MFSD12 mediates the import of cysteine into melanosomes and lysosomes

Adelmann, Charles H.; Traunbauer, Anna K.; Chen, Brandon; Condon, Kendall J.; Chan, Sze Ham; Kunchok, Tenzin; Lewis, Caroline A.; Sabatini, David M.

doi:10.1038/s41586-020-2937-x

Cited by 71 publications

(55 citation statements)

References 41 publications

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“…Among the top differentiated STRs (Fig. 5 b and (see Additional file 18 : Figure S13d–f and Additional file 19 : Table S6), we found genes with functions that are relevant to bone development ( NR6A1 [ 56 ] and FAF1 ), nervous system development ( OPHN1 , ZC4H2 , LAS1L , TMEM132E , CNTN3 , NTN1 , ITSN1 , and NRG1 ), signal transduction ( GRK3 ) and coat colour ( MFSD12 [ 57 ]). Among these, we observed an expanded STR in intron 4 of the FAF1 gene, where the wild boars showed an average of seven additional AC copies compared with domesticated pigs (Fig.…”

Section: Resultsmentioning

confidence: 99%

A worldwide map of swine short tandem repeats and their associations with evolutionary and environmental adaptations

Gong

Zhang

et al. 2021

Genet Sel Evol

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Background Short tandem repeats (STRs) are genetic markers with a greater mutation rate than single nucleotide polymorphisms (SNPs) and are widely used in genetic studies and forensics. However, most studies in pigs have focused only on SNPs or on a limited number of STRs. Results This study screened 394 deep-sequenced genomes from 22 domesticated pig breeds/populations worldwide, wild boars from both Europe and Asia, and numerous outgroup Suidaes, and identified a set of 878,967 polymorphic STRs (pSTRs), which represents the largest repository of pSTRs in pigs to date. We found multiple lines of evidence that pSTRs in coding regions were affected by purifying selection. The enrichment of trinucleotide pSTRs in coding sequences (CDS), 5′UTR and H3K4me3 regions suggests that trinucleotide STRs serve as important components in the exons and promoters of the corresponding genes. We demonstrated that, compared to SNPs, pSTRs provide comparable or even greater accuracy in determining the breed identity of individuals. We identified pSTRs that showed significant population differentiation between domestic pigs and wild boars in Asia and Europe. We also observed that some pSTRs were significantly associated with environmental variables, such as average annual temperature or altitude of the originating sites of Chinese indigenous breeds, among which we identified loss-of-function and/or expanded STRs overlapping with genes such as AHR, LAS1L and PDK1. Finally, our results revealed that several pSTRs show stronger signals in domestic pig—wild boar differentiation or association with the analysed environmental variables than the flanking SNPs within a 100-kb window. Conclusions This study provides a genome-wide high-density map of pSTRs in diverse pig populations based on genome sequencing data, enabling a more comprehensive characterization of their roles in evolutionary and environmental adaptation.

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Section: Resultsmentioning

confidence: 99%

A worldwide map of swine short tandem repeats and their associations with evolutionary and environmental adaptations

Gong

Zhang

et al. 2021

Genet Sel Evol

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“…Additionally, note that human TYRP1 does not act as a DHICA oxidase (Boissy et al., 1998). MFSD12 is a component of the melanosomal cysteine import system (Adelmann et al, 2020). (Modified from Ito & Wakamatsu, 2011a)…”

Section: Chemical Control Of Melanin Synthesismentioning

confidence: 99%

Chemical and biochemical control of skin pigmentation with special emphasis on mixed melanogenesis

Wakamatsu

Zippin

Ito

2021

Pigment Cell Melanoma Res

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Melanins are widely distributed in animals and plants; in vertebrates, most melanins are present on the body surface. The diversity of pigmentation in vertebrates is mainly attributed to the quantity and ratio of eumelanin and pheomelanin synthesis. Most natural melanin pigments in animals consist of both eumelanin and pheomelanin in varying ratios, and thus, their combined synthesis is called “mixed melanogenesis.” Gene expression is an established mechanism for controlling melanin synthesis; however, there are multiple factors that affect melanin synthesis besides gene expression. Due to the differential sensitivity of the eumelanin and pheomelanin synthetic pathways to pH, melanosomal pH likely plays a major role in mixed melanogenesis. Here, we focused on various factors affecting mixed melanogenesis including (1) chemical regulation of melanin synthesis, (2) melanosomal pH regulation during normal melanogenesis and effect on mixed melanogenesis, and (3) mechanisms of melanosomal pH control (proton pumps, channels, transporters, and signaling pathways).

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“…The difference between the effect of CLC7 downregulation on mouse and human pigmentation, while surprising, could be attributed to different mechanisms governing hair and skin pigmentation, or to the absence of CLC7 expression during early developmental stages in mice (14,37). A similar difference between mouse hair and human skin pigmentation phenotypes was recently described for another transporter, MFSD12 (10,38,39): while MFSD12 -/mice in agouti background are grey due to the absence of pheomelanin bands in the hair, human and mouse skin melanocytes have higher overall melanin levels (38).…”

Section: Discussionmentioning

confidence: 53%

“…Maintenance of melanosomal pH requires the movement of ions across the melanosome membrane via resident ion channels and transporters, and is crucial for melanin synthesis (5)(6)(7). Indeed, mutations in several genes encoding ion transport proteins in melanosomes are associated with pigmentation disorders like oculocutaneous albinism (OCA) (8)(9)(10). Despite the importance of melanosome function in pigmentation and vision, the proteins and mechanisms that regulate ionic and pH homeostasis in melanosomes remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

The lysosomal chloride-proton exchanger CLC7 functions in melanosomes as a negative regulator of human pigmentation

Koroma

Scales

Trotman

et al. 2021

Preprint

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Mutations in the Cl-/H+ exchanger CLC7 and its subunit OSTM1 result in osteopetrosis, lysosomal disorders, and pigmentation defects in mice and humans. How CLC7/OSTM1 regulates pigmentation in skin and hair melanocytes remains unexplored. In human epidermal melanocytes, we found CLC7/OSTM1 localized to melanosomes, the organelles in which melanin is synthesized, where it negatively regulates melanin production. Using a novel ratiometric melanosomal pH indicator, we showed that CLC7 acidifies melanosomes, opposing the function of the oculocutaneous albinism II (OCA2) Cl- ion channel. The de novo CLC7 variant (CLC7-Y715C) that causes albinism in humans and mice, decreased melanocytes pigmentation, which was restored by coexpression of OCA2. Remarkably, the enlarged hyperacidic vacuoles caused by CLC7-Y715C were also rescued by OCA2 coexpression in both melanocytes and non-melanocytic cells. Our data uncover a novel mechanism by which CLC7 regulates melanocyte pigmentation and identifies OCA2 as a tool to counteract the effects of CLC7 activating mutations.

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MFSD12 mediates the import of cysteine into melanosomes and lysosomes

Cited by 71 publications

References 41 publications

A worldwide map of swine short tandem repeats and their associations with evolutionary and environmental adaptations

A worldwide map of swine short tandem repeats and their associations with evolutionary and environmental adaptations

Chemical and biochemical control of skin pigmentation with special emphasis on mixed melanogenesis

The lysosomal chloride-proton exchanger CLC7 functions in melanosomes as a negative regulator of human pigmentation

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