Mutations in IMPG2, Encoding Interphotoreceptor Matrix Proteoglycan 2, Cause Autosomal-Recessive Retinitis Pigmentosa Dikla Bandah-Rozenfeld, Rob W.J.

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Mutations in IMPG2, Encoding Interphotoreceptor Matrix Proteoglycan 2, Cause Autosomal-Recessive Retinitis Pigmentosa Dikla Bandah-Rozenfeld, Rob W.J. Collin, Eyal Banin, L. Ingeborgh van den Born, Karlien L.M. Coene, Anna M. Siemiatkowska, Lina Zelinger, Muhammad I. Khan, Dirk J. Lefeber, Inbar Erdinest, Francesco Testa, Francesca Simonelli, Krysta Voesenek, Ellen A.W. Blokland, Tim M. Strom, Caroline C.W. Klaver, Raheel Qamar, Sandro Banfi, Frans P.M. Cremers, Dror Sharon, Anneke I. den Hollander The American Journal of Human Genetics Volume 87, Issue 2, Pages 199-208 (August 2010) DOI: 10.1016/j.ajhg.2010.07.004 Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees and Segregation Analysis in Two Families with IMPG2 Mutations (A) Family MOL0764: selected SNP markers encompassing the shared homozygous region in IV:2 and IV:3 as detected by the 10K Affymetrix array are shown in the right panel. The rs481809 marker is located within the IMPG2 gene. (B) Family W01-299: microsatellite and SNP analysis shows cosegregation of a chromosome-3q-linked haplotype with RP in family W01-299; the flanking SNPs are indicated in italics. Mutation-bearing haplotypes are marked by black bars. Filled symbols represent affected individuals, whereas clear symbols represent unaffected individuals. The position of the markers (in Mb), based on the human genome browser GRCh37/hg19, is indicated. The American Journal of Human Genetics 2010 87, 199-208DOI: (10.1016/j.ajhg.2010.07.004) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 2 Linkage Intervals, Mutation Analysis, and Protein Characterization of IMPG2 (A) Upper panel: part of chromosome 3 showing the linkage intervals and the corresponding flanking SNPs for arRP-families MOL0764 and W01-299. The genomic positions of these markers are indicated in Mb. IMPG2 resides within the region that is shared by the two families. Lower panel: genomic structure of IMPG2; 19 exons are indicated as blue bars. The noncoding parts of exons 1 and 19 are indicated with a smaller bar. (B) Upper panel: PCR analysis of exon 9 of IMPG2. Exon 9 was not amplified in the three affected individuals of family W01-299. All relatives and their position in the pedigree are indicated above the electropherogram. Lower panel: after identification of the breakpoints of the genomic deletion, PCR primers were designed to amplify a product if the deletion is present. This breakpoint PCR shows a product in all three affected individuals and in the heterozygous carriers, i.e., both parents (I:1 and I:2) and one unaffected brother (II:3). (C) Sequence analysis of IMPG2 mRNA derived from EBV-transformed cultured lymphoblasts of individual II:1 and of an unrelated control. RT-PCR and subsequent analysis shows that, because of the genomic deletion, exon 9 of IMPG2 is absent in the mutant IMPG2 mRNA. At the protein level, this is predicted to result in the absence of seven amino acids, i.e., RSPKEND. (D) Graphical representation of the IMPG2 protein. Shown are the signal peptide, two SEA domains and two EGF-like domains in the large extracellular N-terminal part of the protein, and a transmembrane-spanning region. The positions of asparagine and threonine residues that are predicted to undergo N- or O-linked glycosylation, respectively, as well as the serine residues that might serve as core residues for the attachment of glycosaminoglycan side chains, are indicated with symbols described in the figure. The positions of the mutations identified in this study are indicated with arrows. (E) Evolutionary conservation of the mutated phenylalanine residue and surrounding amino acids. Shown are partial protein sequences of human, mouse, bovine, and chicken IMPG2 and IMPG1 proteins. Amino acids that are identical in all proteins are presented in white on a black background, whereas partially conserved residues are shown in black on a gray background. The American Journal of Human Genetics 2010 87, 199-208DOI: (10.1016/j.ajhg.2010.07.004) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 3 Fundus Photographs of RP Patients with IMPG2 Mutations (A and B) A montage of color fundus photos of MOL0764 IV:2 at age 60 shows advanced RP along with myopic changes. (C) Fundus photographs of the right eye of patient W01-299 II:6, aged 44 years, show optic-disc pallor, attenuated vessels, bull's eye maculopathy, and mid-peripheral RPE atrophy with some intra-retinal pigmentations. (D–G) Family W08-1378: (D and E) Montage of color fundus photos of the proband and (F and G) fundus photographs of the affected brother. Both show optic disc pallor, attenuated vessels, and patchy depigmentation of the RPE in the midperiphery with some bone spicules. Only the brother presented with sharply delineated atrophy of the RPE in the macula of both eyes. (H) A fundus photograph of the left eye of proband NAP75, aged 64 years, shows optic-disc pallor, attenuated vessels, atrophic maculopathy, and mid-peripheral RPE atrophy with some intra-retinal pigmentations. (I and J) A fundus photograph of both eyes of the proband of family RP-49 shows optic-disc pallor, attenuated vessels, and bone-spiculed pigmentations. The American Journal of Human Genetics 2010 87, 199-208DOI: (10.1016/j.ajhg.2010.07.004) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 4 Subcellular Localization of Wild-Type and ΔRSPKEND Mutant SEA-Domain Fusion Proteins (A–C) Images of COS-1 cells transiently transfected with a wild-type IMPG2-SEA domain fused to a signal peptide and eCFP. The wild-type fusion protein ([A], in green) localizes to vesicle-like structures in the ER ([B], PDI staining, red) and cytoplasm (open arrows) and is present at the cellular membrane (filled arrows). Nuclei are stained with DAPI (blue). (C) Overlay of (A) and (B). (D–F) Images of COS-1 cells transiently transfected with ΔRSPKEND mutant IMPG2-SEA domain fused to a signal peptide and eCFP. The mutant fusion protein ([D], in green) accumulates in an ER-like region adjacent to the cell nucleus (arrow heads) and does not reach the plasma membrane. (E) PDI staining of the ER, red. Nuclei are stained with DAPI, blue. (F) Overlay of (D) and (E). The American Journal of Human Genetics 2010 87, 199-208DOI: (10.1016/j.ajhg.2010.07.004) Copyright © 2010 The American Society of Human Genetics Terms and Conditions