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Cited by 116melanin and skin pigmentationGenetic Associations and EpidemiologyGenetic Mapping and Diversity in Plants and Animals

Analysis of Cultured Human Melanocytes Based on Polymorphisms within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P Loci

Open access
Cook, Anthony L., Chen, Wei, Thurber, Amy E., Smit, Darren J., Smith, Aaron G., Bladen, Timothy G., Brown, Darren L., Duffy, David L. +5 more·2009·Journal of Investigative Dermatology
DOI 10.1038/jid.2008.211
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Abstract

Single nucleotide polymorphisms (SNPs) within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P genes have been associated with natural variation of pigmentation traits in human populations. Here, we describe the characterization of human primary melanocytic cells genotyped for polymorphisms within the MATP, NCKX5, or OCA2 loci. On the basis of genotype, these cultured cells reflect the phenotypes observed by others in terms of both melanin content and tyrosinase (TYR) activity when comparing skin designated as either "White" or "Black". We found a statistically significant association of MATP-374L (darker skin) with higher TYR protein abundance that was not observed for any NCKX5-111 or OCA2 rs12913832 allele. MATP-374L/L homozygous strains displayed significantly lower MATP transcript levels compared to MATP-374F/F homozygous cells, but this did not reach statistical significance based on NCKX5 or OCA2 genotype. Similarly, we observed significantly increased levels of OCA2 mRNA in rs12913832-T (brown eye) homozygotes compared to rs12913832-C (blue eye) homozygous strains, which was not observed for MATP or NCKX5 gene transcripts. In genotype-phenotype associations performed on a collection of 226 southern European individuals using these same SNPs, we were able to show strong correlations in MATP-L374F, OCA2, and melanocortin-1 receptor with skin, eye, and hair color variation, respectively.

AI snapshot

Written from the paper’s full text.

TL;DR

This study genotyped primary human melanocytes for pigmentation-associated SNPs in SLC45A2/MATP, SLC24A5/NCKX5, and OCA2 and found that cultured cell phenotypes broadly reflected population genotype-phenotype associations. MATP-374L, NCKX5-111A, and OCA2 rs12913832-T were associated with higher melanin/TYR measures, while MATP-374L/L cells had lower MATP mRNA and rs12913832-T/T cells had higher OCA2 mRNA.

Key findings

  • In genotyped Queensland foreskin melanocyte strains, MATP-374L/L had 2.6-fold higher melanin content than MATP-374F/F (P=0.009), NCKX5-111A/A had 2.2-fold higher than NCKX5-111T/T (P=0.04), and OCA2 rs12913832-T/T had 2.4-fold higher than rs12913832-C/C (P=0.05).
  • TYR activity was 2.8-fold higher in MATP-374L/L vs MATP-374F/F (P=0.004), 1.7-fold higher in NCKX5-111A/A vs NCKX5-111T/T (P=0.07), and 2.1-fold higher in rs12913832-T/T vs rs12913832-C/C (P=0.08). TYR protein was 3.0-fold higher in MATP-374L/L vs MATP-374F/F (P=0.009), not significantly different by NCKX5 genotype, and 2.0-fold higher in rs12913832-T/T vs rs12913832-C/C (P=0.17).
  • MATP-374L/L strains had 15–20% of the MATP mRNA level of MATP-374F/F homozygotes (P=0.029 and P=0.003 for two assays), and OCA2 mRNA was 1.6-fold higher in rs12913832-T/T vs rs12913832-C/C strains (P=0.0004). MITF co-transfection activated MATP(Hap1) and MATP(Hap2) reporters similarly, so the authors concluded the MATP mRNA differences were not due to differential MITF-mediated promoter activation.
  • In 226 southern European individuals, MATP-374 was associated with skin color (P=2.2×10−6), OCA2 rs12913832 with eye color (P=4.9×10−23), hair color (P=0.0001), and skin color (P=0.003), and MC1R with hair color (P=1.4×10−20). NCKX5-111 showed no significant skin color association (P=0.06), with no NCKX5-111A/A homozygotes identified.

