Nonsyndromic Retinal Dystrophy due to Bi-Allelic Mutations in the Ciliary Transport Gene IFT140

Invest Ophthalmol Vis Sci. 2016 Mar;57(3):1053-62. doi: 10.1167/iovs.15-17976.

Sarah Hull ¹, Nicholas Owen ², Farrah Islam ³, Dhani Tracey-White ², Vincent Plagnol ⁴, Graham E Holder ¹, Michel Michaelides ¹, Keren Carss ⁵, F Lucy Raymond ⁶, Jean-Michel Rozet ⁷, Simon C Ramsden ⁸, Graeme C M Black ⁹, Isabelle Perrault ⁷, Ajoy Sarkar ¹⁰, Mariya Moosajee ¹, Andrew R Webster ¹, Gavin Arno ¹, Anthony T Moore ¹¹

Affiliations

1 University College London Institute of Ophthalmology, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
2 University College London Institute of Ophthalmology, London, United Kingdom.
3 Moorfields Eye Hospital, London, United Kingdom 3Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan.
4 University College London Genetics Institute, London, United Kingdom.
5 Department of Haematology, University of Cambridge, Cambridge, United Kingdom 6NIHR BioResource-Rare Diseases, Department of Haematology, University of Cambridge, Cambridge, United Kingdom.
6 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.
7 Laboratory of Genetics in Ophthalmology, INSERM UMR 1163, Paris Descartes-Sorbonne University, Imagine Institut, Paris, France.
8 Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, United Kingdom.
9 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.
10 Department of Clinical Genetics, Nottingham City Hospital, Nottingham, United Kingdom.
11 University College London Institute of Ophthalmology, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom 12Ophthalmology, University of California, San Francisco, California, United States.

PMID: 26968735 DOI: 10.1167/iovs.15-17976

Abstract

Purpose: 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.

Name
Email *

	Sorry, but the email address you supplied was invalid.