Genome-wide linkage, exome sequencing and functional analyses identify ABCB6 as the pathogenic gene of dyschromatosis universalis hereditaria.
As a genetic disorder of abnormal pigmentation, the molecular basis of dyschromatosis universalis hereditaria (DUH) had remained unclear until recently when ABCB6 was reported as a causative gene of DUH.We performed genome-wide linkage scan using Illumina Human 660W-Quad BeadChip and exome sequencin...
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3911924?pdf=render |
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| author | Hong Liu Yi Li Ken Kwok Hon Hung Na Wang Chuan Wang Xuechao Chen Donglai Sheng Xi'an Fu Kelvin See Jia Nee Foo Huiqi Low Herty Liany Ishak Darryl Irwan Jian Liu Baoqi Yang Mingfei Chen Yongxiang Yu Gongqi Yu Guiye Niu Jiabao You Yan Zhou Shanshan Ma Ting Wang Xiaoxiao Yan Boon Kee Goh John E A Common Birgitte E Lane Yonghu Sun Guizhi Zhou Xianmei Lu Zhenhua Wang Hongqing Tian Yuanhua Cao Shumin Chen Qiji Liu Jianjun Liu Furen Zhang |
| author_facet | Hong Liu Yi Li Ken Kwok Hon Hung Na Wang Chuan Wang Xuechao Chen Donglai Sheng Xi'an Fu Kelvin See Jia Nee Foo Huiqi Low Herty Liany Ishak Darryl Irwan Jian Liu Baoqi Yang Mingfei Chen Yongxiang Yu Gongqi Yu Guiye Niu Jiabao You Yan Zhou Shanshan Ma Ting Wang Xiaoxiao Yan Boon Kee Goh John E A Common Birgitte E Lane Yonghu Sun Guizhi Zhou Xianmei Lu Zhenhua Wang Hongqing Tian Yuanhua Cao Shumin Chen Qiji Liu Jianjun Liu Furen Zhang |
| author_sort | Hong Liu |
| collection | DOAJ |
| description | As a genetic disorder of abnormal pigmentation, the molecular basis of dyschromatosis universalis hereditaria (DUH) had remained unclear until recently when ABCB6 was reported as a causative gene of DUH.We performed genome-wide linkage scan using Illumina Human 660W-Quad BeadChip and exome sequencing analyses using Agilent SureSelect Human All Exon Kits in a multiplex Chinese DUH family to identify the pathogenic mutations and verified the candidate mutations using Sanger sequencing. Quantitative RT-PCR and Immunohistochemistry was performed to verify the expression of the pathogenic gene, Zebrafish was also used to confirm the functional role of ABCB6 in melanocytes and pigmentation.Genome-wide linkage (assuming autosomal dominant inheritance mode) and exome sequencing analyses identified ABCB6 as the disease candidate gene by discovering a coding mutation (c.1358C>T; p.Ala453Val) that co-segregates with the disease phenotype. Further mutation analysis of ABCB6 in four other DUH families and two sporadic cases by Sanger sequencing confirmed the mutation (c.1358C>T; p.Ala453Val) and discovered a second, co-segregating coding mutation (c.964A>C; p.Ser322Lys) in one of the four families. Both mutations were heterozygous in DUH patients and not present in the 1000 Genome Project and dbSNP database as well as 1,516 unrelated Chinese healthy controls. Expression analysis in human skin and mutagenesis interrogation in zebrafish confirmed the functional role of ABCB6 in melanocytes and pigmentation. Given the involvement of ABCB6 mutations in coloboma, we performed ophthalmological examination of the DUH carriers of ABCB6 mutations and found ocular abnormalities in them.Our study has advanced our understanding of DUH pathogenesis and revealed the shared pathological mechanism between pigmentary DUH and ocular coloboma. |
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| institution | Directory Open Access Journal |
| issn | 1932-6203 |