Methods

  • Primary human melanoblasts were cultured from neonatal foreskin and differentiated to melanocytes; 301 strains were genotyped for MATP-374 and NCKX5-111, 351 for OCA2 rs12913832, and selected QF strains were used for cellular assays. A separate collection of 226 southern European individuals was genotyped and phenotyped for hair, skin, and eye color.
  • Cellular phenotypes were assessed by melanin assays, transmission electron microscopy, L-DOPA reactivity, in situ TYR activity, immunoblotting for TYR/TYRP1/DCT/MART1/MITF, TaqMan real-time RT-PCR for pigmentation-associated mRNAs, and luciferase reporter assays for MATP promoter haplotypes.
  • Statistical analysis used unpaired t-tests comparing homozygous states for each SNP, two-way ANOVA with Bonferroni posttest for luciferase assays, and genotype-phenotype association tests in the southern European sample.

Limitations

  • The paper states that MATP-374, NCKX5-111, and OCA2 rs12913832 were considered independently, and no attempts were made to assess additive or synergistic effects of variant forms of these genes.
  • The paper states that MATP-272K/K individuals were too infrequent for cellular analysis, and that the southern European sample lacked NCKX5-111A/A homozygotes, limiting NCKX5 association testing.
  • The paper notes that the cellular results are from foreskin-derived melanocytes, not iridial stromal melanocytes, when suggesting OCA2 transcript differences may account for blue-brown eye color; evident from the text, some genotype groups were very small (e.g., MATP-374L/L n=2 and NCKX5-111T/A n=2 in the population sample, and only two MATP promoter deletion homozygotes for one analysis).

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/jid.2008.211

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 37 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    MATP-374L is statistically significantly associated with higher TYR protein abundance.

    “We found a statistically significant association of MATP-374L (darker skin) with higher TYR protein abundance”
    Quote in the paperSubstantial claim
  • Findingown data

    MATP-374L/L homozygous strains displayed significantly lower MATP transcript levels compared to MATP-374F/F homozygous cells.

    “MATP-374L/L homozygous strains displayed significantly lower MATP transcript levels compared to MATP-374F/F homozygous cells”
    Quote in the paperSubstantial claim
  • Findingown data

    MC1R is strongly correlated with hair color variation in 226 southern European individuals.

    “In genotype-phenotype associations performed on a collection of 226 southern European individuals using these same SNPs, we were able to show strong correlations in MATP-L374F, OCA2, and melanocortin-1 receptor with skin, eye, and hair color variation, respectively.”
    Quote in the paperSubstantial claim
  • Findingown data

    OCA2 is strongly correlated with eye color variation in 226 southern European individuals.

    “In genotype-phenotype associations performed on a collection of 226 southern European individuals using these same SNPs, we were able to show strong correlations in MATP-L374F, OCA2, and melanocortin-1 receptor with skin, eye, and hair color variation, respectively.”
    Quote in the paperSubstantial claim
  • Findingown data

    OCA2 mRNA levels are significantly increased in rs12913832-T (brown eye) homozygotes compared to rs12913832-C (blue eye) homozygous strains.

    “Similarly, we observed significantly increased levels of OCA2 mRNA in rs12913832-T (brown eye) homozygotes compared to rs12913832-C (blue eye) homozygous strains”
    Quote in the paperSubstantial claim
  • May combine two claims. 20
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 15

  • May combine two claims.

    Findingown data

    MATP-374L/L strains had 3.0-fold (P=0.009) more TYR protein on average compared to MATP-374F/F strains, with heterozygous strains having an intermediate level.

    “On the basis of genotype, MATP-374L/L strains had 3.0-fold (P ¼ 0.009) more TYR protein on average compared to MATP-374F/F strains, with heterozygous strains having an intermediate level of TYR”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MATP mRNA levels varied considerably between strains and were consistent between two separate primer/probe sets.

    “However, MATP mRNA levels varied considerably between strains and were consistent between two separate primer/probe sets”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In QF strains genotyped for the indel polymorphism, strains homozygous for the insertion allele had on average similar MATP transcript to indel heterozygotes, with the two deletion allele homozygous individuals averaging the highest transcript based on genotype.

