPS3 protein.
|Illustration of Mutations in
Gene & Protein
The blue mutation (L76R) is not within or near known functional domains of HPS3 (Figure 2).
Please see the record pam gray for information about Hps3.
Mutations in Hps3 have been documented to result in pigmentation defects [(1); MGI:2153839; pam gray; gandalf]. Mutations in Hps3 may alter protein trafficking during the maturation of melanosomes, resulting in hypopigmentation (2;3). Proteins affected may include LAMP1 and LAMP3, and components of the melanin biosynthesis pathway, tyrosinase (mutated in ghost, pale rider, siamese), Tyrp1 (mutated in chi), and Tyrp2.
Blue genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide transition.
Blue(F): 5’- AGTCAAATGCATCACGTACCTTCCG -3’
Blue(R): 5’- CACACCTCAGAGGCTGTTGCTTAG-3’
Blue_seq(F): 5’- CCATGTATAGGGTCTGACTCCAG -3’
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 ∞
The following sequence of 664 nucleotides is amplified (Chr.3: 20030295-20030958, GRCm38; NC_000069):
agtcaaatgc atcacgtacc ttccgcctct ttcaatggat tgctggtttc ttgtgggtgg
tggtcaacac tctctccatg tatagggtct gactccagtt ttaggagtaa gacttctaaa
tcagacatga cagcaacata tccaacacaa aaagagattt caacaggagt gatattatct
atgtgtataa ttaatgaacg ttcaaagttc aatattgaga attcctcatt aatgatatca
tacttcaaag taaataacac taacttattt gtacatccaa caagaagatc tcctttcaca
ggacaacacg aaaagcacaa aggggcctca gacattggca tctcaattat agacatctgg
tctctaaagc tttcacagaa ggatgcctcc acattgtggc caaccattcg aatgcacaca
cgggagttgt cgctcctctt actcctccaa ttcacgtaag cacgcaggaa tatagttttg
tttttctcct caattgctac cagatagtct cctaaaaaag gaagcaagat tgcatttgga
tcttagaatt acaaactcaa cgacttattt tgctgcctga aaatggaatg tataatataa
cacaggaatc actaactcaa agaaggaaca cagctgacat ctaagcaaca gcctctgagg
Primer binding sites are underlined and the sequencing primer is highlighted; the mutated nucleotide is shown in red text (A>C, Chr. + strand; T>G, sense strand).
1. Suzuki, T., Li, W., Zhang, Q., Novak, E. K., Sviderskaya, E. V., Wilson, A., Bennett, D. C., Roe, B. A., Swank, R. T., and Spritz, R. A. (2001) The Gene Mutated in Cocoa Mice, Carrying a Defect of Organelle Biogenesis, is a Homologue of the Human Hermansky-Pudlak Syndrome-3 Gene. Genom. 78, 30-37.
2. Boissy, R. E., Richmond, B., Huizing, M., Helip-Wooley, A., Zhao, Y., Koshoffer, A., and Gahl, W. A. (2005) Melanocyte-Specific Proteins are Aberrantly Trafficked in Melanocytes of Hermansky-Pudlak Syndrome-Type 3. Am J Pathol. 166, 231-240.
|Science Writers||Anne Murray|
|Illustrators||Diantha La Vine, Peter Jurek|