Whole-Exome Sequencing Links a Variant in DHDDS to Retinitis Pigmentosa

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• 作者：Stephan Zü ; chner¹ ; ² ; Julia Dallman⁶ ; Rong Wen³ ; Gary Beecham¹ ; ² ; Adam Naj¹ ; ² ; Amjad Farooq⁴ ; ⁵ ; Martin A. Kohli¹ ; ² ; Patrice L. Whitehead¹ ; ² ; William Hulme¹ ; ² ; Ioanna Konidari¹ ; ² ; Yvonne J.K. Edwards¹ ; ² ; Guiqing Cai⁷ ; Inga Peter⁸ ; David Seo¹ ; ² ; Joseph D. Buxbaum⁷ ; ⁸ ; Jonathan L. Haines⁹ ; Susan Blanton¹ ; ² ; Juan Young¹ ; ² ; Eduardo Alfonso³ ; Jeffery M. Vance¹ ; ² ; Byron L. Lam³ ; ^{blam@med.miami.edu} ; Margaret A. Perič ; ak-Vance¹ ; ² ; ^{mpericak@med.miami.edu}
• 刊名：The American Journal of Human Genetics
• 出版年：2011
• 出版时间：11 February 2011
• 年：2011
• 卷：88
• 期：2
• 页码：201-206
• 全文大小：738 K

文摘

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.