    “In QF strains genotyped for this polymorphism (Table 1), we observed that strains homozygous for the insertion allele had on average, a similar level of MATP transcript to indel heterozygotes, with the two deletion allele homozygous individual averaging the highest level of transcript based on genotype (Figure 5e).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    We confirmed higher luciferase activity with pGl3-MATP(Hap2) compared to pGl3-MATP(Hap1) in MM96Lc8D cells and in BRN2-ablated MM96Lc8LC cells (1.3- or 1.7-fold).

    “We confirmed this observation using MM96Lc8D cells, but saw similar results in the BRN2-ablated MM96Lc8LC cell line that has lost expression of many melanocytic markers, including MITF and TYRP1 (Figures 5b-d; Thomson et al., 1995).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Allele frequencies for 226 southern European individuals were: MATP-374, 0.9F and 0.1L; MATP-272, 0.96E and 0.04K; NCKX5-111, 0.996T and 0.004A; OCA2 rs12913832, 0.49C and 0.51T.

    “Allele frequencies for this sample collection of 226 individuals were as follows: MATP-374, 0.9F, and 0.1L; MATP-272, 0.96E, and 0.04K; NCKX5-111, 0.996T, and 0.004A (two individuals were NCKX5-111T/A); and OCA2 rs12913832, 0.49C, and 0.51T.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The indel polymorphism is 4 bp downstream of the core E-box (CATGTG) motif bound by MITF, which was additionally preceded by the preferred T residue.

    “Closer inspection of the two sequences suggested that the insertion/deletion (indel) polymorphism was 4 bp downstream of the core E-box (CATGTG) motif bound by MITF (Figure 5a), which was additionally preceded by the preferred T residue (Aksan and Goding, 1998).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For most mRNAs measured, levels of transcript were similar between individual strains when normalizing to 18S ribosomal RNA, and levels of most mRNAs did not correlate with genotype.

    “For most mRNAs measured, we observed similar levels of transcript between individual strains when normalizing to 18S ribosomal RNA levels (Figures 4a-c and Figures S2a-c), thus the levels of most mRNAs examined did not correlate with genotype”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MATP transcript levels were on average most highly expressed in MATP-374F/F homozygous samples, whereas MATP-374L/L homozygous samples had the lowest level, having 15-20% of the MATP mRNA level of MATP-374F/F homozygotes (P=0.029 and P=0.003).

    “When we considered MATP genotype, we found that MATP transcript levels were on average most highly expressed in MATP-374F/F homozygous samples, whereas MATP-374L/L homozygous samples had the lowest level of transcript, having 15-20% of the MATP mRNA level of MATP-374F/F homozygotes (Figures 4i and j; P ¼ 0.029 and P ¼ 0.003, respectively).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MITF-M-dependent induction was similar for both reporter constructs, being 6.6- and 7.7-fold (P<0.001 for both compared to pGl3-basic) higher than the pcDNA3.1 co-transfection for the pGl3-MATP(Hap1) and pGl3-MATP(Hap2) constructs, respectively.

    “Notably, this MITF-M-dependent induction was similar for both reporter constructs, being 6.6-and 7.7-fold (Po0.001 for both MATP reporters compared to pGl3-basic) higher than the pcDNA3.1 co-transfection for the pGl3-MATP(Hap1) and pGl3-MAT-P(Hap2) constructs, respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    MM96Lc8LC cells have lost expression of many melanocytic markers, including MITF and TYRP1, and also MATP, OCA2, and NCKX5.

    “Importantly, the MM96Lc8LC cells have also lost expression of MATP, OCA2, and NCKX5 (Figure 5c; data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Polymorphism frequencies in the QF melanocyte strain collection and the southern European samples displayed similar trends such that the MC1R and OCA2 loci were more heterogeneous than the MATP-374, MATP-272, and NCKX5-111 SNPs.

    “Polymorphism frequencies in the QF melanocyte strain collection and the southern European samples tested here displayed similar trends such that the MC1R and OCA2 loci were more heterogenous than the MATP-374, MATP-272, and NCKX5-111 SNPs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    We have observed an increase in TYR activity in all strains examined using ammonium chloride (7/7) and in most strains using bafilomycin A (5/7), but have not observed any genotype-based selectivity of these compounds.

    “We have observed an increase in TYR activity in all strains examined using ammonium chloride (7/7) and in most strains using bafilomycin A (5/7), but have not observed any genotype-based selectivity of these compounds (data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    13.33% of rs12913832-T/T individuals had dark skin compared to only 3.51% of rs12913832-C/C individuals.

    “Conversely, 13.33% of rs12913832-T/T individuals had dark skin compared to only 3.51% of rs12913832-C/C individuals.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The SNP A111T (rs1426654) within the coding region of human SLC24A5 has been associated with natural pigmentation variation.

    “Like SLC45A2, a SNP within the coding region of the human SLC24A5 gene, A111T (rs1426654), has been associated with natural pigmentation variation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Lamason et al., 2005 source

      Not checked in the free run.

    • cites Norton et al., 2007 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The NCKX5-111A ancestral form has a high frequency within more darkly pigmented populations such as Africans, indigenous Americans, and East Asians, whereas the 111T variant allele is predominant in Europeans.

    “The NCKX5-111A ancestral form of the protein has a high frequency within more darkly pigmented populations, such as Africans, indigenous Americans, and East Asians, whereas the 111T variant allele is predominant in Europeans”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Lamason et al., 2005 source

      Not checked in the free run.

    • cites Norton et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The MATP allele encoding 374L is found at a higher frequency in non-Caucasian populations than the 374F allele and is associated with darker pigmentation of the skin, hair, and eyes in populations of European ancestry.

    “The MATP allele encoding 374L was found at a higher frequency in non-Caucasian populations than the 374F allele, and also to be associated with darker pigmentation of the skin, hair, and eyes in populations of European ancestry”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Nakayama et al., 2002 source

      Not checked in the free run.

    • cites Graf et al., 2005 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Normal polymorphism of OCA2 is predominantly associated with eye color, although effects on skin and hair color have also been reported.

    “Normal polymorphism of OCA2 appears to be predominantly associated with eye color, although effects on skin and hair color have also been reported”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Sturm and Frudakis, 2004

      Not checked in the free run.

    • cites Duffy et al., 2007 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Due to the low frequency of MATP-272K/K individuals, cellular analysis of pigmentation based on this SNP has not been conducted.

    “Due to the low frequency of MATP-272K/K individuals in our collection (Table 1 and Table S1), we have not yet conducted a cellular analysis of pigmentation based on this SNP.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    MATP-374, NCKX5-111, and OCA2 rs12913832 were considered independently, and no attempts to consider potential additive or synergistic effects were made.

    “Throughout our cellular analysis of melanogenesis, we have considered MATP-374, NCKX5-111, and OCA2 rs12913832 independently of each other for these initial studies, and no attempts to consider potential additive or synergistic effects of variant forms of these genes on pigmentation levels have yet been made.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The effects of MATP-374, NCKX5-111, and OCA2 rs12913832 on pigmentation can be analyzed independently without additive or synergistic effects.

  • May combine two claims.

    Interpretationreasoning

    As the preferred MITF E-box was present in both MATP(Hap1) and MATP(Hap2), the reason the MITF site was differentially detected bioinformatically was due to the GT residues 5 bp downstream of the E-box.

    “Importantly, as the preferred MITF E-box (shaded in Figure 5a) was present in both MATP(Hap1) and MATP(Hap2), it seems that the reason the MITF site was differentially detected bioinformatically was due to the GT residues 5 bp downstream of the E-box (underlined in Figure 5a).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    For each independently examined SNP, data from at least three strains for both homozygous and heterozygous states were analyzed.

    “Strain selection was such that for each independently examined SNP, we were able to analyze data from at least three strains for both homozygous as well as the heterozygous states.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    These values are in agreement with our results based on MATP, but not NCKX5, genotype.

    “These values are again in agreement with our results presented here based on MATP, but not NCKX5, genotype.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A 3 bp duplication polymorphism within the MATP promoter was recently reported to be associated with normal variation of human skin color.

    “A 3 bp duplication polymorphism within the MATP promoter was recently reported, which was associated with normal variation of human skin color (Graf et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Graf et al., 2007 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    The results presented here are from foreskin-derived melanocytes and not iridial stromal melanocytes.

