title: Nonsyndromic Retinal Dystrophy due to Bi-Allelic Mutations in the Ciliary Transport Gene IFT140.
abstract: OBJECTIVE
  Mutations in the ciliary transporter gene IFT140, usually associated with a severe syndromic ciliopathy, may also cause isolated retinal dystrophy. A series of patients with nonsyndromic retinitis pigmentosa (RP) due to IFT140 was investigated in this study.
  
  
  METHODS
  Five probands and available affected family members underwent detailed phenotyping including retinal imaging and electrophysiology. Whole exome sequencing was performed on two probands, a targeted sequencing panel of 176 retinal genes on a further two, and whole genome sequencing on the fifth. Missense mutations of IFT140 were further investigated in vitro using transient plasmid transfection of hTERT-RPE1 cells.
  
  
  RESULTS
  Eight affected patients from five families had preserved visual acuity until at least the second decade; all had normal development without skeletal manifestations or renal failure at age 13 to 67 years (mean, 42 years; median, 44.5 years). Bi-allelic mutations in IFT140 were identified in all families including two novel mutations: c.2815T > C (p.Ser939Pro) and c.1422_23insAA (p.Arg475Asnfs*14). Expression studies demonstrated a significantly reduced number of cells showing localization of mutant IFT140 with the basal body for two nonsyndromic mutations and two syndromic mutations compared with the wild type and a polymorphism.
  
  
  CONCLUSIONS
  This study highlights the phenotype of nonsyndromic RP due to mutations in IFT140 with milder retinal dystrophy than that associated with the syndromic disease.
authors.affiliation: University College London Institute of Ophthalmology, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hull
authors.affiliation: University College London Institute of Ophthalmology, London, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Owen
authors.affiliation: Moorfields Eye Hospital, London, United Kingdom 3Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan.
authors.forename: Farrah
authors.initials: F
authors.lastname: Islam
authors.affiliation: University College London Institute of Ophthalmology, London, United Kingdom.
authors.forename: Dhani
authors.initials: D
authors.lastname: Tracey-White
authors.affiliation: University College London Genetics Institute, London, United Kingdom.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: University College London Institute of Ophthalmology, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
authors.forename: Graham E
authors.initials: GE
authors.lastname: Holder
authors.affiliation: University College London Institute of Ophthalmology, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
authors.forename: Michel
authors.initials: M
authors.lastname: Michaelides
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom 6NIHR BioResource-Rare Diseases, Department of Haematology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Keren
authors.initials: K
authors.lastname: Carss
authors.affiliation: NIHR BioResource-Rare Diseases, Department of Haematology, University of Cambridge, Cambridge, United Kingdom 7Department 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: Laboratory of Genetics in Ophthalmology, INSERM UMR 1163, Paris Descartes-Sorbonne University, Imagine Institut, Paris, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rozet
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, United Kingdom.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Ramsden
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, United Kingdom 10Manchester Centre for Genomic Medicine, Institute of Human D.
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Black
authors.affiliation: Laboratory of Genetics in Ophthalmology, INSERM UMR 1163, Paris Descartes-Sorbonne University, Imagine Institut, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Perrault
authors.affiliation: Department of Clinical Genetics, Nottingham City Hospital, Nottingham, United Kingdom.
authors.forename: Ajoy
authors.initials: A
authors.lastname: Sarkar
authors.affiliation: University College London Institute of Ophthalmology, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
authors.forename: Mariya
authors.initials: M
authors.lastname: Moosajee
authors.affiliation: University College London Institute of Ophthalmology, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.affiliation: University College London Institute of Ophthalmology, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
authors.forename: Gavin
authors.initials: G
authors.lastname: Arno
authors.affiliation: University College London Institute of Ophthalmology, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom 12Ophthalmology, University of California, San Francisco, California, United States.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002924:Ciliary Body / Q000378:metabolism* / Q000473:pathology; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D058499:Retinal Dystrophies / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; C000603049:IFT140 protein, human; D004247:DNA