Mutations in ABCB6 Cause Dyschromatosis Universalis Hereditaria
Mutations in ABCB6 Cause Dyschromatosis Universalis Hereditaria
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ABCB6 突变会导致遗传性普遍色素异常症。
DOI：
10.1038/jid.2013.145
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发表时间：
2013-09-01
影响因子：
6.5
通讯作者：
Deng, Yunhua
中科院分区：
文献类型：
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作者：
Zhang, Caie;Li, Duanzhuo;Deng, Yunhua
遗传性泛发性色素异常是一种色素性遗传性皮肤病，其特征是色素沉着和色素减退的混合斑随机分布在全身。迄今为止尚未报道致病基因。在这项研究中，我们调查了一个五代同堂的中国DUH大家庭。在排除了两个已知的DUH基因座后，我们进行了全基因组连锁分析，并确定了染色体2q33.3-q36.1上的DUH基因座，最大LOD得分为3.49，标记D2 S2382。外显子组测序鉴定了DUH家族ABCB 6（ATP结合盒亚家族B，成员6）外显子3的c.1067 T>C（p.Leu356 Pro）突变。通过对散发性DUH患者进行突变筛查，在6例患者中的2例中发现了另外两个错义突变，ABCB 6外显子1的c.508A>G（p.Ser170Gly）和外显子12的c.1736G>A（p.Gly579Glu）。活检标本中的免疫组织学检查显示，ABCB 6在表皮中表达，并具有弥漫性胞质分布。在B16小鼠黑色素瘤细胞系中对野生型ABCB 6的亚细胞定位的检查显示，其定位于内体样隔室和树突尖端，而ABCB 6的致病突变导致其保留在高尔基体中。我们的研究确定ABCB 6是DUH的第一个致病基因。这些发现表明ABCB 6可能是皮肤色素沉着的生理因素。
Dyschromatosis universalis hereditaria (DUH) is a pigmentary genodermatosis characterized by a mixture of hyperpigmented and hypopigmented macules distributed randomly over the body. No causative genes have been reported to date. In this study, we investigated a large five-generation Chinese family with DUH. After excluding the two known DUH loci, we performed genome-wide linkage analysis and identified a DUH locus on chromosome 2q33.3-q36.1 with a maximum LOD score of 3.49 with marker D2S2382. Exome sequencing identified a c.1067T>C (p.Leu356Pro) mutation in exon 3 ofABCB6(ATP-binding cassette subfamily B, member 6) in the DUH family. Two additional missense mutations, c.508A>G (p.Ser170Gly) in exon 1 and c.1736G>A (p.Gly579Glu) in exon 12 ofABCB6, were found in two out of six patients by mutational screening using sporadic DUH patients. Immunohistologic examination in biopsy specimens showed that ABCB6 is expressed in the epidermis and had a diffuse cytoplasmic distribution. Examination of subcellular localization of wild-type ABCB6 in a B16 mouse melanoma cell line revealed that it is localized to the endosome-like compartment and dendrite tips, whereas disease-causing mutations of ABCB6 resulted in its retention in the Golgi apparatus. Our studies identifiedABCB6as the first pathogenic gene associated with DUH. These findings suggest that ABCB6 may be a physiological factor for skin pigmentation.