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1. CRB1-associated retinal dystrophies: a prospective natural history study in anticipation of future clinical trials

Author

Nguyen, Xuan-Thanh-An, Talib, Mays, van Schooneveld, Mary J, Wijnholds, Jan, van Genderen, Maria M, Schalij-Delfos, Nicoline E, Klaver, Caroline C W, Talsma, Herman E, Fiocco, Marta, Florijn, Ralph J, Ten Brink, Jacoline B, Cremers, Frans P M, Meester-Smoor, Magda A, Ingeborgh van den Born, L, Hoyng, Carel B, Thiadens, Alberta A H J, Bergen, Arthur A, Boon, Camiel J F, Nguyen, Xuan-Thanh-An, Talib, Mays, van Schooneveld, Mary J, Wijnholds, Jan, van Genderen, Maria M, Schalij-Delfos, Nicoline E, Klaver, Caroline C W, Talsma, Herman E, Fiocco, Marta, Florijn, Ralph J, Ten Brink, Jacoline B, Cremers, Frans P M, Meester-Smoor, Magda A, Ingeborgh van den Born, L, Hoyng, Carel B, Thiadens, Alberta A H J, Bergen, Arthur A, and Boon, Camiel J F

Abstract

PURPOSE: To describe the natural disease course of CRB1-associated retinal dystrophies, and to identify clinical endpoints for future clinical trials.DESIGN: Single center, prospective case series.METHODS: An investigator-initiated nationwide collaborative study that included 22 patients with CRB1-associated retinal dystrophies. Patients underwent ophthalmic assessment at baseline and 2 years after baseline. Clinical examination included best-corrected visual acuity (BCVA) using ETDRS charts, Goldmann kinetic perimetry (V4e isopter seeing retinal areas), microperimetry, full-field electroretinography (ERG), full-field stimulus threshold (FST), fundus photography, spectral-domain optical coherence tomography and fundus autofluorescence imaging.RESULTS: Based on genetic, clinical and electrophysiological data, patients were diagnosed with retinitis pigmentosa (n = 19; 86%), cone-rod dystrophy (n = 2; 9%) or isolated macular dystrophy (n = 1; 5%). Two-year analysis of the entire cohort showed no significant changes in BCVA (p = 0.069) or V4e isopter seeing retinal areas (p = 0.616), although signs of clinical progression were present in individual patients. Macular sensitivity measured on microperimetry revealed a significant reduction at 2-year follow-up (p < 0.001). FST responses were measurable in patients with non-recordable ERGs. On average, FST responses remained stable during follow-up.CONCLUSION: In CRB1-associated retinal dystrophies, visual acuity and visual field measures remain relatively stable over the course of 2 years. Microperimetry showed a significant decrease in retinal sensitivity during follow-up, and may be a more sensitive progression marker. Retinal sensitivity on microperimetry may serve as a functional clinical endpoint in future human treatment trials for CRB1-associated retinal dystrophies.

Published
2022

2. X-Linked Retinoschisis: Novel Clinical Observations and Genetic Spectrum in 340 Patients

Author

Infection & Immunity, MS Oogheelkunde, Child Health, Hahn, Leo C., van Schooneveld, Mary J., Wesseling, Nieneke L., Florijn, Ralph J., ten Brink, Jacoline B., Lissenberg-Witte, Birgit I., Strubbe, Ine, Meester-Smoor, Magda A., Thiadens, Alberta A., Diederen, Roselie M., van Cauwenbergh, Caroline, de Zaeytijd, Julie, Walraedt, Sophie, de Baere, Elfride, Klaver, Caroline C.W., Ossewaarde-van Norel, Jeannette, Ingeborgh van den Born, L., Hoyng, Carel B., van Genderen, Maria M., Sieving, Paul A., Leroy, Bart P., Bergen, Arthur A., Boon, Camiel J.F., Infection & Immunity, MS Oogheelkunde, Child Health, Hahn, Leo C., van Schooneveld, Mary J., Wesseling, Nieneke L., Florijn, Ralph J., ten Brink, Jacoline B., Lissenberg-Witte, Birgit I., Strubbe, Ine, Meester-Smoor, Magda A., Thiadens, Alberta A., Diederen, Roselie M., van Cauwenbergh, Caroline, de Zaeytijd, Julie, Walraedt, Sophie, de Baere, Elfride, Klaver, Caroline C.W., Ossewaarde-van Norel, Jeannette, Ingeborgh van den Born, L., Hoyng, Carel B., van Genderen, Maria M., Sieving, Paul A., Leroy, Bart P., Bergen, Arthur A., and Boon, Camiel J.F.

