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ISCIII","doi-asserted-by":"publisher","award":["PI19\/00321"],"award-info":[{"award-number":["PI19\/00321"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"a Miguel Servet program contract from ISCIII","doi-asserted-by":"publisher","award":["PI22\/00321"],"award-info":[{"award-number":["PI22\/00321"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"a Miguel Servet program contract from ISCIII","doi-asserted-by":"publisher","award":["PT13\/0010\/0012"],"award-info":[{"award-number":["PT13\/0010\/0012"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"a Miguel Servet program contract from ISCIII","doi-asserted-by":"publisher","award":["CPII21\/00015"],"award-info":[{"award-number":["CPII21\/00015"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>PRPH2, one of the most frequently inherited retinal dystrophy (IRD)-causing genes, implies a high phenotypic variability. This study aims to analyze the PRPH2 mutational spectrum in one of the largest cohorts worldwide, and to describe novel pathogenic variants and genotype\u2013phenotype correlations. A study of 220 patients from 103 families recruited from a database of 5000 families. A molecular diagnosis was performed using classical molecular approaches and next-generation sequencing. Common haplotypes were ascertained by analyzing single-nucleotide polymorphisms. We identified 56 variants, including 11 novel variants. Most of them were missense variants (64%) and were located in the D2-loop protein domain (77%). The most frequently occurring variants were p.Gly167Ser, p.Gly208Asp and p.Pro221_Cys222del. Haplotype analysis revealed a shared region in families carrying p.Leu41Pro or p.Pro221_Cys222del. Patients with retinitis pigmentosa presented an earlier disease onset. We describe the largest cohort of IRD families associated with PRPH2 from a single center. Most variants were located in the D2-loop domain, highlighting its importance in interacting with other proteins. Our work suggests a likely founder effect for the variants p.Leu41Pro and p.Pro221_Cys222del in our Spanish cohort. Phenotypes with a primary rod alteration presented more severe affectation. Finally, the high phenotypic variability in PRPH2 hinders the possibility of drawing genotype\u2013phenotype correlations.<\/jats:p>","DOI":"10.3390\/ijms25052913","type":"journal-article","created":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T05:31:12Z","timestamp":1709530272000},"page":"2913","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["PRPH2-Related Retinal Dystrophies: Mutational Spectrum in 103 Families from a Spanish Cohort"],"prefix":"10.3390","volume":"25","author":[{"given":"Lidia","family":"Fern\u00e1ndez-Caballero","sequence":"first","affiliation":[{"name":"Department of Genetics & Genomics, Instituto de Investigaci\u00f3n Sanitaria-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain"},{"name":"Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inmaculada","family":"Mart\u00edn-Merida","sequence":"additional","affiliation":[{"name":"Department of Genetics & Genomics, Instituto de Investigaci\u00f3n Sanitaria-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain"},{"name":"Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Blanco-Kelly","sequence":"additional","affiliation":[{"name":"Department of Genetics & Genomics, Instituto de Investigaci\u00f3n Sanitaria-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain"},{"name":"Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Almudena","family":"Avila-Fernandez","sequence":"additional","affiliation":[{"name":"Department of Genetics & Genomics, Instituto de Investigaci\u00f3n Sanitaria-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain"},{"name":"Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0055-9547","authenticated-orcid":false,"given":"Ester","family":"Carre\u00f1o","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Fernandez-San Jose","sequence":"additional","affiliation":[{"name":"Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Department of Genetics, Ram\u00f3n y Cajal University Hospital, 28034 Madrid, Spain"},{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0425-8522","authenticated-orcid":false,"given":"Cristina","family":"Irigoyen","sequence":"additional","affiliation":[{"name":"Ophthalmology Service, Donostia University Hospital, 20014 Donostia-San Sebasti\u00e1n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belen","family":"Jimenez-Rolando","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fermina","family":"Lopez-Grondona","sequence":"additional","affiliation":[{"name":"Department of Genetics & Genomics, Instituto de Investigaci\u00f3n Sanitaria-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain"},{"name":"Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0558-6541","authenticated-orcid":false,"given":"Ignacio","family":"Mahillo","sequence":"additional","affiliation":[{"name":"Department of Statistics, Instituto de Investigaci\u00f3n Sanitaria-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Pilar","family":"Martin-Gutierrez","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4099-9421","authenticated-orcid":false,"given":"Pablo","family":"Minguez","sequence":"additional","affiliation":[{"name":"Department