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Published on: September 7, 2013
The MFSD12 p.Tyr182His common variant is sufficient to alter mouse agouti coat color
Dawn E Watkins-Chow1, Arturo A Incao1, Cecelia Rivas2
1Genomics, Development and Disease Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Abstract:
MFSD12 functions as a transmembrane protein required for import of cysteine into melanosomes and lysosomes. The MFSD12 locus has been associated with phenotypic variation in skin color across African, Latin American, and East Asian populations. The frequency of a particular MFSD12 coding variant, rs2240751 (MAF = 0.08), has been reported to correlate with solar radiation and occur at highest frequency in Peruvian (PEL MAF = 0.48) and Han Chinese (CHB MAF = 0.40) populations, suggesting it could be causative for associated phenotypic variation in skin color. We have generated a mouse knock-in allele, Mfsd12Y182H , to model the human missense p.Tyr182His human variant. We demonstrate that the variant transcript is stably expressed and that agouti mice homozygote for the variant allele are viable with an altered coat color. This in vivo data confirms that the MFSD12 p.Tyr182His variant functions as a hypomorphic allele sufficient to alter mammalian pigmentation.
Insights
The MFSD12 gene influences skin color variation. A specific MFSD12 variant (p.Tyr182His) was modeled in mice, confirming its role in altering mammalian pigmentation.
Area of Science:
- Genetics
- Molecular Biology
- Human Physiology
Background:
- MFSD12 is a transmembrane protein crucial for cysteine transport into melanosomes and lysosomes.
- Genetic variations in MFSD12 are linked to human skin color diversity across global populations.
- A specific MFSD12 variant (rs2240751) shows a frequency correlation with solar radiation, particularly in Peruvian and Han Chinese populations.
Purpose of the Study:
- To investigate the functional impact of the human MFSD12 p.Tyr182His variant on mammalian pigmentation.
- To create and analyze a mouse model for the human MFSD12 p.Tyr182His variant.
Main Methods:
- Generated a mouse knock-in allele (Mfsd12Y182H) to replicate the human missense variant.
- Assessed the expression stability of the variant transcript.
- Observed the phenotype of agouti mice homozygous for the variant allele.
Main Results:
- The Mfsd12Y182H variant transcript was stably expressed in mice.
- Mice homozygous for the Mfsd12Y182H allele were viable and exhibited altered coat color.
- In vivo data confirmed the hypomorphic nature of the MFSD12 p.Tyr182His variant.
Conclusions:
- The MFSD12 p.Tyr182His variant acts as a hypomorphic allele.
- This variant is sufficient to cause changes in mammalian coat color, providing a functional link to pigmentation variation.
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