High frequency of Hermansky-Pudlak syndrome type 1 (HPS1) among Japanese albinism patients and functional analysis of HPS1 mutant protein
High frequency of Hermansky-Pudlak syndrome type 1 (HPS1) among Japanese albinism patients and functional analysis of HPS1 mutant protein
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DOI：
10.1111/j.0022-202x.2005.23884.x
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发表时间：
2005-10-01
影响因子：
6.5
通讯作者：
Tomita, Y
中科院分区：
文献类型：
--
作者：
Ito, S;Suzuki, T;Tomita, Y
Hermansky-Pudlak综合征(HPS)是一种常染色体隐性遗传病，以眼皮肤白化病(OCA)、出血倾向和类蜡样物质溶酶体积聚为特征。人类已知有七种不同的HPS基因亚型；大多数在波多黎各以外的地方很少见。在这里，我们描述了24例日本OCA患者的HPS1基因分析，这些患者缺乏引起OCA的四个已知基因(TYR/OCA1、P/OCA2、TYRP1/OCA3和MATP/OCA4)的突变，并在其中10例患者中鉴定出8种不同的HPS1突变，其中4种是新发现的(W583X、L668P、532insC、1691delA)。IVS5+5G-->；A剪接共识突变尤其频繁，这是日本患者该等位基因的创始人效应的结果。通过将L668P变异体导入Hps1突变的Melan-EP小鼠黑素细胞进行的功能分析表明，这种错义替换是病理性的，导致HPS-1蛋白无法组装到溶酶体相关细胞器复合体-3的生物发生中。
Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism (OCA), bleeding tendency, and lysosomal accumulation of ceroid-like material. Seven genetically distinct subtypes of HPS are known in humans; most are rare outside of Puerto Rico. Here, we describe the analysis of the HPS1 gene in 24 Japanese OCA patients who lacked mutations in the four genes known to cause OCA (TYR/OCA1, P/OCA2, TYRP1/OCA3, and MATP/OCA4), and the identification of eight different HPS1 mutations in ten of these patients, four of which were novel (W583X, L668P, 532insC, 1691delA). An IVS5 + 5G --> A splice consensus mutation was particularly frequent, the result of a founder effect for this allele in Japanese patients. Functional analysis by transfection of the L668P variant into Hps1-mutant melan-ep mouse melanocytes showed that this missense substitution is pathologic, resulting in an Hps-1 protein that is unable to assemble into the biogenesis of lysosome-related organelles complex-3.