of Genetics & Genomics, Instituto de Investigaci\u00f3n Sanitaria-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain"},{"name":"Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Bioinformatics Unit, Instituto de Investigaci\u00f3n Sanitaria-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Perea-Romero","sequence":"additional","affiliation":[{"name":"Department of Genetics & Genomics, Instituto de Investigaci\u00f3n Sanitaria-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain"},{"name":"Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3934-0873","authenticated-orcid":false,"given":"Marta","family":"Del Pozo-Valero","sequence":"additional","affiliation":[{"name":"Department of Genetics & Genomics, Instituto de Investigaci\u00f3n Sanitaria-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain"},{"name":"Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Riveiro-Alvarez","sequence":"additional","affiliation":[{"name":"Department of Genetics & Genomics, Instituto de Investigaci\u00f3n Sanitaria-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain"},{"name":"Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2339-6872","authenticated-orcid":false,"given":"Cristina","family":"Rodilla","sequence":"additional","affiliation":[{"name":"Department of Genetics & Genomics, Instituto de Investigaci\u00f3n Sanitaria-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain"},{"name":"Center for Biomedical 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Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3684-9076","authenticated-orcid":false,"given":"Saoud T.","family":"Swafiri","sequence":"additional","affiliation":[{"name":"Department of Genetics & Genomics, Instituto de Investigaci\u00f3n Sanitaria-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain"},{"name":"Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Jos\u00e9","family":"Trujillo-Tiebas","sequence":"additional","affiliation":[{"name":"Department of Genetics & Genomics, Instituto de Investigaci\u00f3n Sanitaria-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain"},{"name":"Center for Biomedical Network Research on Rare Diseases 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Investigaci\u00f3n Sanitaria-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain"},{"name":"Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9242-7065","authenticated-orcid":false,"given":"Carmen","family":"Ayuso","sequence":"additional","affiliation":[{"name":"Department of Genetics & Genomics, Instituto de Investigaci\u00f3n Sanitaria-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain"},{"name":"Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/nrg2717","article-title":"Photoreceptor degeneration: Genetic and mechanistic dissection of a complex trait","volume":"11","author":"Wright","year":"2010","journal-title":"Nat. Rev. Genet."},{"key":"ref_2","first-page":"3","article-title":"Retinitis Pigmentosa: Disease Encumbrance in the Eurozone","volume":"2","author":"Vaidya","year":"2015","journal-title":"Int. J. Ophthalmol. Clin. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1016\/S0140-6736(06)69740-7","article-title":"Retinitis pigmentosa","volume":"368","author":"Hartong","year":"2006","journal-title":"Lancet Lond. Engl."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1136\/jmedgenet-2018-105691","article-title":"Genetic characteristics of retinitis pigmentosa in 1204 Japanese patients","volume":"56","author":"Koyanagi","year":"2019","journal-title":"J. Med. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1002\/ajmg.c.31843","article-title":"Genetic testing for inherited eye conditions in over 6000 individuals through the EYEGENE network","volume":"184","author":"Goetz","year":"2020","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1016\/j.ophtha.2020.04.008","article-title":"Genetic Basis of Inherited Retinal Disease in a Molecularly Characterized Cohort of More Than 3000 Families from the United Kingdom","volume":"127","author":"Pontikos","year":"2020","journal-title":"Ophthalmology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1038\/s41598-021-81093-y","article-title":"Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications","volume":"11","author":"Gordo","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4691","DOI":"10.1021\/bi00471a025","article-title":"Molecular cloning, primary structure, and orientation of the vertebrate photoreceptor cell protein peripherin in the rod outer segment disk membrane","volume":"29","author":"Connell","year":"1990","journal-title":"Biochemistry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/0304-3940(81)90051-3","article-title":"Absence of receptor outer segments in the retina of rds mutant mice","volume":"21","author":"Sanyal","year":"1981","journal-title":"Neurosci. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1083\/jcb.116.3.659","article-title":"Localization of peripherin\/rds in the disk membranes of cone and rod photoreceptors: Relationship to disk membrane morphogenesis and retinal degeneration","volume":"116","author":"Arikawa","year":"1992","journal-title":"J. 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