眼皮肤白化病（OCA）是一种具有遗传异质性的常染色体隐性遗传病，在全世界的流行率约为1/17000，人群携带率约1/65，为我国北方地区相对常见的单基因遗传病。该病表现为皮肤、毛发和眼的黑色素减少或完全缺失，通常伴有畏光、斜视、眼球震颤等，可导致视力低下或丧失，是导致先天性眼残疾的常见原因之一。目前，已明确的人类OCA的致病基因有非综合征性OCA 基因4个和综合征性OCA 基因13个。研究表明仍有一些OCA患者可能由其它未知致病基因引起。
中科院遗传与发育生物学研究所李巍研究组长期致力于OCA致病基因的克隆和相关发病机制的研究，特别是其中一类综合征性HPS白化病的发生机制。通过对相关HPS基因功能的研究，发现有多个HPS相关蛋白复合体（HPAC），其复合体组成和功能在最近发表于Pigment Cell & Melanoma Research的一篇综述中进行了详细阐述。在对大量中国白化病遗传资源的收集和分子流行病学分析、基因诊断和产前诊断的基础上，发现约5%的白化病患者的致病基因未明。利用全外显子组测序方法，在一个非综合征性白化病家系中鉴定出一个色素合成相关基因SLC24A5，是导致OCA的新致病基因，命名为OCA6。相关研究发表在Journal of Investigative Dermatology(doi: 10.1038/jid.2013.49）上。这一发现对于白化病的基因诊断和产前诊断有重要意义，也有助于更深入了解色素产生的机制和人类肤色、毛色多样性的遗传基础。
该项研究是与首都医科大学附属北京同仁医院、深圳华大基因研究院合作完成的，得到国家自然科学基金、科技部973项目以及分子发育生物学国家重点实验室开放课题的资助。(生物谷Bioon.com)
DOI:10.1038/jid.2013.49
PMC:
PMID:
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.