Published
2022

3. BBS1 branchpoint variant is associated with non-syndromic retinitis pigmentosa.

Author

Fadaie, Zeinab, Whelan, Laura, Dockery, Adrian, Li, Catherina H. Z., Ingeborgh van den Born, L., Hoyng, Carel B., Gilissen, Christian, Corominas, Jordi, Rowlands, Charlie, Megaw, Roly, Lampe, Anne K., Cremers, Frans P. M., Farrar, Gwyneth Jane, Ellingford, Jamie M., Kenna, Paul F., and Roosing, Susanne

Abstract

Background Inherited retinal diseases (IRDs) can be caused by variants in >270 genes. The Bardet-Biedl syndrome 1 (BBS1) gene is one of these genes and may be associated with syndromic and non-syndromic autosomal recessive retinitis pigmentosa (RP). Here, we identified a branchpoint variant in BBS1 and assessed its pathogenicity by in vitro functional analysis. Methods Whole genome sequencing was performed for three unrelated monoallelic BBS1 cases with nonsyndromic RP. A fourth case received MGCM 105 gene panel analysis. Functional analysis using a midigene splice assay was performed for the putative pathogenic branchpoint variant in BBS1. After confirmation of its pathogenicity, patients were clinically re-evaluated, including assessment of non-ocular features of BardetBiedl syndrome. Results Clinical assessments of probands showed that all individuals displayed non-syndromic RP with macular involvement. Through detailed variant analysis and prioritisation, two pathogenic variants in BBS1, the most common missense variant, c.1169T>G (p.(Met390Arg)), and a branchpoint variant, c.592-21A>T, were identified. Segregation analysis confirmed that in all families, probands were compound heterozygous for c.1169T>Gand c.592-21A>T. Functional analysis of the branchpoint variant revealed a complex splicing defect including exon 8 and exon 7/8 skipping, and partial inframe deletion of exon 8. Conclusion A putative severe branchpoint variant in BBS1, together with a mild missense variant, underlies non-syndromic RP in four unrelated individuals. To our knowledge, this is the first report of a pathogenic branchpoint variant in IRDs that results in a complex splice defect. In addition, this research highlights the importance of the analysis of non-coding regions in order to provide a conclusive molecular diagnosis. [ABSTRACT FROM AUTHOR]

Published
2022
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4. Late-Onset Stargardt Disease Due to Mild, Deep-Intronic ABCA4 Alleles

Author

Runhart, E.H., Valkenburg, D., Cornelis, S.S., Khan, M., Sangermano, R., Albert, S., Bax, N.M., Astuti, G.D.N, Gilissen, C.F., Blokland, E.A.W., Cremers, F.P.M., Ingeborgh van den Born, L., Hoyng, C.B., Runhart, E.H., Valkenburg, D., Cornelis, S.S., Khan, M., Sangermano, R., Albert, S., Bax, N.M., Astuti, G.D.N, Gilissen, C.F., Blokland, E.A.W., Cremers, F.P.M., Ingeborgh van den Born, L., and Hoyng, C.B.

Abstract

Contains fulltext : 209464.pdf (publisher's version ) (Open Access)

Published
2019

5. Clinical characterization of 66 patients with congenital retinal disease due to the deep-intronic c.2991+1655A>G mutation in CEP290

Author

Valkenburg, Dyon, van Cauwenbergh, Caroline, Lorenz, Birgit, van Genderen, Mies M., Bertelsen, Mette, Pott, Jan Willem R., Coppieters, Frauke, de Zaeytijd, Julie, Thiadens, Alberta A.H.J., Klaver, Caroline C.W., Kroes, Hester Y., van Schooneveld, Mary J., Preising, Markus, Hoyng, Carel B., Leroy, Bart P., Ingeborgh van den Born, L., Collin, Rob W.J., Valkenburg, Dyon, van Cauwenbergh, Caroline, Lorenz, Birgit, van Genderen, Mies M., Bertelsen, Mette, Pott, Jan Willem R., Coppieters, Frauke, de Zaeytijd, Julie, Thiadens, Alberta A.H.J., Klaver, Caroline C.W., Kroes, Hester Y., van Schooneveld, Mary J., Preising, Markus, Hoyng, Carel B., Leroy, Bart P., Ingeborgh van den Born, L., and Collin, Rob W.J.