    “Although the results presented here are from foreskin-derived melanocytes and not iridial stromal melanocytes, this result suggests that differences in OCA2 transcript levels may account for bluebrown eye color.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mutations of the MC1R gene in patients diagnosed with OCA2 alter hair color.

    “and mutations of the MC1R gene in patients diagnosed with OCA2 also alter hair color (King et al., 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites King et al., 2003 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MATP and NCKX5 have additive contributions to human skin coloration.

    “Recent studies have also suggested additive contributions of MATP and NCKX5 to human skin coloration (Stokowski et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Stokowski et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    As MATP-374L and NCKX5-111A alleles both occur at maximal frequencies in Asians and Africans, other populations that show substantial differences in the degree of pigmentation have these and other polymorphisms contribute to these phenotypic differences.

    “Notably, as MATP-374L and NCKX5-111A alleles both occur at maximal frequencies in Asians and Africans (reviewed in Sturm, 2006), other populations that show substantial differences in the degree of pigmentation (Tadokoro et al., 2003;Norton et al., 2007) have these and other polymorphisms contribute to these phenotypic differences.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Sturm, 2006 source

      Not checked in the free run.

    • cites Tadokoro et al., 2003 source

      Not checked in the free run.

    • cites Norton et al., 2007 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A 3 bp indel polymorphism in the MATP promoter, with the absence of the 3 bp, is associated with lighter pigmentation.

    “One of these included a 3 bp indel polymorphism, with the absence of the 3 bp associated with lighter pigmentation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Graf et al., 2007 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    SLC45A2/MATP gene promoter polymorphisms are associated with skin color variation within European populations.

    “SLC45A2/MATP gene promoter polymorphisms have recently been associated with skin color variation within European populations (Graf et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Graf et al., 2007 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    This may indicate a requirement for tight regulation of these genes, as their protein products may adversely affect the homeostasis of ions within subcellular compartments.

    “This may indicate a requirement for tight regulation of these genes, as their protein products may adversely affect the homeostasis of ions with the subcellular compartments.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Combinatorial effects are observed in mouse models when double-mutant homozygous mice are compared to mice harboring homozygous mutations in either gene alone.

    “Combinatorial effects are also observed in mouse models, when mutant melanogenic gene alleles being considered in double-mutant homozygous mice are compared to mice harboring homozygous mutations in either gene alone (Prota et al., 1995;Lehman et al., 2000).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Prota et al., 1995 source

      Not checked in the free run.

    • cites Lehman et al., 2000 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An effect of eye color on phenotypes associated with MC1R variant alleles has been reported.

    “In this manner, an effect of eye color on phenotypes associated with MC1R variant alleles has been reported (Duffy et al., 2004)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Duffy et al., 2004 source

      Not checked in the free run.

32 of 32

  • The paper relies on this without support.

    The molecular function of MATP remains unknown.

    “Despite its identification and cloning as a mouse pigmentation mutation, the molecular function of MATP remains unknown.”

  • The paper relies on this without support.

    The mechanism causing mislocalization of the TYRP-family of proteins in OCA4 is not yet defined.

    “The mechanism causing mislocalization of the TYRP-family of proteins in OCA4 is not yet defined”

  • The paper relies on this without support.

    No substrate for transportation across the MATP membrane has been identified.

    “however no substrate for transportation across the membrane has been identified.”

  • The paper relies on this without support.

    The effects of MATP-374, NCKX5-111, and OCA2 rs12913832 on pigmentation can be analyzed independently without additive or synergistic effects.

    “Throughout our cellular analysis of melanogenesis, we have considered MATP-374, NCKX5-111, and OCA2 rs12913832 independently of each other for these initial studies, and no attempts to consider potential additive or synergistic effects of variant forms of these genes on pigmentation levels have yet been made.”

  • The paper relies on this without support.

    Foreskin-derived melanocytes are a valid model for iridial stromal melanocytes with respect to OCA2 transcript levels and eye color.

    “Although the results presented here are from foreskin-derived melanocytes and not iridial stromal melanocytes, this result suggests that differences in OCA2 transcript levels may account for bluebrown eye color.”

  • The paper relies on this without support.

    Cultured QF melanocyte MATP mRNA levels reflect MATP mRNA levels in individuals with corresponding skin pigmentation.

