PURPOSE: Retinitis pigmentosa (RP) is the most common inherited retinal disease with high genetic heterogeneity and variable phenotypes. Characteristic symptoms include night blindness and progressive loss of visual field, leading to blindness. Mutations in >60 genes have been identified to date as causative for RP, and additional candidate genes are assumed. METHODS: To find the disease-causing mutations in the affected members of five Turkish families, we sequenced whole exomes using an Illumina platform. RESULTS: Among all candidate genes for retinal degeneration we found two previously known sequence variations: a 4 bp deletion in the RPGR gene (c.1662_1665delAGAA; p.Glu555Glyfs*14) and a recently described USH1-causing missense mutation in MYO7A (c.472G>A, p.Gly158Arg). Furthermore, a novel 1 bp deletion in the VCAN gene (c.5118delA; p.Ser1707Valfs*44) was detected as well as a large deletion in EYS, spanning ∼ 400kb and comprising exons 16-26 (p.fs*). In one family, exome analyses of two affected individuals revealed a homozygous missense mutation (c.883G>A; p.Asp295Asn) in the AGBL5 (Agbl5; CCP5) gene, previously not reported to be associated with RP. RNA and protein analyses showed expression in human retina, as well as in mouse retina, brain and testis. Furthermore, cDNA analyses indicate the existence of tissue-specific AGBL5 splice variations in humans. AGBL5/CCP5 immunoreactivity was also visualized in human and mouse retinae. CONCLUSION: Due to the characteristic RP phenotype in patients carrying the AGBL5 missense mutation we suggest this gene as a candidate for a new form of autosomal recessively inherited RP and recommend further investigation to confirm this hypothesis.
PURPOSE:Retinitis pigmentosa (RP) is the most common inherited retinal disease with high genetic heterogeneity and variable phenotypes. Characteristic symptoms include night blindness and progressive loss of visual field, leading to blindness. Mutations in >60 genes have been identified to date as causative for RP, and additional candidate genes are assumed. METHODS: To find the disease-causing mutations in the affected members of five Turkish families, we sequenced whole exomes using an Illumina platform. RESULTS: Among all candidate genes for retinal degeneration we found two previously known sequence variations: a 4 bp deletion in the RPGR gene (c.1662_1665delAGAA; p.Glu555Glyfs*14) and a recently described USH1-causing missense mutation in MYO7A (c.472G>A, p.Gly158Arg). Furthermore, a novel 1 bp deletion in the VCAN gene (c.5118delA; p.Ser1707Valfs*44) was detected as well as a large deletion in EYS, spanning ∼ 400kb and comprising exons 16-26 (p.fs*). In one family, exome analyses of two affected individuals revealed a homozygous missense mutation (c.883G>A; p.Asp295Asn) in the AGBL5 (Agbl5; CCP5) gene, previously not reported to be associated with RP. RNA and protein analyses showed expression in human retina, as well as in mouse retina, brain and testis. Furthermore, cDNA analyses indicate the existence of tissue-specific AGBL5 splice variations in humans. AGBL5/CCP5 immunoreactivity was also visualized in human and mouse retinae. CONCLUSION: Due to the characteristic RP phenotype in patients carrying the AGBL5 missense mutation we suggest this gene as a candidate for a new form of autosomal recessively inherited RP and recommend further investigation to confirm this hypothesis.
Authors: Vandana Shashi; Maria M Magiera; Dennis Klein; Maha Zaki; Kelly Schoch; Sabine Rudnik-Schöneborn; Andrew Norman; Osorio Lopes Abath Neto; Marina Dusl; Xidi Yuan; Luca Bartesaghi; Patrizia De Marco; Ahmed A Alfares; Ronit Marom; Stefan T Arold; Francisco J Guzmán-Vega; Loren Dm Pena; Edward C Smith; Maja Steinlin; Mohamed Oe Babiker; Payam Mohassel; A Reghan Foley; Sandra Donkervoort; Rupleen Kaur; Partha S Ghosh; Valentina Stanley; Damir Musaev; Caroline Nava; Cyril Mignot; Boris Keren; Marcello Scala; Elisa Tassano; Paolo Picco; Paola Doneda; Chiara Fiorillo; Mahmoud Y Issa; Ali Alassiri; Ahmed Alahmad; Amanda Gerard; Pengfei Liu; Yaping Yang; Birgit Ertl-Wagner; Peter G Kranz; Ingrid M Wentzensen; Rolf Stucka; Nicholas Stong; Andrew S Allen; David B Goldstein; Benedikt Schoser; Kai M Rösler; Majid Alfadhel; Valeria Capra; Roman Chrast; Tim M Strom; Erik-Jan Kamsteeg; Carsten G Bönnemann; Joseph G Gleeson; Rudolf Martini; Carsten Janke; Jan Senderek Journal: EMBO J Date: 2018-11-12 Impact factor: 11.598
Authors: Kari Branham; Hiroko Matsui; Pooja Biswas; Aditya A Guru; Michael Hicks; John J Suk; He Li; David Jakubosky; Tao Long; Amalio Telenti; Naoki Nariai; John R Heckenlively; Kelly A Frazer; Paul A Sieving; Radha Ayyagari Journal: Physiol Genomics Date: 2016-10-07 Impact factor: 3.107