FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a transporter protein that mediates melanin synthesis. The protein is expressed in a high percentage of melanoma cell lines. Mutations in this gene are a cause of oculocutaneous albinism type 4, and polymorphisms in this gene are associated with variations in skin and hair color. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009] PHENOTYPE: Homozygotes for spontaneous mutations exhibit varied degrees of hypopigmentation of the eyes, skin, and hair, especially the underfur. Eyes are very light at birth but darken with age. [provided by MGI curators]
Figure 1. The goku mice exhibit hypopigmentation of the fur. A wild-type littermate is shown for reference.
The goku phenotype was identified among G3 mice of the pedigree R5896, some of which showed hypopigmentation of the fur (Figure 1).
Nature of Mutation
Figure 2.Linkage mapping of the hypopigmentation phenotype using a recessive model of inheritance. Manhattan plot shows -log10 P values (Y-axis) plotted against the chromosome positions of 76 mutations (X-axis) identified in the G1 male of pedigree R5896. 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 76 mutations. The pigmentation phenotype was linked to a mutation Slc45a2: a T to A transversion at base pair 11,000,855 (v38) on chromosome 15, or base pair 135 in the GenBank genomic region NC_000081 encoding Slc45a2. Linkage was found with a recessive model of inheritance (P = 6.661 x 10-16), wherein 15 affected mice were homozygous for the variant allele, and 68 unaffected mice were either heterozygous (N = 44) or homozygous for the reference allele (N = 24) (Figure 3)
The mutation corresponds to residue 135 in the mRNA sequence NM_053077 within exon 1 of 7 total exons.
The mutated nucleotide is indicated in red. The mutation results in substitution of tyrosine 13 for a premature stop codon (Y13*) in the SLC45A2 protein.
Figure 3. Protein topology and domain structure of SLC45A2. SLC45A2 is a 55kD protein with 12 membrane-spanning (TM) domains, an elongated N-terminus, and enlarged cytoplasmic loop between transmembrane domains six and seven. The sucrose-transporter signature sequence, R-W-G-R-R is noted. The goku mutation (red asterisk) causes substitution of tyrosine 13 for a premature stop codon. This image is interactive. Click on the mutations for more specific information.
The goku mutation occurs within the N-terminal tail preceding the first transmembrane domain (Figure 3). The function of the N-terminus is unknown. The cytoplasmic N-terminus of SLC45A2 (amino acids 1-45) does not contain any defined domains (UniProt) or post-translational modifications. However, SMART defines a Major Facilitator Superfamily (MFS)_1 Pfam domain, a domain shared by carriers that transport small solutes, consisting of amino acids 36-364.
Please see the record cardigan for information about Slc45a2.
Homozygous mice with Slc45a2 mutations exhibit varied degrees of hypopigmentation of the eyes, skin, and fur (1). In addition, mutations in SLC45A2 can cause oculocutaneous albinism, type IV (OCA4; OMIM: #606574). Mutations at or near the cytoplasmic N-terminus have not been documented in either mouse or human. Expression of SLC45A2goku has not been examined, but the hypopigmentation phenotype resembles that of the proposed null mutant cardigan, indicating loss of SLC45A2 expression in goku.
goku(F):5'- TCTGTCATGCTTCCGAGTG -3'
goku(R):5'- CTGTACAGGCTCTTAGGCAG -3'
goku_seq(F):5'- ATGCTTCCGAGTGCCAAC -3'
goku_seq(R):5'- TCTTAGGCAGGCCCACG -3'