Published
2018

6. Clinical characterization of 66 patients with congenital retinal disease due to the deep-intronic c.2991+1655A>G mutation in CEP290

Author

Genetica, Genetica Klinische Genetica, Child Health, Valkenburg, Dyon, van Cauwenbergh, Caroline, Lorenz, Birgit, van Genderen, Mies M., Bertelsen, Mette, Pott, Jan Willem R., Coppieters, Frauke, de Zaeytijd, Julie, Thiadens, Alberta A.H.J., Klaver, Caroline C.W., Kroes, Hester Y., van Schooneveld, Mary J., Preising, Markus, Hoyng, Carel B., Leroy, Bart P., Ingeborgh van den Born, L., Collin, Rob W.J., Genetica, Genetica Klinische Genetica, Child Health, Valkenburg, Dyon, van Cauwenbergh, Caroline, Lorenz, Birgit, van Genderen, Mies M., Bertelsen, Mette, Pott, Jan Willem R., Coppieters, Frauke, de Zaeytijd, Julie, Thiadens, Alberta A.H.J., Klaver, Caroline C.W., Kroes, Hester Y., van Schooneveld, Mary J., Preising, Markus, Hoyng, Carel B., Leroy, Bart P., Ingeborgh van den Born, L., and Collin, Rob W.J.

Published
2018

8. Development of Refractive Errors—What Can We Learn From Inherited Retinal Dystrophies?

Author

Hendriks, Michelle, Verhoeven, Virginie J M, Buitendijk, Gabriëlle H.S., Polling, Jan Roelof, Meester-Smoor, Magda A., Hofman, Albert, van Huet, Ramon A C, Klevering, B Jeroen, Bax, Nathalie M., Lambertus, Stanley, Klaver, Caroline C W, Hoyng, Carel B., Oomen, Clasien J, van Zelst-Stams, Wendy A. G., Cremers, Frans Pm, Plomp, Astrid S, van Schooneveld, Mary J., van Genderen, Mies M., Schuil, José, Boonstra, F Nienke, Schlingemann, Reinier O, Bergen, Arthur A., Pierrache, Laurence, Meester-Smoor, Magda, van den Born, L Ingeborgh, Boon, Camiel J.F., Pott, Jan W.R., van Leeuwen, Redmer, Kroes, Hester Y., de Jong-Hesse, Yvonne, Kamermans, Maarten, Ingeborgh van den Born, L., and RD5000 Consortium

Subjects
Ophthalmology, Journal Article
Abstract

Purpose It is unknown which retinal cells are involved in the retina-to-sclera signaling cascade causing myopia. As inherited retinal dystrophies (IRD) are characterized by dysfunction of a single retinal cell type and have a high risk of refractive errors, a study investigating the affected cell type, causal gene, and refractive error in IRDs may provide insight herein. Design Case-control study. Methods STUDY POPULATION: Total of 302 patients with IRD from 2 ophthalmogenetic centers in the Netherlands. REFERENCE POPULATION: Population-based Rotterdam Study-III and Erasmus Rucphen Family Study (N = 5550). Distributions and mean spherical equivalent (SE) were calculated for main affected cell type and causal gene; and risks of myopia and hyperopia were evaluated using logistic regression. Results Bipolar cell-related dystrophies were associated with the highest risk of SE high myopia 239.7; odds ratio (OR) mild hyperopia 263.2, both P

