PUBLICATION
Whole-Exome Sequencing Links a Variant in DHDDS to Retinitis Pigmentosa
- Authors
- Zuchner, S., Dallman, J., Wen, R., Beecham, G., Naj, A., Farooq, A., Kohli, M.A., Whitehead, P.L., Hulme, W., Konidari, I., Edwards, Y.J., Cai, G., Peter, I., Seo, D., Buxbaum, J.D., Haines, J.L., Blanton, S., Young, J., Alfonso, E., Vance, J.M., Lam, B.L., and Periak-Vance, M.A.
- ID
- ZDB-PUB-110214-4
- Date
- 2011
- Source
- American journal of human genetics 88(2): 201-206 (Journal)
- Registered Authors
- Dallman, Julia
- Keywords
- none
- MeSH Terms
-
- Alkyl and Aryl Transferases/genetics*
- Animals
- Dolichols/analogs & derivatives
- Dolichols/metabolism
- Exons/genetics*
- Female
- Genes, Dominant
- Genetic Variation/genetics*
- Glycosylation
- Humans
- Male
- Mutation/genetics*
- Pedigree
- Phenotype
- Polymerase Chain Reaction
- Retinitis Pigmentosa/genetics*
- Rhodopsin/genetics*
- Sequence Analysis, DNA
- Zebrafish/genetics
- Zebrafish/growth & development
- Zebrafish Proteins/antagonists & inhibitors
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 21295283 Full text @ Am. J. Hum. Genet.
Citation
Zuchner, S., Dallman, J., Wen, R., Beecham, G., Naj, A., Farooq, A., Kohli, M.A., Whitehead, P.L., Hulme, W., Konidari, I., Edwards, Y.J., Cai, G., Peter, I., Seo, D., Buxbaum, J.D., Haines, J.L., Blanton, S., Young, J., Alfonso, E., Vance, J.M., Lam, B.L., and Periak-Vance, M.A. (2011) Whole-Exome Sequencing Links a Variant in DHDDS to Retinitis Pigmentosa. American journal of human genetics. 88(2):201-206.
Abstract
Increasingly, mutations in genes causing Mendelian disease will be supported by individual and small families only; however, exome sequencing studies have thus far focused on syndromic phenotypes characterized by low locus heterogeneity. In contrast, retinitis pigmentosa (RP) is caused by >50 known genes, which still explain only half of the clinical cases. In a single, one-generation, nonsyndromic RP family, we have identified a gene, dehydrodolichol diphosphate synthase (DHDDS), demonstrating the power of combining whole-exome sequencing with rapid in vivo studies. DHDDS is a highly conserved essential enzyme for dolichol synthesis, permitting global N-linked glycosylation. Zebrafish studies showed virtually identical photoreceptor defects as observed with N-linked glycosylation-interfering mutations in the light-sensing protein rhodopsin. The identified Lys42Glu variant likely arose from an ancestral founder, because eight of the nine identified alleles in 27,174 control chromosomes were of confirmed Ashkenazi Jewish ethnicity. These findings demonstrate the power of exome sequencing linked to functional studies when faced with challenging study designs and, importantly, link RP to the pathways of N-linked glycosylation, which promise new avenues for therapeutic interventions.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping