眼皮膚白化?。∣CA）是一種具有遺傳異質性的常染色體隱性遺傳病,，在全世界的流行率約為1/17000，人群攜帶率約1/65,，為我國北方地區(qū)相對常見的單基因遺傳病,。該病表現(xiàn)為皮膚、毛發(fā)和眼的黑色素減少或完全缺失,，通常伴有畏光,、斜視、眼球震顫等,，可導致視力低下或喪失,，是導致先天性眼殘疾的常見原因之一。目前,，已明確的人類OCA的致病基因有非綜合征性OCA 基因4個和綜合征性OCA 基因13個,。研究表明仍有一些OCA患者可能由其它未知致病基因引起。
中科院遺傳與發(fā)育生物學研究所李巍研究組長期致力于OCA致病基因的克隆和相關發(fā)病機制的研究,，特別是其中一類綜合征性HPS白化病的發(fā)生機制,。通過對相關HPS基因功能的研究，發(fā)現(xiàn)有多個HPS相關蛋白復合體（HPAC）,，其復合體組成和功能在最近發(fā)表于Pigment Cell & Melanoma Research的一篇綜述中進行了詳細闡述,。在對大量中國白化病遺傳資源的收集和分子流行病學分析、基因診斷和產(chǎn)前診斷的基礎上,，發(fā)現(xiàn)約5%的白化病患者的致病基因未明,。利用全外顯子組測序方法，在一個非綜合征性白化病家系中鑒定出一個色素合成相關基因SLC24A5,，是導致OCA的新致病基因,，命名為OCA6。相關研究發(fā)表在Journal of Investigative Dermatology(doi: 10.1038/jid.2013.49）上,。這一發(fā)現(xiàn)對于白化病的基因診斷和產(chǎn)前診斷有重要意義,，也有助于更深入了解色素產(chǎn)生的機制和人類膚色、毛色多樣性的遺傳基礎,。
該項研究是與首都醫(yī)科大學附屬北京同仁醫(yī)院,、深圳華大基因研究院合作完成的,，得到國家自然科學基金、科技部973項目以及分子發(fā)育生物學國家重點實驗室開放課題的資助,。(生物谷Bioon.com)
DOI:10.1038/jid.2013.49
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Exome Sequencing Identifies SLC24A5 as a Candidate Gene for Non-syndromic Oculocutaneous Albinism
Ai-Hua Wei1,2,4, Dong-Jie Zang1,4, Zhe Zhang1,4, Xuan-Zhu Liu3,4, Xin He1, Lin Yang1, Yi Wang1, Zhi-Yong Zhou1, Ming-Rong Zhang3, Lan-Lan Dai3, Xiu-Min Yang2 and Wei Li1
Oculocutaneous albinism (OCA) is a heterogeneous and autosomal recessive disorder with hypopigmentation in eye, hair and skin color. Four genes, TYR, OCA2, TYRP1 and SLC45A2, have been identified as causative genes for non-syndromic OCA1-4 respectively. The genetics identity of OCA5 locus on 4q24 is unknown. Additional unknown OCA genes may exist as at least 5% of OCA patients have not been characterized during mutational screening in several populations. We here used exome sequencing with a family-based recessive mutation model to determine that SLC24A5 is a previously unreported candidate gene for non-syndromic OCA, which we designate as OCA6. Two deleterious mutations in this patient, c.591G>A and c.1361insT, were identified. We found apparent increase of immature melanosomes and less mature melanosomes in the patient’s skin melanocytes. However, no defects in the platelet dense granules were observed, excluding it from typical Hermansky-Pudlak syndrome (HPS), a well-known syndromic OCA. Moreover, the SLC24A5 protein was reduced in steady-state levels in mouse HPS mutants with deficiencies in BLOC-1 and BLOC-2. Our results suggest that SLC24A5 is a previously unreported non-syndromic OCA candidate gene and that the SLC24A5 transporter is transported into mature melanosomes by HPS protein complexes.
