Skin pigmentation is a highly heterogeneous trait with diverse consequences worldwide. SLC24A5 , encoding a potent K⁺‐dependent Na⁺/Ca²⁺ exchanger, is among the known color‐coding genes that participate in melanogenesis by maintaining pH in melanosomes. Deficient SLC24A5 activity results in oculocutaneous albinism (OCA) type 6 in humans. In this study, by utilizing a exome sequencing (ES) approach, we identified two new variants [p. (Gly110Arg) and p. (IIe189Ilefs*1)] of SLC24A5 cosegregating with the OCA phenotype, including nystagmus, strabismus, foveal hypoplasia, albinotic fundus, and vision impairment, in three large consanguineous Pakistani families. Both of these variants failed to rescue the pigmentation in zebrafish slc24a5 morphants, confirming the pathogenic effects of the variants. We also phenotypically characterized a commercially available zebrafish mutant line (slc24a5^ko ) that harbors a nonsense (p.Tyr208*) allele of slc24a5 . Similar to morphants, homozygous slc24a5^ko mutants had significantly reduced melanin content and pigmentation. Next, we used these slc24a5^ko zebrafish mutants to test the efficacy of nitisinone, a compound known to increase ocular and fur pigmentation in OCA1 (TYR ) mutant mice. Treatment of slc24a5^ko mutant zebrafish embryos with varying doses of nitisinone did not improve melanin production and pigmentation, suggesting that treatment with nitisinone is unlikely to be therapeutic in OCA6 patients.

中文翻译：

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SLC24A5 变体的分子特征和 OCA6 斑马鱼模型中尼替西农治疗效果的评估。

皮肤色素沉着是一种高度异质性的特征，在全球范围内具有不同的后果。SLC24A5编码一种有效的 K ⁺依赖性 Na ⁺ /Ca ²⁺交换剂，是已知的通过维持黑素体中的 pH 值参与黑素生成的颜色编码基因之一。缺乏 SLC24A5 活性会导致人类 6 型眼皮肤白化病 (OCA)。在这项研究中，通过利用外显子组测序 (ES) 方法，我们确定了两个新的变体 [p. (Gly110Arg) 和 p。(IIe189Ilefs*1)] SLC24A5在三个大型近亲巴基斯坦家庭中与 OCA 表型共同分离，包括眼球震颤、斜视、中心凹发育不全、白化病眼底和视力障碍。这两种变体都未能挽救斑马鱼lc24a5 morphant 的色素沉着，证实了这些变体的致病作用。我们还表型表征了一种商业上可获得的斑马鱼突变系 ( slc24a5 ^ko )，它含有 slc24a5 的无意义 (p.Tyr208*)等位基因。与morphant 相似，纯合slc24a5 ^ko 突变体具有显着降低的黑色素含量和色素沉着。接下来，我们使用了这些slc24a5 ^ko 斑马鱼突变体测试尼替西农的功效，尼替西农是一种已知会增加 OCA1 ( TYR ) 突变小鼠的眼部和毛皮色素沉着的化合物。用不同剂量的尼替西农治疗slc24a5 ^ko 突变斑马鱼胚胎并没有改善黑色素生成和色素沉着，这表明用尼替西农治疗不太可能对 OCA6 患者有治疗作用。