TY - JOUR
T1 - Mutations in C8orf37, encoding a ciliary protein, are associated with autosomal-recessive retinal dystrophies with early macular involvement
AU - Estrada-Cuzcano, Alejandro
AU - Neveling, Kornelia
AU - Kohl, Susanne
AU - Banin, Eyal
AU - Rotenstreich, Ygal
AU - Sharon, Dror
AU - Falik-Zaccai, Tzipora C.
AU - Hipp, Stephanie
AU - Roepman, Ronald
AU - Wissinger, Bernd
AU - Letteboer, Stef J.F.
AU - Mans, Dorus A.
AU - Blokland, Ellen A.W.
AU - Kwint, Michael P.
AU - Gijsen, Sabine J.
AU - Van Huet, Ramon A.C.
AU - Collin, Rob W.J.
AU - Scheffer, H.
AU - Veltman, Joris A.
AU - Zrenner, Eberhart
AU - Den Hollander, Anneke I.
AU - Klevering, B. Jeroen
AU - Cremers, Frans P.M.
N1 - Funding Information:
We thank all participating families, and we thank Emine Bolat, Lisette Hetterschijt, Liliana Mizrahi-Meissonnier, Susanne Roosing, and Theo Peters for their scientific and technical support. We thank Christian Gilissen and Nienke Wieskamp for their excellent bioinformatical analysis and Carsten Janke for antibody GT335. The other members of the European Retinal Disease Consortium are Carmen Ayuso, Sandro Banfi, Tamar Ben-Yosef, Elfride De Baere, Christian Hamel, Chris Inglehearn, Robert K. Koenekoop, Bart P. Leroy, and Carmel Toomes. These studies were supported by the Radboud University Nijmegen Medical Centre (to F.P.M.C. and A.I.d.H.); the European Community's Seventh Framework Programs FP7/2007–2013 under grant agreement number 223143–TECHGENE (to H.S. and J.A.V.) and FP7/2009 under grant agreement number 241955–SYSCILIA (to R.R.); the Netherlands Organization for Health Research and Development ZonMW grants 917-66-363, 911-08-025 (to J.A.V.), and Vidi-917-86-396 (to R.R.); the Foundation Fighting Blindness USA (BR-GE-0510-0489-RAD, to A.I.d.H.; BR-GE-0510-0490-HUJ to D.S.); Algemene Nederlandse Vereniging ter Voorkoming van Blindheid; Gelderse Blinden Stichting; Landelijke Stichting voor Blinden en Slechtzienden; Retina Nederland; Stichting Oogfonds Nederland; Stichting Wetenschappelijk Onderzoek het Oogziekenhuis; Rotterdamse Stichting Blindenbelangen; and Stichting AF Deutman Researchfonds Oogheelkunde (to F.P.M.C. and A.I.d.H.).
PY - 2012/1/13
Y1 - 2012/1/13
N2 - Cone-rod dystrophy (CRD) and retinitis pigmentosa (RP) are clinically and genetically overlapping heterogeneous retinal dystrophies. By using homozygosity mapping in an individual with autosomal-recessive (ar) RP from a consanguineous family, we identified three sizeable homozygous regions, together encompassing 46 Mb. Next-generation sequencing of all exons, flanking intron sequences, microRNAs, and other highly conserved genomic elements in these three regions revealed a homozygous nonsense mutation (c.497T>A [p.Leu166]) in C8orf37, located on chromosome 8q22.1. This mutation was not present in 150 ethnically matched control individuals, single-nucleotide polymorphism databases, or the 1000 Genomes database. Immunohistochemical studies revealed C8orf37 localization at the base of the primary cilium of human retinal pigment epithelium cells and at the base of connecting cilia of mouse photoreceptors. C8orf37 sequence analysis of individuals who had retinal dystrophy and carried conspicuously large homozygous regions encompassing C8orf37 revealed a homozygous splice-site mutation (c.156-2A>G) in two siblings of a consanguineous family and homozygous missense mutations (c.529C>T [p.Arg177Trp]; c.545A>G [p.Gln182Arg]) in siblings of two other consanguineous families. The missense mutations affect highly conserved amino acids, and in silico analyses predicted that both variants are probably pathogenic. Clinical assessment revealed CRD in four individuals and RP with early macular involvement in two individuals. The two CRD siblings with the c.156-2A>G mutation also showed unilateral postaxial polydactyly. These results underline the importance of disrupted ciliary processes in the pathogenesis of retinal dystrophies.
AB - Cone-rod dystrophy (CRD) and retinitis pigmentosa (RP) are clinically and genetically overlapping heterogeneous retinal dystrophies. By using homozygosity mapping in an individual with autosomal-recessive (ar) RP from a consanguineous family, we identified three sizeable homozygous regions, together encompassing 46 Mb. Next-generation sequencing of all exons, flanking intron sequences, microRNAs, and other highly conserved genomic elements in these three regions revealed a homozygous nonsense mutation (c.497T>A [p.Leu166]) in C8orf37, located on chromosome 8q22.1. This mutation was not present in 150 ethnically matched control individuals, single-nucleotide polymorphism databases, or the 1000 Genomes database. Immunohistochemical studies revealed C8orf37 localization at the base of the primary cilium of human retinal pigment epithelium cells and at the base of connecting cilia of mouse photoreceptors. C8orf37 sequence analysis of individuals who had retinal dystrophy and carried conspicuously large homozygous regions encompassing C8orf37 revealed a homozygous splice-site mutation (c.156-2A>G) in two siblings of a consanguineous family and homozygous missense mutations (c.529C>T [p.Arg177Trp]; c.545A>G [p.Gln182Arg]) in siblings of two other consanguineous families. The missense mutations affect highly conserved amino acids, and in silico analyses predicted that both variants are probably pathogenic. Clinical assessment revealed CRD in four individuals and RP with early macular involvement in two individuals. The two CRD siblings with the c.156-2A>G mutation also showed unilateral postaxial polydactyly. These results underline the importance of disrupted ciliary processes in the pathogenesis of retinal dystrophies.
UR - http://www.scopus.com/inward/record.url?scp=84855827116&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2011.11.015
DO - 10.1016/j.ajhg.2011.11.015
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C2 - 22177090
AN - SCOPUS:84855827116
SN - 0002-9297
VL - 90
SP - 102
EP - 109
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -