title: Mutations in AGBL5, Encoding α-Tubulin Deglutamylase, Are Associated With Autosomal Recessive Retinitis Pigmentosa.
abstract: OBJECTIVE
  AGBL5, encoding ATP/GTP binding protein-like 5, was previously proposed as an autosomal recessive retinitis pigmentosa (arRP) candidate gene based on the identification of missense variants in two families. In this study, we performed next-generation sequencing to reveal additional RP cases with AGBL5 variants, including protein-truncating variants.
  
  
  METHODS
  Whole-genome sequencing (WGS) or whole-exome sequencing (WES) was performed in three probands. Subsequent Sanger sequencing and segregation analysis were performed in the selected candidate genes. The medical history of individuals carrying AGBL5 variants was reviewed and additional ophthalmic examinations were performed, including fundus photography, fundus autofluorescence imaging, and optical coherence tomography.
  
  
  RESULTS
  AGBL5 variants were identified in three unrelated arRP families, comprising homozygous variants in family 1 (c.1775G>A:p.(Trp592*)) and family 2 (complex allele: c.[323C>G; 2659T>C]; p.[(Pro108Arg; *887Argext*1)]), and compound heterozygous variants (c.752T>G:p.(Val251Gly) and c.1504dupG:p.(Ala502Glyfs*15)) in family 3. All affected individuals displayed typical RP phenotypes.
  
  
  CONCLUSIONS
  Our study convincingly shows that variants in AGBL5 are associated with arRP. The identification of AGBL5 and TTLL5, a previously described RP-associated gene encoding the tubulin tyrosine ligase-like family, member 5 protein, highlights the importance of poly- and deglutamylation in retinal homeostasis. Further studies are required to investigate the underlying disease mechanism associated with AGBL5 variants.
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands 2Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands 3Division of Human Genetics, Center for Biomedical Research, Faculty of Medicine, Diponegoro University, Semarang, Indonesia.
authors.forename: Galuh D N
authors.initials: GD
authors.lastname: Astuti
authors.affiliation: University College London, Institute of Ophthalmology, London, United Kingdom.
authors.forename: Gavin
authors.initials: G
authors.lastname: Arno
authors.affiliation: University College London, Institute of Ophthalmology, London, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hull
authors.affiliation: The Rotterdam Eye Hospital, Rotterdam, The Netherlands 6Rotterdam Ophthalmic Institute, Rotterdam, The Netherlands 7Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands 8Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Laurence
authors.initials: L
authors.lastname: Pierrache
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud University, Nijmegen, The Netherlands.
authors.forename: Hanka
authors.initials: H
authors.lastname: Venselaar
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom 11National Institute for Health Research England BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom.
authors.forename: Keren
authors.initials: K
authors.lastname: Carss
authors.affiliation: National Institute for Health Research England BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom 12Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: F Lucy
authors.initials: FL
authors.lastname: Raymond
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands 13Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, The Netherlands.
authors.forename: Rob W J
authors.initials: RW
authors.lastname: Collin
authors.affiliation: Division of Human Genetics, Center for Biomedical Research, Faculty of Medicine, Diponegoro University, Semarang, Indonesia.
authors.forename: Sultana M H
authors.initials: SM
authors.lastname: Faradz
authors.affiliation: The Rotterdam Eye Hospital, Rotterdam, The Netherlands.
authors.forename: L Ingeborgh
authors.initials: LI
authors.lastname: van den Born
authors.affiliation: University College London, Institute of Ophthalmology, London, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands 13Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, The Netherlands.
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002268:Carboxypeptidases / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014404:Tubulin; D004247:DNA; C000607347:AGBL5 protein, human; D002268:Carboxypeptidases