Exome Sequencing Identifies SLC24A5 as a Candidate Gene for Nonsyndromic Oculocutaneous Albinism
Exome Sequencing Identifies SLC24A5 as a Candidate Gene for Nonsyndromic Oculocutaneous Albinism
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外显子组测序将 SLC24A5 确定为非综合征性眼皮肤白化病的候选基因
DOI：
10.1038/jid.2013.49
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发表时间：
2013-07-01
影响因子：
6.5
通讯作者：
Li, Wei
中科院分区：
文献类型：
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作者：
Wei, Ai-Hua;Zang, Dong-Jie;Li, Wei
眼皮肤白化病（OCA）是一种异源性常染色体隐性遗传病，眼部、头发和皮肤色素沉着降低。四个基因，TYR, OCA2， TYRP1和SLC45A2，分别被鉴定为非综合征性OCA1-4的致病基因。4q24上OCA5位点的遗传身份尚不清楚。其他未知的OCA基因可能存在，因为至少5%的OCA患者在一些人群的突变筛查中未被表征。我们使用基于家族的隐性突变模型的外显子组测序来确定SLC24A5是以前未报道的非综合征性OCA候选基因，我们将其命名为OCA6。在该患者中发现了两种有害突变，c.591G >a和c.1361insT。我们发现患者皮肤黑色素细胞中未成熟的黑素体和未成熟的黑素体明显增加。然而，除了典型的Hermansky-Pudlak综合征（一种众所周知的综合征性OCA）外，未观察到血小板致密颗粒存在缺陷。此外，在缺乏block -1和block -2的小鼠HPS突变体中，SLC24A5蛋白在稳态水平上降低。我们的研究结果表明，SLC24A5是一个以前未报道的非综合征性OCA候选基因，SLC24A5转运体通过HPS蛋白复合物转运到成熟的黑素小体中。
Oculocutaneous albinism (OCA) is a heterogeneous and autosomal recessive disorder with hypopigmentation in the eye, hair, and skin color. Four genes, TYR, OCA2, TYRP1, and SLC45A2, have been identified as causative genes for nonsyndromic OCA1-4, respectively. The genetic 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 used exome sequencing with a family-based recessive mutation model to determine that SLC24A5 is a previously unreported candidate gene for nonsyndromic 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 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 nonsyndromic OCA candidate gene and that the SLC24A5 transporter is transported into mature melanosomes by HPS protein complexes.