title: Homozygosity Mapping and Whole-Genome Sequencing Links a Missense Mutation in POMGNT1 to Autosomal Recessive Retinitis Pigmentosa.
abstract: OBJECTIVE
  To identify the genetic cause in five families with autosomal recessive retinitis pigmentosa, a genetic disorder involving retinal degeneration and visual loss with high genetic heterogeneity.
  
  
  METHODS
  We performed whole-genome single nucleotide polymorphism genotyping on 35 members from the five families to map the region of homozygosity shared by all patients. Whole-genome sequencing was then conducted on one of the patients and a novel variant was identified in POMGNT1 from the homozygous region, which was confirmed by Sanger sequencing and sequenced in all family members. Mutant and wild-type POMGNT1 were expressed in heterologous cells to assess enzyme activity.
  
  
  RESULTS
  A 1.8-Mb homozygous region was identified at 1p34-p33 shared by all 17 patients. Whole-genome sequencing revealed a novel missense mutation in POMGNT1 (c.359A>C, p.Leu120Arg) from this homozygous region, which was shown to co-segregate with disease phenotype. The mutant protein carrying this missense mutation showed an approximately 80% decrease in POMGNT1 enzyme activity compared with the wild type.
  
  
  CONCLUSIONS
  We identified a novel mutation in POMGNT1 that causes nonsyndromic autosomal recessive retinitis pigmentosa, adding to the genetic heterogeneity of this retinal disease. POMGNT1 encodes a glycosyltransferase in O-mannosyl glycosylation and was previously found to be responsible for a group of congenital muscular dystrophies called dystroglycanopathies. Our discovery suggests the involvement of O-mannosyl glycosylation in retinitis pigmentosa and presents an instance of POMGNT1 mutation that does not involve muscular dystrophy.
authors.affiliation: Molecular Medicine Program Taiwan International Graduate Program, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 2Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 3Institute of Biochemistry and Molecular Biology, School.
authors.forename: Nana Hsiang-Hua
authors.initials: NH
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan 5School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Chi-Fan
authors.initials: CF
authors.lastname: Yang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Hui-Ping
authors.initials: HP
authors.lastname: Chuang
authors.affiliation: Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan 7Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yung-Hsiu
authors.initials: YH
authors.lastname: Lu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Chien-Hsiun
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Jer-Yuarn
authors.initials: JY
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan 7Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Dau-Ming
authors.initials: DM
authors.lastname: Niu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yuan-Tsong
authors.initials: YT
authors.lastname: Chen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002874:Chromosome Mapping / Q000379:methods; D003241:Consanguinity; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D010375:Pedigree; D012174:Retinitis Pigmentosa / Q000235:genetics*; D055815:Young Adult
chemical_list: D017351:N-Acetylglucosaminyltransferases; C443106:protein O-mannose beta-1,2-N-acetylglucosaminyltransferase