Published
2017

9. Development of Refractive Errors—What Can We Learn From Inherited Retinal Dystrophies?

Author

MS Oogheelkunde, Infection & Immunity, Genetica Klinische Genetica, Child Health, Hendriks, Michelle, Verhoeven, Virginie J M, Buitendijk, Gabriëlle H.S., Polling, Jan Roelof, Meester-Smoor, Magda A., Hofman, Albert, van Huet, Ramon A C, Klevering, B Jeroen, Bax, Nathalie M., Lambertus, Stanley, Klaver, Caroline C W, Hoyng, Carel B., Oomen, Clasien J, van Zelst-Stams, Wendy A. G., Cremers, Frans Pm, Plomp, Astrid S, van Schooneveld, Mary J., van Genderen, Mies M., Schuil, José, Boonstra, F Nienke, Schlingemann, Reinier O, Bergen, Arthur A., Pierrache, Laurence, Meester-Smoor, Magda, van den Born, L Ingeborgh, Boon, Camiel J.F., Pott, Jan W.R., van Leeuwen, Redmer, Kroes, Hester Y., de Jong-Hesse, Yvonne, Kamermans, Maarten, Ingeborgh van den Born, L., RD5000 Consortium, MS Oogheelkunde, Infection & Immunity, Genetica Klinische Genetica, Child Health, Hendriks, Michelle, Verhoeven, Virginie J M, Buitendijk, Gabriëlle H.S., Polling, Jan Roelof, Meester-Smoor, Magda A., Hofman, Albert, van Huet, Ramon A C, Klevering, B Jeroen, Bax, Nathalie M., Lambertus, Stanley, Klaver, Caroline C W, Hoyng, Carel B., Oomen, Clasien J, van Zelst-Stams, Wendy A. G., Cremers, Frans Pm, Plomp, Astrid S, van Schooneveld, Mary J., van Genderen, Mies M., Schuil, José, Boonstra, F Nienke, Schlingemann, Reinier O, Bergen, Arthur A., Pierrache, Laurence, Meester-Smoor, Magda, van den Born, L Ingeborgh, Boon, Camiel J.F., Pott, Jan W.R., van Leeuwen, Redmer, Kroes, Hester Y., de Jong-Hesse, Yvonne, Kamermans, Maarten, Ingeborgh van den Born, L., and RD5000 Consortium

Published
2017

10. Development of Refractive Errors—What Can We Learn From Inherited Retinal Dystrophies?

Author

Hendriks, Michelle, primary, Verhoeven, Virginie J.M., additional, Buitendijk, Gabriëlle H.S., additional, Polling, Jan Roelof, additional, Meester-Smoor, Magda A., additional, Hofman, Albert, additional, Kamermans, Maarten, additional, Ingeborgh van den Born, L., additional, Klaver, Caroline C.W., additional, van Huet, Ramon A., additional, Klevering, B. Jeroen, additional, Bax, Nathalie M., additional, Lambertus, Stanley, additional, Hoyng, Carel B., additional, Oomen, Clasien J., additional, van Zelst-Stams, Wendy A., additional, Cremers, Frans P., additional, Plomp, Astrid S., additional, van Schooneveld, Mary J., additional, van Genderen, Mies M., additional, Schuil, José, additional, Boonstra, F. Nienke, additional, Schlingemann, Reinier O., additional, Bergen, Arthur A., additional, Pierrache, Laurence, additional, Meester-Smoor, Magda, additional, van den Born, L. Ingeborgh, additional, Boon, Camiel J., additional, Pott, Jan W.R., additional, van Leeuwen, Redmer, additional, Kroes, Hester Y, additional, and de Jong-Hesse, Yvonne, additional

Published
2017
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11. Loss-of-function variants in UBAP1Lcause autosomal recessive retinal degeneration

Author

Han, Ji Hoon, Rodenburg, Kim, Hayman, Tamar, Calzetti, Giacomo, Kaminska, Karolina, Quinodoz, Mathieu, Marra, Molly, Wallerich, Sandrine, Allon, Gilad, Nagy, Zoltán Z., Knézy, Krisztina, Li, Yumei, Chen, Rui, Salgueiro Barboni, Mirella Telles, Yang, Paul, Pennesi, Mark E., Ingeborgh van den Born, L., Varsányi, Balázs, Szabó, Viktória, Sharon, Dror, Banin, Eyal, Ben-Yosef, Tamar, Roosing, Susanne, Koenekoop, Robert K., and Rivolta, Carlo

Abstract

Inherited retinal diseases (IRDs) are a group of monogenic conditions that can lead to progressive blindness. Their missing heritability is still considerable, due in part to the presence of disease genes that await molecular identification. The purpose of this work was to identify novel genetic associations with IRDs.

Published
2024
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12. IQCB1 mutations in patients with leber congenital amaurosis

Author

Estrada-Cuzcano, Alejandro, Koenekoop, Robert, Coppieters, Frauke, Kohl, Susanne, Lopez, Irma, Collin, Rob R.W.J., De Baere, Elfride, Roeleveld, Debbie, Marek, Jonah, Bernd, Antje, Rohrschneider, Klaus, Ingeborgh van den Born, L., Meire, Françoise, Maumenee, Irene I.H., Jacobson, Samuel S.G., Hoyng, Carel C.B., Zrenner, Eberhart, Cremers, Frans P M, den Hollander, Anneke A.I., Estrada-Cuzcano, Alejandro, Koenekoop, Robert, Coppieters, Frauke, Kohl, Susanne, Lopez, Irma, Collin, Rob R.W.J., De Baere, Elfride, Roeleveld, Debbie, Marek, Jonah, Bernd, Antje, Rohrschneider, Klaus, Ingeborgh van den Born, L., Meire, Françoise, Maumenee, Irene I.H., Jacobson, Samuel S.G., Hoyng, Carel C.B., Zrenner, Eberhart, Cremers, Frans P M, and den Hollander, Anneke A.I.

