title: Whole-exome sequencing links a variant in DHDDS to retinitis pigmentosa.
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.
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.forename: Julia
authors.initials: J
authors.lastname: Dallman
authors.forename: Rong
authors.initials: R
authors.lastname: Wen
authors.forename: Gary
authors.initials: G
authors.lastname: Beecham
authors.forename: Adam
authors.initials: A
authors.lastname: Naj
authors.forename: Amjad
authors.initials: A
authors.lastname: Farooq
authors.forename: Martin A
authors.initials: MA
authors.lastname: Kohli
authors.forename: Patrice L
authors.initials: PL
authors.lastname: Whitehead
authors.forename: William
authors.initials: W
authors.lastname: Hulme
authors.forename: Ioanna
authors.initials: I
authors.lastname: Konidari
authors.forename: Yvonne J K
authors.initials: YJ
authors.lastname: Edwards
authors.forename: Guiqing
authors.initials: G
authors.lastname: Cai
authors.forename: Inga
authors.initials: I
authors.lastname: Peter
authors.forename: David
authors.initials: D
authors.lastname: Seo
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Susan
authors.initials: S
authors.lastname: Blanton
authors.forename: Juan
authors.initials: J
authors.lastname: Young
authors.forename: Eduardo
authors.initials: E
authors.lastname: Alfonso
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Vance
authors.forename: Byron L
authors.initials: BL
authors.lastname: Lam
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Peričak-Vance
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000235:genetics*; D000818:Animals; D004286:Dolichols / Q000031:analogs & derivatives / Q000378:metabolism; D005091:Exons / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D014644:Genetic Variation / Q000235:genetics*; D006031:Glycosylation; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012174:Retinitis Pigmentosa / Q000235:genetics*; D012243:Rhodopsin / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D004286:Dolichols; D029961:Zebrafish Proteins; C079181:dehydrodolichol; D012243:Rhodopsin; D019883:Alkyl and Aryl Transferases; C051389:dehydrodolichyl diphosphate synthetase