新发现白化病基因OCA6的功能研究

Albinism is a heterogeneous and autosomal recessive skin disorder. It manifests as a reduction or complete loss of melanin in the skin, hair, and eyes, often accompanied with eye symptoms such as photophobia, strabismus, moderate to severe visual impairment, and nystagmus. In some cases, severe complications such as lung fibrosis, colitis, and immune deficiency may lead to death in childhood or mid-age adulthood. Currently, there is no cure for albinism. In China, baby selection by prenatal diagnosis is an intervention to avoid the birth of albino babies. Accurate gene diagnosis is required for this intervention. The discovery of unknown albinism genes and the elucidation of their pathogenesis are key steps in the current study of albinism. Using exome sequencing, we have recently identified SLC24A5 as a new causative gene for albinism, which is now named as OCA6. However, how the mutation of this gene causes defects in melanosome maturation and pigment production remains elusive. In this project, we aim to elucidate the molecular and cellular mechanism of OCA6, to gain insights into the pathogenesis of albinism. This will be significant for the translational research and intervention of albinism in China.

白化病是一种常见遗传性皮肤病，主要表现为皮肤、毛发、眼睛色素缺乏。通常伴有眼球震颤、畏光、视力低下等眼部症状，是导致先天性弱视或失明的常见遗传病之一。部分综合征性白化病亚型还可合并其他脏器或系统的病变，例如肺纤维化、肠炎、免疫缺陷等，可导致患者幼年或中年期死亡。白化病目前尚无有效治疗办法，产前基因诊断预防患儿出生是目前主要的干预措施，已被列入我国出生缺陷干预的疾病。因此明确白化病的致病基因和发病机制是白化病的主要研究方向，也是分子分型及产前诊断、遗传咨询所迫切需要解决的问题。2013年我们利用全外显子组测序方法，在一个白化病家系中鉴定出了一个新的致病基因SLC24A5，又被命名为OCA6。但目前对于其发病机制仍缺乏了解。本课题主要利用分子细胞生物学等手段，阐明OCA6基因突变导致黑色素小体成熟障碍和色素生成减少的病理机制，为我国白化病的转化研究和预防、干预奠定基础。

眼皮白化病（oculocutaneous albinism, OCA）是一种具有遗传异质性的单基因遗传病，表现为常染色体隐性遗传模式。其发生机制是色素合成或黑素小体生物发生过程中涉及的基因突变所致。目前，已鉴定出6种人类非综合征型OCA致病基因及其相应的6种亚型（OCA-1~4, 6, 7）。前期研究中，我们在国际上首次确认SLC24A5/NCKX5是OCA6的致病基因，然而尚不清楚SLC24A5/NCKX5基因突变后致人类白化病发生的病理机制。本课题研究中，我们发现NCKX5定位于线粒体，而不是黑素小体。抑制线粒体的正常生理功能或抑制NCKX5的离子交换活性都会减少色素的产生。NCKX5的功能缺失影响了黑素小体Ca2+的富集，从而影响PMEL纤维丝结构的形成、黑素小体的成熟以及色素的生成。因此，我们定义了一种新的白化病类型，即线粒体型白化病，因线粒体功能紊乱导致的色素减退。这一机制还可以部分解释白癜风、老龄白发等现象，为人类色素产生的调控机制提供了新的认识。

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