|Coordinate||56,324,680 bp (GRCm38)|
|Base Change||C ⇒ T (forward strand)|
|Gene Name||oculocutaneous albinism II|
|Synonym(s)||D7H15S12, p, D7H15S12|
|Chromosomal Location||56,239,760-56,536,518 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes the human homolog of the mouse p (pink-eyed dilution) gene. The encoded protein is believed to be an integral membrane protein involved in small molecule transport, specifically tyrosine, which is a precursor to melanin synthesis. It is involved in mammalian pigmentation, where it may control skin color variation and act as a determinant of brown or blue eye color. Mutations in this gene result in type 2 oculocutaneous albinism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]
PHENOTYPE: Mutations generally result in varying degrees of coat and eye pigment dilution. Specific alleles produce cleft palate, reproductive, endocrine or neurological disorders, and/or lethality. [provided by MGI curators]
|Amino Acid Change||Proline changed to Leucine|
|Institutional Source||Beutler Lab|
|Gene Model||not available|
AA Change: P459L
|Predicted Effect||probably damaging
PolyPhen 2 Score 0.999 (Sensitivity: 0.14; Specificity: 0.99)
|Predicted Effect||probably benign|
|Predicted Effect||probably benign|
|Meta Mutation Damage Score||Not available|
|Is this an essential gene?||Probably nonessential (E-score: 0.235)|
|Candidate Explorer Status||CE: no linkage results|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Local Stock||Embryos, gDNA|
|Last Updated||2018-01-12 4:36 PM by Diantha La Vine|
The snowflake mutation was induced by ENU mutagenesis on the C57BL/6J (black) background and was discovered in G3 animals. Snowflake is a strictly recessive phenotype with very light fur and ocular albinism, similar to the phenotype created by mutations at the Oca2 or p (pink-eyed dilution) locus. Mutations at Oca2 are known to cause a reduction of eumelanin (black-brown) pigment and altered morphology of black pigment granules (eumelanosomes), but have little effect on pheomelanin (yellow-red) pigment (1;2).
Due to a high resemblance in their phenotypes, snowflake and whitemouse mutants were tested for allelism and found to be allelic. Since snowflake was mapped to Chromosome 7 and is phenotypically similar to classical p locus mutations, sequencing of the p locus was undertaken at the genomic level and the causative mutation was identified for both snowflake and whitemouse mutants.
Homozygous snowflake mice exhibit normal resistance to infection with murine cytomegalovirus (MCMV), and similar splenic viral titers to wild type mice after infection. Susceptibility to L. monocytogenes infection has not been tested in snowflake mice.
|Nature of Mutation|
The snowflake mutation was mapped to Chromosome 7, and corresponds to a C to T transition at position 1506 of the Oca2 transcript, in exon 14 of 24 total exons.
The mutated nucleotide is indicated in red lettering, and results in a proline to leucine change at amino acid 459 in the OCA2 protein.
The snowflake mutation occurs between the fifth and sixth transmembrane domains of the OCA2 protein and is located on the lumenal side of the vesicular membrane (Figure 1). It is unknown whether normal levels of the altered OCA2 protein exist in snowflake mice or whether this protein is localized appropriately.
Please see the record for quicksilver for information about Oca2.
The snowflake mutation results in a P459L change in the lumenal region of the protein located between transmembrane domains 5 and 6. This region is highly conserved between mouse and human OCA2, but the function is unknown. Both proline and leucine are nonpolar, neutral amino acids, but proline is often found in turns and is usually solvent-exposed while leucine is hydrophobic. Amino acid 458 in OCA2 is located in a lumenal loop, more consistent with proline function than with leucine function. This region of the protein appears to be important for function as the OCA2 mutation occurring in quicksilver and faded mice (E453K), also occurs in the same region. Human mutations in this region do cause oculocutaneous albinism although none of the mutations lie adjacent to the amino acid affected in snowflake mice. The lighter coat color of snowflake and whitemouse mutants suggests that the mutations present in these animals more severely impair OCA2 protein function than the mutations present in the darker quicksilver, faded or charbon mice.
For a further explanation of the snowflake mutant phenotype, please refer to the record for quicksilver.
|Primers||Primers cannot be located by automatic search.|
Snowflake genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide change. The same primers used for quicksilver/faded genotyping are used.
Primers for PCR amplification
1) 94°C 2:00
2) 94°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
Quick_seq(F): 5’- CACTCTCTGGACTGAAGGAATCTG -3’
Quick_seq(R): 5’- AGCCCCTTAATCTTGAAGACTG -3’
The following sequence of 1056 nucleotides (from Genbank genomic region NC_000073 for linear DNA sequence of Oca2) is amplified:
84209 gg ctttccaaga catagactgt cccagggaat
84241 ataggcaaga gatttgtgca gattgctagg taccaagagt ttttgctcat ggtttcccac
84301 attttcatct tccacctatt catagagctt agtcttcaac agatcagggt ataggacttc
84361 caaagatccc aagacaaata tcatgcagcc aacctatagc caagaggaag taaaggtaat
84421 gattcaagta atgagcagag agggtttaaa gtctcttcag aaaagggaga gcacacaagg
84481 gtctaagtca gcaggcttag tgttatttta ttgctggtga tttttgattc cccaccactc
84541 tctggactga aggaatctga tagctgatgt ccattcacct gctccaggcc ctttcctcta
84601 ctgtggccct acacgtggag ctcaacactc ccccagggct gtgggagcag gcagaagcca
84661 taccatcaca cggatagctc agactgtggt gtgtgaactt agaagtatac ttgtaatttg
84721 ttgtatctga ggatgttact gctgatagtc attccctgca ttatgtgtgt tttggggagt
84781 gtgcgtatgt gtgcatgtga atcgatgtgc cttcctgtac aagcaaatac tttaaaaatt
84841 tgggttgtgg acggacctta tcactgtctt ccattcatgg taggttatgt gaagtgctca
84901 atcttgatcc gagacaagtc ctcattgcag aagtgatctt cacaaacatt ggaggagctg
84961 ccactgctat tggggaccca ccaaatgtta tcattgtttc caatcaggag ttgagaaaaa
85021 tggtaggtaa cagcacggta gggttgattt caggaaatgt aaactcaaca gagcactcta
85081 tgcagcttcc tttaataagt actgtgaacc aaggttcttg ctgtcacctg ttcacagcag
85141 gtgctattga tcataagtag tttaggaggg gaaaatcagg agagacagtc ttcaagatta
85201 aggggctgca tttagggcct gtattgacag taacgtgatg ggaggtggtt tcgtcactga
PCR primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated C is shown in red text.
1. Rinchik, E. M., Bultman, S. J., Horsthemke, B., Lee, S. T., Strunk, K. M., Spritz, R. A., Avidano, K. M., Jong, M. T., and Nicholls, R. D. (1993) A gene for the mouse pink-eyed dilution locus and for human type II oculocutaneous albinism, Nature 361, 72-76.
|Science Writers||Nora G. Smart|
|Illustrators||Diantha La Vine|
|Authors||Sophie Rutschmann, Karine Crozat, Bruce Beutler|