title: SPP2 Mutations Cause Autosomal Dominant Retinitis Pigmentosa.
abstract: Retinitis pigmentosa (RP) shows progressive loss of photoreceptors involved with heterogeneous genetic background. Here, by exome sequencing and linkage analysis on a Chinese family with autosomal dominant RP, we identified a putative pathogenic variant, p.Gly97Arg, in the gene SPP2, of which expression was detected in multiple tissues including retina. The p.Gly97Arg was absent in 800 ethnically matched chromosomes and 1400 in-house exome dataset, and was located in the first of the two highly conserved disulfide bonded loop of secreted phosphoprotein 2 (Spp-24) encoded by SPP2. Overexpression of p.Gly97Arg and another signal peptide mutation, p.Gly29Asp, caused cellular retention of both endogenous wild type and exogenous mutants in vitro, and primarily affected rod photoreceptors in zebrafish mimicking cardinal feature of RP. Taken together, our data indicate that the two mutations of SPP2 have dominant negative effects and cellular accumulation of Spp-24 might be particularly toxic to photoreceptors and/or retinal pigment epithelium. SPP2 has a new role in retinal degeneration.
authors.affiliation: Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China.|Department of Ophthalmology, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, China.
authors.forename: Qihua
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Ophthalmology, School of Medicine, Henan Polytechnic University, Henan 454150, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Ophthalmology &Visual Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Pancy O S
authors.initials: PO
authors.lastname: Tam
authors.affiliation: Tianjin Medical University, Tianjin Eye Hospital, Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin 300040, China.
authors.forename: Kanxing
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Department of Ophthalmology, School of Medicine, Henan Polytechnic University, Henan 454150, China.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology &Visual Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Li Jia
authors.initials: LJ
authors.lastname: Chen
authors.affiliation: Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China.
authors.forename: Wenshuang
authors.initials: W
authors.lastname: Jia
authors.affiliation: Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China.
authors.forename: Qingshun
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Genetics, Stanford University School of Medicine, CA 94305, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Vollrath
authors.affiliation: Department of Ophthalmology &Visual Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Chi Pui
authors.initials: CP
authors.lastname: Pang
authors.affiliation: Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China.|State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat Sen University, Guangzhou, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D004252:DNA Mutational Analysis; D004596:Electroretinography; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015870:Gene Expression; D005799:Genes, Dominant; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010786:Photoreceptor Cells / Q000378:metabolism; D021381:Protein Transport; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics*; D041623:Tomography, Optical Coherence; D055815:Young Adult; D015027:Zebrafish
chemical_list: D010750:Phosphoproteins; C551869:SPP2 protein, human; C091340:secreted phosphoprotein 24