Mutations In ABCB6Cause Dyschromatosis Universalis Hereditaria

Dyschromatosis universalis hereditaria (DUH) is a pigmentary genodermatosis characterized by a mixture of hyper-and hypo-pigmented macules distributed randomly over the body. It was initially described in1933, but the pathogenic mechanism is remains unknown. Two chromosome loci have been reported to be associated with DUH, one is mapped to chromosome6q24.2-q25.2, and the other is on12q21-q23. However, no causative gene(s) for DUH has been reported to date.In this study, we investigated a large five-generation Han nationality family associated with DUH from Hubei province. After excluding the two known loci, we performed genome-wide linkage analysis and identified a novel DUH locus on chromosome2q33.3-q36.1with a maximum LOD score of3.49with marker D2S2382. Exome sequencing identified a c.1067T>C(p.Leu356Pro) mutation in exon3of ABCB6in the DUH family. Direct DNA sequencing and co-segregation analysis showed that the c.1067T>C mutation occurred in all affected members, but not in any of the unaffected individuals of the family. DNA sequence analysis with a panel of500unaffected control individuals matched for the geographical location did not detect this mutation. Furthermore, additional missense mutations, c.508A>G (p.Ser170Gly) in exon1, and c.1736G>A (p.Gly579Glu) in exon12of ABCB6were found in two out of six patients by mutational screening using sporadic DUH patients. Neither of the ABCB6mutations was found in400control individuals.ABCB6belongs to the large family of ATP-binding cassette transporters. To investigate the mechanism by which mutations of ABCB6causing DUH, we performed immunohistologic examination in normal human skin. We found that ABCB6is expressed in the epidermis and had a diffuse cytoplasmic distribution. More over, western blot results showed that ABCB6express in HaCaT (human keratinocyte line) and A375cells (a human malignant melanoma cell line). In addition, the wild-type and three mutant forms ABCB6were tagged with EGFP fusion proteins and then transfected into mouse B16cells, respectively. The localization of the various fusion proteins was determined by confocal microscopy. Subcellular localization examination of wild-type ABCB6revealed that it localized to the endosome-like compartment, and its accumulation in the dendrites could be clearly seen. In comparison, disease-causing mutations of ABCB6resulted in its retention in the Golgi apparatus.In conclusion, we identified the first causative gene for DUH. Linked the ATP-binding cassette transporter6to Dyschromatosis universalis hereditaria, may be great help to understand the molecular basis of this disease. The metabolism of skin pigment is complicated and delicated. Identification of ABCB6as an pathogenic gene for pigmentary genodermatosis, will open a novel avenue to understanding of the mechanism of pigmentogenesis.