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

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 02/2011; 88(2):201-6. DOI: 10.1016/j.ajhg.2011.01.001
Source: PubMed


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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    • "Ever since it was first described in 2009 as proof-of-concept for Freeman-Sheldon syndrome [21], several studies have successfully employed WES for identifying dozens of genes in inherited diseases. With regard to retinal phenotypes, it was first employed to study an Ashkenazi Jewish family, in which WES of three affected siblings revealed a mutation in a novel gene, DHDDS, as a cause of RP [27]. Table 1 provides a summary of published reports of novel retinal disease genes discovered by WES. "
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    • "Reads were mapped to the human genome reference sequence (NCBI build 36.1) and call of variants was performed according to previously published algorithms and procedures [24]. These procedures were performed by BGI, under a fee-for-service agreement. "
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    • "The altered amino acid resides proximally to the farnesyl-diphosphate binding site of the DHDDS protein (Fig. 1), which is predicted to result in significant reduction of the dolichol phosphate pool required for glycosylation of rod photoreceptor proteins. The same mutation was also identified in an Ashkenazi Jewish family with an affected sibship employing whole exome sequencing [Züchner et al., 2011]. These authors documented the pathogenicity of this variant employing gene inactivation with morpholinos in the zebra fish homologue, replicating the ocular anomalies observed in patients. "
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