Abstract

Purpose. Leber congenital amaurosis (LCA) is genetically heterogeneous, with 15 genes identified thus far, accounting for ~70% of LCA patients. The aim of the present study was to identify new genetic causes of LCA. Methods. Homozygosity mapping in >150 LCA patients of worldwide origin was performed with high-density SNP microarrays to identify new disease-causing genes. Results. In three isolated LCA patients, the authors identified large homozygous regions on chromosome 3 encompassing the IQCB1 gene, which has been associated with Senior-Loken syndrome (SLSN), characterized by nephronophthisis and retinal degeneration. Mutation analysis of IQCB1 in these three patients and a subsequent cohort of 222 additional LCA patients identified frameshift and nonsense mutations in 11 patients diagnosed with LCA. On re-inspection of the patient'sdisease status, seven were found to have developed SLSN, but four maintained the diagnosis of LCA as the kidney function remained normal. Conclusions. Results show that the onset of renal failure in patients with IQCB1 mutations is highly variable, and that mutations are also found in LCA patients without nephronophthisis, rendering IQCB1 a new gene for LCA. However, these patients are at high risk for developing renal failure, which in early stages is often not recognized and can cause sudden death from fluid and electrolyte imbalance. It is therefore recommended that all LCA patients be screened for IQCB1 mutations, to follow them more closely for kidney disease. © 2011 The Association for Research in Vision and Ophthalmology, Inc., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2011

13. Mutations in IMPG2, Encoding Interphotoreceptor Matrix Proteoglycan 2, Cause Autosomal-Recessive Retinitis Pigmentosa

Author

Bandah-Rozenfeld, Dikla, primary, Collin, Rob W.J., additional, Banin, Eyal, additional, Ingeborgh van den Born, L., additional, Coene, Karlien L.M., additional, Siemiatkowska, Anna M., additional, Zelinger, Lina, additional, Khan, Muhammad I., additional, Lefeber, Dirk J., additional, Erdinest, Inbar, additional, Testa, Francesco, additional, Simonelli, Francesca, additional, Voesenek, Krysta, additional, Blokland, Ellen A.W., additional, Strom, Tim M., additional, Klaver, Caroline C.W., additional, Qamar, Raheel, additional, Banfi, Sandro, additional, Cremers, Frans P.M., additional, Sharon, Dror, additional, and den Hollander, Anneke I., additional

Published
2010
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14. Autosomal recessive retinitis pigmentosa with RP1 mutations is associated with myopia.

Author

Chassine, Thomas, Bocquet, Béatrice, Daien, Vincent, Avila-Fernandez, Almudena, Ayuso, Carmen, Collin, Rob W. J., Corton, Marta, Fielding Hejtmancik, J., Ingeborgh van den Born, L., Jeroen Klevering, B., Amer Riazuddin, S., Sendon, Nathacha, Lacroux, Annie, Meunier, Isabelle, and Hamel, Christian P.

Subjects
RETINITIS pigmentosa, PIGMENTATION disorders, RETINAL degeneration, MYOPIA, OPHTHALMOLOGY
Abstract

Objective To determine the refractive error in patients with autosomal recessive retinitis pigmentosa (arRP) caused by RP1 mutations and to compare it with that of other genetic subtypes of RP. Methods Twenty-six individuals had arRP with RP1 mutations, 25 had autosomal dominant RP (adRP) with RP1 mutation, 8 and 33 had X-linked RP (xlRP) with RP2 and RPGR mutations, respectively, 198 and 93 had Usher syndrome and arRP without RP1 mutations, respectively. The median of the spherical equivalent (SE) and the IQR (Q25-Q75) was determined and multiple comparisons were performed. Results arRP patients with RP1 mutations had SE median at -4.0 dioptres (D) OD (Ocula Dextra); -3.88 D OS (Ocula Sinistra), whereas arRP patients without RP1 mutations (-0.50 D OD; -0.75 D OS) and Usher syndrome patients (-0.50 D OD; -0.38 D OS) were significantly less myopic (p<0.0001). Conversely, myopia of xlRP patients with either an RPGR mutation (-4.50 D OD; -5.25 D OS) or an RP2 mutation (-6.25 D OD; -6.88 D OS) was not significantly different from the arRP group with RP1 mutations. arRP without RP1 mutations, Usher syndrome and adRP with RP1 mutation had a narrow IQR (-9.06 to -1.13 D), whereas arRP with RP1 mutations and xlRP with RP2 or RPGR mutations had a larger range (-9.06; -1.13 D). Conclusions arRP patients with RP1 mutations have myopia not different from patients with xlRP with RP2 or RPGR mutations, while RP patients from other genetic subgroups were emmetropic or mildly myopic. We suggest that arRP patients with high myopic refractive error should be preferentially analysed for RP1 mutations. [ABSTRACT FROM AUTHOR]

