Mutations in ABCB6 Cause Dyschromatosis Universalis Hereditaria

JOURNAL OF INVESTIGATIVE DERMATOLOGY

卷:133

Article

Zhang, Caie^1,2  Li, Duanzhuo³  Zhang, Jianguo^4,5  Chen, Xingping²  Huang, Mi³  Archacki, Stephen^6,7  Tian, Yuke¹  Ren, Weiping²  Mei, Aihua²  Zhang, Qingyan⁴  Fang, Mingyan⁴  Su, Zheng⁴  Yin, Ye⁴  Liu, Dongxian²  Chen, Yingling²  Cui, Xiukun³  Li, Chang³  Yang, Huanming⁴  Wang, Qing³  Wang, Jun^4,8  Liu, Mugen³  Deng, Yunhua² 

[1] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Core Lab,Dept Anesthesiol, Wuhan 430030, Hubei, Peoples R China

[2] Huazhong Univ Sci & Technol, Dept Dermatol, Tongji Hosp, Tongji Med Coll, Wuhan 430030, Hubei, Peoples R China

[3] Huazhong Univ Sci & Technol, Ctr Human Genome Res, Coll Life Sci & Technol, Key Lab Mol Biophys,Minist Educ, Wuhan 430030, Hubei, Peoples R China

[4] BGI Shenzhen, Shenzhen, Guangdong, Peoples R China

[5] Fudan Univ, T Life Res Ctr, Shanghai 200433, Peoples R China

[6] Cleveland Clin Fdn, Dept Mol Cardiol, Ctr Cardiovasc Genet, Cleveland, OH 44195 USA

[7] Cleveland Clin Fdn, Lerner Res Inst, Cleveland, OH 44195 USA

[8] Univ Copenhagen, Dept Biol, Copenhagen, Denmark

DOI  :  10.1038/jid.2013.145

来源: Elsevier

【 摘 要 】

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 of ABCB6 (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 of ABCB6, 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 identified ABCB6 as the first pathogenic gene associated with DUH. These findings suggest that ABCB6 may be a physiological factor for skin pigmentation.

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