    “Our results suggest that lighter-skinned individuals have higher MATP mRNA levels, as we found MATP mRNA levels associated with MATP-374 amino-acid changes (Figures 4i and j).”

  • The paper relies on this without support.

    The MATP-374 genotype is associated with lighter skin color in the QF melanocyte donors.

    “Our results suggest that lighter-skinned individuals have higher MATP mRNA levels, as we found MATP mRNA levels associated with MATP-374 amino-acid changes (Figures 4i and j).”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • It is less clear whether the SLC45A2 and TYR derived alleles are codominant, recessive, or dominant.

    “However, although there is strong evidence that the derived HERC2 rs12913832 G allele is recessive (36), it is less clear whether the SLC45A2 and TYR derived alleles are codominant, recessive, or dominant (22, 35).”

    From Direct evidence for positive selection of skin, hair, and eye pigmentation in Europeans during the last 5,000 y (2014) · cites this paper as [22]

  • Cook et al. (2009) showed that melanocytes homozygous for the blue-eye associated allele of rs12913832 of BEH2 produced significantly less melanin than heterozygotes or those homozygous for the ancestral allele, but did not control for other SNPs in the region.

    “Cook et al. (2009) showed melanocytes homozygous for the blue-eye associated allele of rs12913832 of BEH2 produced significantly less melanin than heterozygotes or those that were homozygous for the ancestral allele, but did not control for other SNPs in the region.”

    From A global view of the OCA2-HERC2 region and pigmentation (2012) · cites this paper as Cook et al. (2009)

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • OCA2 SNP identifier differs in the genotyping method

    Minor

    The genotyping method names rs1293832, whereas the results and Table 1 identify the OCA2 SNP under study as rs12913832. These are different identifiers, leaving the reported method inconsistent with the reported results.

  • MATP F/F dark-skin percentage differs from Table 2

    Minor

    The discussion says 3% of MATP-374F/F individuals had dark skin, but Table 2 reports 2.17%. Rounded to a whole percent, the table value is 2%, not 3%.

2 of 2

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References 78 · Cited by 116

Authors
Cook, A. L., Chen, W., Thurber, A. E., Smit, D. J., Smith, A. G., Bladen, T. G., Brown, D. L., Duffy, D. L., Pastorino, L., Bianchi-Scarra, G., Helen Leonard, J., Stow, J. L., & Sturm, R. A.
Affiliations
  • The University of Queensland (AU)
  • QIMR Berghofer Medical Research Institute (AU)
  • University of Genoa (IT)
Corresponding author
Sturm, Richard A.
ORCID
Venue
Journal of Investigative Dermatology
Publisher
Elsevier BV
Published
2009-02
Volume
129
Issue
2
Pages
392-405
ISSN
0022-202X (ISSN-L)
DOI
10.1038/jid.2008.211
OpenAlex
W1973153817
Cited by
116
References
78
Citations by year
2026: 4 · 2025: 4 · 2024: 3 · 2023: 2 · 2022: 4 · 2021: 3 · 2020: 12 · 2019: 8 · 2018: 5 · 2017: 7 · 2016: 2 · 2015: 7 · 2014: 11 · 2013: 9 · 2012: 9
FWCI
3.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Investigative Dermatology (publishedVersion)
  • PubMed (publishedVersion)
  • eCite Digital Repository (University of Tasmania) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
Funders
  • QIMR Berghofer Medical Research Institute
  • Queensland University of Technology
  • Australian Research Council (DP0771169, DP0451738)
  • National Health and Medical Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords
melanocytes, OCA2, single nucleotide polymorphisms, skin pigmentation, melanin content, tyrosinase activity, genotype-phenotype correlation, MC1R, eye color, hair color, southern European population
MeSH terms
Antigens, Neoplasm, Cells, Cultured, Eye Color, Gene Expression Regulation, Genotype, Hair Color, Humans, Melanins, Melanocytes, Phenotype, Promoter Regions, Genetic, RNA, Messenger, Skin, Skin Pigmentation, Antiporters, Polymorphism, Single Nucleotide, Membrane Transport Proteins, Receptor, Melanocortin, Type 1, White People, Microphthalmia-Associated Transcription Factor

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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