Published
2015
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15. Mutations in IMPG2, Encoding Interphotoreceptor Matrix Proteoglycan 2, Cause Autosomal-Recessive Retinitis Pigmentosa

Author

Ellen A.W. Blokland, Frans P.M. Cremers, Lina Zelinger, Dikla Bandah-Rozenfeld, Dirk J. Lefeber, Tim M. Strom, Karlien L.M. Coene, Francesco Testa, Inbar Erdinest, Caroline C W Klaver, Francesca Simonelli, Anneke I. den Hollander, Krysta Voesenek, L. Ingeborgh van den Born, Anna M. Siemiatkowska, Raheel Qamar, Rob W.J. Collin, Muhammad Imran Khan, Dror Sharon, Sandro Banfi, Eyal Banin, Hematology, Ophthalmology, Bandah Rozenfeld, D, Collin, Rw, Banin, E, Ingeborgh van den Born, L, Coene, Kl, Siemiatkowska, Am, Zelinger, L, Khan, Mi, Lefeber, Dj, Erdinest, I, Testa, Francesco, Simonelli, Francesca, Voesenek, K, Blokland, Ea, Strom, Tm, Klaver, Cc, Qamar, R, Banfi, Sandro, Cremers, Fp, Sharon, D, and den Hollander, Ai

Subjects
Adult, Male, Genetics and epigenetic pathways of disease [NCMLS 6], Fundus Oculi, Genetic Linkage, Nonsense mutation, DNA Mutational Analysis, Molecular Sequence Data, Genes, Recessive, Gene mutation, Biology, Interphotoreceptor matrix, Neuroinformatics [DCN 3], medicine.disease_cause, Article, Genomic disorders and inherited multi-system disorders [IGMD 3], Exon, Chromosome Segregation, Retinitis pigmentosa, Chlorocebus aethiops, medicine, Genetics, Missense mutation, Animals, Humans, Genetics(clinical), Amino Acid Sequence, Genetics (clinical), Aged, Mutation, Base Sequence, Homozygote, Chromosome Mapping, Glycostation disorders [IGMD 4], Middle Aged, medicine.disease, Pedigree, COS Cells, Mutation testing, Female, Mutant Proteins, Proteoglycans, Retinitis Pigmentosa, Subcellular Fractions
Abstract

Contains fulltext : 89392.pdf (Publisher’s version ) (Closed access) Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases caused by progressive degeneration of the photoreceptor cells. Using autozygosity mapping, we identified two families, each with three affected siblings sharing large overlapping homozygous regions that harbored the IMPG2 gene on chromosome 3. Sequence analysis of IMPG2 in the two index cases revealed homozygous mutations cosegregating with the disease in the respective families: three affected siblings of Iraqi Jewish ancestry displayed a nonsense mutation, and a Dutch family displayed a 1.8 kb genomic deletion that removes exon 9 and results in the absence of seven amino acids in a conserved SEA domain of the IMPG2 protein. Transient transfection of COS-1 cells showed that a construct expressing the wild-type SEA domain is properly targeted to the plasma membrane, whereas the mutant lacking the seven amino acids appears to be retained in the endoplasmic reticulum. Mutation analysis in ten additional index cases that were of Dutch, Israeli, Italian, and Pakistani origin and had homozygous regions encompassing IMPG2 revealed five additional mutations; four nonsense mutations and one missense mutation affecting a highly conserved phenylalanine residue. Most patients with IMPG2 mutations showed an early-onset form of RP with progressive visual-field loss and deterioration of visual acuity. The patient with the missense mutation, however, was diagnosed with maculopathy. The IMPG2 gene encodes the interphotoreceptor matrix proteoglycan IMPG2, which is a constituent of the interphotoreceptor matrix. Our data therefore show that mutations in a structural component of the interphotoreceptor matrix can cause arRP.

Published
2010

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