Genome-Wide Linkage, Exome Sequencing and Functional Analyses Identify ABCB6 as the Pathogenic Gene of Dyschromatosis Universalis Hereditaria
- Authors
- Liu, H., Li, Y., Hung, K.K., Wang, N., Wang, C., Chen, X., Sheng, D., Fu, X., See, K., Foo, J.N., Low, H., Liany, H., Irwan, I.D., Liu, J., Yang, B., Chen, M., Yu, Y., Yu, G., Niu, G., You, J., Zhou, Y., Ma, S., Wang, T., Yan, X., Goh, B.K., Common, J.E., Lane, B.E., Sun, Y., Zhou, G., Lu, X., Wang, Z., Tian, H., Cao, Y., Chen, S., Liu, Q., Liu, J., and Zhang, F.
- ID
- ZDB-PUB-140415-1
- Date
- 2014
- Source
- PLoS One 9(2): e87250 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- ATP-Binding Cassette Transporters/genetics*
- ATP-Binding Cassette Transporters/metabolism
- Amino Acid Sequence
- Animals
- Base Sequence
- Chromosome Mapping
- DNA Mutational Analysis
- Exome/genetics*
- Family Health
- Female
- Genetic Predisposition to Disease/genetics*
- Genome-Wide Association Study/methods*
- Humans
- Immunohistochemistry
- Lod Score
- Male
- Melanocytes/metabolism
- Molecular Sequence Data
- Mutation, Missense
- Pedigree
- Pigmentation Disorders/congenital*
- Pigmentation Disorders/genetics
- Pigmentation Disorders/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Sequence Homology, Amino Acid
- Sequence Homology, Nucleic Acid
- Skin/metabolism
- Skin/pathology
- Skin Diseases, Genetic/genetics*
- Skin Diseases, Genetic/metabolism
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 24498303 Full text @ PLoS One
Background
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.
Methodology
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.
Results
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.
Conclusion
Our study has advanced our understanding of DUH pathogenesis and revealed the shared pathological mechanism between pigmentary DUH and ocular coloboma.