Whole-exome sequencing links a variant in DHDDS to retinitis pigmentosa |
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Authors: | Züchner Stephan Dallman Julia Wen Rong Beecham Gary Naj Adam Farooq Amjad Kohli Martin A Whitehead Patrice L Hulme William Konidari Ioanna Edwards Yvonne J K Cai Guiqing Peter Inga Seo David Buxbaum Joseph D Haines Jonathan L Blanton Susan Young Juan Alfonso Eduardo Vance Jeffery M Lam Byron L Peričak-Vance Margaret A |
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Affiliation: | 1John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA;2Dr. John T. Macdonald Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136, USA;3Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA;4Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA;5Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33146, USA;6Department of Biology, University of Miami, Miami, FL 33146, USA;7Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA;8Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA;9Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN 37232, USA |
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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. |
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