One of the key pigmentation genes in humans is SLC24A5 (OMIM 609802). It is located on chromosome 15q21.1 and encodes a protein called SLC24A5 (NCKX5). The association of this gene with lighter pigmentation was initially discovered in zebrafish. Using admixed populations, it was further demonstrated that a non-synonymous variant (ref SNP ID: rs1426654) in the third exon of SLC24A5 gene explains 25-38% of the skin color variation between Europeans and West Africans. Functional assays suggested its direct involvement in human melanogenesis through cation-exchange activity.
|Basic Information of SLC24A5|
|Protein Name||Sodium/potassium/calcium exchanger 5|
|Aliases||Na(+)/K(+)/Ca(2+)-exchange protein 5, Solute carrier family 24 member 5, NCKX5|
|Organism||Homo sapiens (Human)|
Variation of a non-synonymous single-nucleotide polymorphism (nsSNP; rs1426654) in the gene SLC24A5 is associated with differences in constitutive skin color in South Asians. The nsSNP encodes the substitution of alanine for threonine at residue 111 (A111T) near a transmembrane region required for exchanger activity, a region which is highly conserved across different species and between NCKX family members. We have shown that SLC24A5 is located at the trans-Golgi network of melanocytes and functions as a potassium-dependent sodium-calcium exchanger. When heterologously expressed, the A111T variant of SLC24A5 shows significantly lower exchanger activity than the wide type. It has postulated that lower exchanger activity causes reduced melanogenesis.
Fig.1 Potential role(s) and regulation of calcium (Ca) transport genes, i.e., TRPV5/6, calbindins, PCMA1, and NCX1/NCKX3, in reproductive tissues for Ca transport and reproductive functions. (Choi, 2011)
This article implies that NCKX5 exchanger function influences natural variation in skin pigmentation via a novel, unknown mechanism affecting cellular sterol levels.
This article proposes that two mutations in SLC24A5 affect iris pigmentation in tiger-eye PRPF horses. Further, unlike OCA6 in humans, the Tiger-eye 1 mutation in its homozygous state or as a compound heterozygote (Tiger-eye 1/Tiger-eye 2) does not appear to cause ocular anomalies or a change in coat color in the PRPF horse.
This article suggests that NCKX5 directly regulates human epidermal melanogenesis and natural skin color through its intracellular potassium-dependent exchanger activity.
By studying the localization and function of the zebrafish slc24a5 gene, the authors believe that the SLC24A5 gene plays an important role in human pigmentation.
This article reveals that NCKX5 is not a PM resident and is exclusively located in the TGN. Moreover, the large cytoplasmic loop is the determinant for retaining NCKX5 in the TGN.
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