title: Mutations in POMGNT1 cause non-syndromic retinitis pigmentosa.
abstract: A growing number of human diseases have been linked to defects in protein glycosylation that affects a wide range of organs. Among them, O-mannosylation is an unusual type of protein glycosylation that is largely restricted to the muscular and nerve system. Consistently, mutations in genes involved in the O-mannosylation pathway result in infantile-onset, severe developmental defects involving skeleton muscle, brain and eye, such as the muscle-eye-brain disease (MIM no. 253280). However, the functional importance of O-mannosylation in these tissues at later stages remains largely unknown. In our study, we have identified recessive mutations in POMGNT1, which encodes an essential component in O-mannosylation pathway, in three unrelated families with autosomal recessive retinitis pigmentosa (RP), but without extraocular involvement. Enzymatic assay of these mutant alleles demonstrate that they greatly reduce the POMGNT1 enzymatic activity and are likely to be hypomorphic. Immunohistochemistry shows that POMGNT1 is specifically expressed in photoreceptor basal body. Taken together, our work identifies a novel disease-causing gene for RP and indicates that proper protein O-mannosylation is not only essential for early organ development, but also important for maintaining survival and function of the highly specialized retinal cells at later stages.
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center.
authors.forename: Mingchu
authors.initials: M
authors.lastname: Xu
authors.affiliation: Molecular Glycobiology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo 173-0015, Japan.
authors.forename: Takeyuki
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Ophthalmology, Peking Union Medical College, Beijing 100730, China.
authors.forename: Zixi
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center.
authors.forename: Aiden
authors.initials: A
authors.lastname: Eblimit
authors.affiliation: McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, Quebec H3H 1P3, Canada and.
authors.forename: Irma
authors.initials: I
authors.lastname: Lopez
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Molecular Glycobiology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo 173-0015, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Manya
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center.
authors.forename: Shan
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Structural and Computational Biology and Molecular Biophysics Graduate Program.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Departments of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Adva
authors.initials: A
authors.lastname: Kimchi
authors.affiliation: Departments of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Sharon
authors.affiliation: Department of Ophthalmology, Peking Union Medical College, Beijing 100730, China.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Sui
authors.affiliation: Molecular Glycobiology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo 173-0015, Japan.
authors.forename: Tamao
authors.initials: T
authors.lastname: Endo
authors.affiliation: McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, Quebec H3H 1P3, Canada and.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Structural and Computational Biology and Molecular Biophysics Graduate Program, The Verna and Marrs Mclean Department of Biochemistry and Molecular Biology and Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA, ruichen@bcm.edu.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D006031:Glycosylation; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics* / Q000378:metabolism*; D010375:Pedigree; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000473:pathology*; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: D017351:N-Acetylglucosaminyltransferases; C443106:protein O-mannose beta-1,2-N-acetylglucosaminyltransferase