Manga Prashiela, Loftus Stacie
The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, USA.
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Ann Hum Genet. 2025 Jul 3:e70003. doi: 10.1111/ahg.70003.
Skin, hair, and eye (oculocutaneous) color is due to melanin, a pigment produced by melanocytes. This review considers processes required for pigmentation and the complex genetic network that regulates them. The first requisite is migration of neural crest-derived melanoblasts, which populate various embryonic sites, then differentiate into melanocytes or seed stem cell niches. Differentiation is marked by expression of genes essential for melanogenesis, which takes place in melanosomes and involves conversion of tyrosine into melanin. Melanosome biogenesis requires premelanosome maturation through coordinated delivery of melanogenic enzymes such as tyrosinase (TYR), structural proteins, and transporters that establish an intraluminal environment conducive to melanogenesis. Sorting of proteins through endolysosomal pathways and delivery to melanosomes is facilitated by trafficking protein complexes. Finally, melanin is transferred to keratinocytes to protect against ultraviolet light. Numerous pigment-related disorders result from disruption of these pathways, including Waardenburg syndrome caused by melanoblast migration disruption, oculocutaneous albinism presenting with absent/reduced melanogenesis, and melanoma resulting from dysregulation of proliferation/survival. Genetic variants also determine normal color variation, which is pronounced across populations that, historically, lived in different geographical regions. This variation, shaped by genetic factors, environmental influences, and evolutionary pressures, underpins the wide range of pigmentation phenotypes seen today.
皮肤、毛发和眼睛（眼皮肤）的颜色归因于黑色素，它是由黑素细胞产生的一种色素。本综述探讨了色素沉着所需的过程以及调节这些过程的复杂遗传网络。首先需要神经嵴衍生的成黑素细胞迁移，这些细胞定位于各种胚胎部位，然后分化为黑素细胞或种子干细胞龛。分化的标志是黑素生成所需基因的表达，黑素生成发生在黑素小体中，涉及酪氨酸转化为黑色素。黑素小体的生物发生需要通过协调递送诸如酪氨酸酶（TYR）等黑素生成酶、结构蛋白和转运蛋白来实现前黑素小体的成熟，这些物质建立了有利于黑素生成的腔内环境。通过内溶酶体途径对蛋白质进行分选并递送至黑素小体，这一过程由运输蛋白复合物促进。最后，黑色素被转移到角质形成细胞以抵御紫外线。许多与色素相关的疾病是由这些途径的破坏引起的，包括由成黑素细胞迁移破坏导致的瓦登伯革氏综合征、黑素生成缺失/减少的眼皮肤白化病，以及增殖/存活失调导致的黑色素瘤。基因变异也决定了正常的颜色差异，这种差异在历史上生活在不同地理区域的人群中尤为明显。这种由遗传因素、环境影响和进化压力塑造的差异，构成了如今所见的广泛色素沉着表型的基础。
