Whole-Exome Sequencing Links a Variant in DHDDS to Retinitis Pigmentosa Stephan Züchner, Julia Dallman, Rong Wen, Gary Beecham, Adam Naj, Amjad Farooq,

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Whole-Exome Sequencing Links a Variant in DHDDS to Retinitis Pigmentosa Stephan Züchner, Julia Dallman, Rong Wen, Gary Beecham, Adam Naj, Amjad Farooq, Martin A. Kohli, Patrice L. Whitehead, William Hulme, Ioanna Konidari, Yvonne J.K. Edwards, Guiqing Cai, Inga Peter, David Seo, Joseph D. Buxbaum, Jonathan L. Haines, Susan Blanton, Juan Young, Eduardo Alfonso, Jeffery M. Vance, Byron L. Lam, Margaret A. Peričak-Vance The American Journal of Human Genetics Volume 88, Issue 2, Pages 201-206 (February 2011) DOI: 10.1016/j.ajhg.2011.01.001 Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 1 DHDDS Harbors a Mutation Causing RP (A) Pedigree of the studied family with three affected offspring indicating a recessive trait. (B) Three-dimensional structural model of DHDDS indicates an important role for Arg38 in the organization of the enzyme active site. The Lys42Glu mutant allele, being negatively charged, will likely ion pair with the positively charged Arg38 and, in so doing, may lead to distortion of the active site and compromise the binding of farnesyl-pyrophosphate (arrow). A detailed description of the mechanism is provided in Figure S2. (C) Sanger sequencing confirmed the identified mutation and revealed complete cosegregation with the phenotype. (D) Lys42 (red box) is a highly conserved residue in multiple species and is located close to the active site of the protein (orange box), indicating strong evolutionary constraints. The American Journal of Human Genetics 2011 88, 201-206DOI: (10.1016/j.ajhg.2011.01.001) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 2 Photoreceptor Degeneration Induced by Suppression of DHDDS Expression and Illustration of the Involved Pathways of N-Linked Glycosylation (A–F) Microphotographs in (A) and (D) show representative retinal sections of control and fish treated with MO. The areas in red rectangles are shown at higher magnification in (B) and (E). The layers of the retina are indicated by the white bars in (A), including the retinal pigment epithelium (1), the outer nuclear layer (2), the inner nuclear layer (3), the inner plexiform layer (4), and the retinal ganglion cell layer (5). In the retinas treated with MO, the outer segments of photoreceptors are very short, or completely missing (E, arrowhead), compared to the controls (B, arrowhead). Staining of cone outer segments with peanut agglutinin (PNA) highlights that cone outer segments in MO-treated zebrafish (F, arrowhead), but not in controls (C, arrowhead), are missing. Semithin plastic sections (A, B, D, and E) were stained with toluidine blue. Cryosections (C and F) were stained with PNA (conjugated with Alexa Fluor 488). Scale bars represent 25 μm for (A) and (D), 10 μm for (B) and (E), and 20 μm for (C) and (F). (G) A simplified schematic of essential N-linked glycosylation pathways (steps 1–4). An emphasis is given to key processes upstream and downstream of dolichol-PP synthesis (DHDDS) that are also related to RP phenotypes. (1) The cytoplasmic mevalonate pathway produces isoprenoide units, which are (2) chained to ER membrane-bound dolichol species, dolichol-pyrophosphate (dolichol-PP). (3) Dolichol-PP serves as an intermediate lipid to bind a common core of carbohydrates, en bloc, forming the lipid-linked oligosaccharide (LLO). The LLO is “flipped” within the ER membrane to face the ER lumen. (4) Finally, the common core of carbohydrates is transferred to proteins, such as rhodopsin. Along this pathway, mevalonate kinase deficiency is associated with RP,14 mutations in PMM2 (phosphomannomutase 2; MIM 601785) lead to congenital disorder of glycosylation Ia (CDGIa), often involving RP, and, finally, glycosylation defects in rhodopsin cause RP. N denotes asparagine. The American Journal of Human Genetics 2011 88, 201-206DOI: (10.1016/j.ajhg.2011.01.001) Copyright © 2011 The American Society of Human Genetics Terms and Conditions