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

Mar 1, 2016

Sarah Hull, Nicholas Owen, Farrah Islam, Dhani Tracey-White, Vincent Plagnol, Graham E. Holder, Michel Michaelides, Keren Carss; F. Lucy Raymond, Jean-Michel Rozet, Simon C. Ramsden, Graeme C. M. Black, Isabelle Perrault, Ajoy Sarkar, Mariya Moosajee, Andrew R. Webster, Gavin Arno, Anthony T. Moore | Investigative Ophthalmology & Visual Science | March 2016 | Vol. 57 | pgs. 1053-1062 | doi.org/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.


Introduction

The outer segments of photoreceptors are highly modified, photosensitive cilia, which lack any capability for protein production.1 Thus, they are reliant on the intraflagellar transport (IFT) system, which comprises large protein complexes for transport from the cell body to cilium tip and back driven by the motors kinesin-2 and dynein-2, respectively.2 The IFT-B complex is essential for cilium assembly and anterograde transport, whereas the IFT-A complex is responsible for retrograde transport, with additional roles in anterograde transport by connecting kinesin to the IFT complex and in facilitating entry of proteins in to the cilium.3,4 IFT140, a subunit of IFT-A, is vital for both the development and the maintenance of outer segments and has a specific role in opsin transport across the connecting cilium.2 


Mutations in IFT140 have been associated with Jeune asphyxiating thoracic dystrophy and Mainzer-Saldino syndrome, ciliopathies forming part of a spectrum of skeletal dysplasias now collectively termed short rib thoracic dysplasia 9 with or without polydactyly (SRTD9, mendelian inheritance in man [MIM]#266920).5–7 First described in 1970, patients have variable skeletal features including shortened ribs, short stature, cone-shaped phalangeal epiphyses (prepubertal), brachymesophalangy, and acetabular spurring or metaphyseal defect of the femoral head.8 Nonskeletal features in the majority of patients include a severe early-onset retinal dystrophy and end-stage renal failure secondary to nephronophthisis by the teenage years, with cerebellar ataxia, epilepsy, facial dysmorphism, learning difficulties, and cholestasis also reported.5–7 


Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy, with more than 60 genes associated with the nonsyndromic, recessive form.9–12 These include ciliopathy genes such as CEP290 and BBS1, which manifest both syndromic and nonsyndromic phenotypes.13,14 Recently, IFT140 mutations have been identified in patients with isolated retinal dystrophy.15,16 The present study reports eight patients from five families with isolated retinal dystrophy and bi-allelic IFT140 variants with detailed characterization of the ocular phenotype. Functional analysis of two of these variants with protein localization studies in hTERT-RPE1 cells supports their pathogenicity. 



 

References

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  16. Bifari IN, Elkhamary SM, Bolz HJ, Khan AO. The ophthalmic phenotype of IFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy [published online ahead of print September 10 2015]. Br J Ophthalmol. doi:10.1136/bjophthalmol-2015-307555.

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