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| spelling | doaj.art-12befc761e4c478db72d4c3c7b4edf872022-12-21T20:11:17ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0192e8725010.1371/journal.pone.0087250Genome-wide linkage, exome sequencing and functional analyses identify ABCB6 as the pathogenic gene of dyschromatosis universalis hereditaria.Hong LiuYi LiKen Kwok Hon HungNa WangChuan WangXuechao ChenDonglai ShengXi'an FuKelvin SeeJia Nee FooHuiqi LowHerty LianyIshak Darryl IrwanJian LiuBaoqi YangMingfei ChenYongxiang YuGongqi YuGuiye NiuJiabao YouYan ZhouShanshan MaTing WangXiaoxiao YanBoon Kee GohJohn E A CommonBirgitte E LaneYonghu SunGuizhi ZhouXianmei LuZhenhua WangHongqing TianYuanhua CaoShumin ChenQiji LiuJianjun LiuFuren ZhangAs a genetic disorder of abnormal pigmentation, the molecular basis of dyschromatosis universalis hereditaria (DUH) had remained unclear until recently when ABCB6 was reported as a causative gene of DUH.We performed genome-wide linkage scan using Illumina Human 660W-Quad BeadChip and exome sequencing analyses using Agilent SureSelect Human All Exon Kits in a multiplex Chinese DUH family to identify the pathogenic mutations and verified the candidate mutations using Sanger sequencing. Quantitative RT-PCR and Immunohistochemistry was performed to verify the expression of the pathogenic gene, Zebrafish was also used to confirm the functional role of ABCB6 in melanocytes and pigmentation.Genome-wide linkage (assuming autosomal dominant inheritance mode) and exome sequencing analyses identified ABCB6 as the disease candidate gene by discovering a coding mutation (c.1358C>T; p.Ala453Val) that co-segregates with the disease phenotype. Further mutation analysis of ABCB6 in four other DUH families and two sporadic cases by Sanger sequencing confirmed the mutation (c.1358C>T; p.Ala453Val) and discovered a second, co-segregating coding mutation (c.964A>C; p.Ser322Lys) in one of the four families. Both mutations were heterozygous in DUH patients and not present in the 1000 Genome Project and dbSNP database as well as 1,516 unrelated Chinese healthy controls. Expression analysis in human skin and mutagenesis interrogation in zebrafish confirmed the functional role of ABCB6 in melanocytes and pigmentation. Given the involvement of ABCB6 mutations in coloboma, we performed ophthalmological examination of the DUH carriers of ABCB6 mutations and found ocular abnormalities in them.Our study has advanced our understanding of DUH pathogenesis and revealed the shared pathological mechanism between pigmentary DUH and ocular coloboma.http://europepmc.org/articles/PMC3911924?pdf=render |
| spellingShingle | Hong Liu Yi Li Ken Kwok Hon Hung Na Wang Chuan Wang Xuechao Chen Donglai Sheng Xi'an Fu Kelvin See Jia Nee Foo Huiqi Low Herty Liany Ishak Darryl Irwan Jian Liu Baoqi Yang Mingfei Chen Yongxiang Yu Gongqi Yu Guiye Niu Jiabao You Yan Zhou Shanshan Ma Ting Wang Xiaoxiao Yan Boon Kee Goh John E A Common Birgitte E Lane Yonghu Sun Guizhi Zhou Xianmei Lu Zhenhua Wang Hongqing Tian Yuanhua Cao Shumin Chen Qiji Liu Jianjun Liu Furen Zhang Genome-wide linkage, exome sequencing and functional analyses identify ABCB6 as the pathogenic gene of dyschromatosis universalis hereditaria. PLoS ONE |
| title | Genome-wide linkage, exome sequencing and functional analyses identify ABCB6 as the pathogenic gene of dyschromatosis universalis hereditaria. |
| title_full | Genome-wide linkage, exome sequencing and functional analyses identify ABCB6 as the pathogenic gene of dyschromatosis universalis hereditaria. |
| title_fullStr | Genome-wide linkage, exome sequencing and functional analyses identify ABCB6 as the pathogenic gene of dyschromatosis universalis hereditaria. |
| title_full_unstemmed | Genome-wide linkage, exome sequencing and functional analyses identify ABCB6 as the pathogenic gene of dyschromatosis universalis hereditaria. |
| title_short | Genome-wide linkage, exome sequencing and functional analyses identify ABCB6 as the pathogenic gene of dyschromatosis universalis hereditaria. |
| title_sort | genome wide linkage exome sequencing and functional analyses identify abcb6 as the pathogenic gene of dyschromatosis universalis hereditaria |
| url | http://europepmc.org/articles/PMC3911924?pdf=render |
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