IFT81 as a Candidate Gene for Nonsyndromic Retinal Degeneration.

TitleIFT81 as a Candidate Gene for Nonsyndromic Retinal Degeneration.
Publication TypeJournal Article
Year of Publication2017
AuthorsDharmat, R, Liu, W, Ge, Z, Sun, Z, Yang, L, Li, Y, Wang, K, Thomas, K, Sui, R, Chen, R
JournalInvest Ophthalmol Vis Sci
Date Published2017 May 01
KeywordsAnimals, Cells, Cultured, Codon, Nonsense, Disease Models, Animal, DNA, DNA Mutational Analysis, Female, Humans, Male, Muscle Proteins, Mutation, Phenotype, Retina, Retinal Degeneration, Zebrafish

PURPOSE: IFT81, a core component of the IFT-B complex, involved in the bidirectional transport of ciliary proteins, has been recently implicated in syndromic ciliopathies. However, none of the IFT-B core complex proteins have been associated with nonsyndromic retinal dystrophies. Given the importance of ciliary transport in photoreceptor function and structural maintenance, we sought to investigate the impact of IFT (intraflagellar transport) mutations in nonsyndromic retinopathies.METHODS: Whole exome sequencing was performed on 50 cone-rod dystrophy (CRD) patients that were previously screened for mutations in known retinal disease genes. The impact of candidate mutation was studied using in vitro cell system and in vivo zebrafish assay to determine the pathogenicity of the variant.RESULTS: Compound heterozygous mutations in IFT81, including one nonsense (c.1213C>T, p.R405*) and one missense variant (c.1841T>C, p.L614P), were identified in a nonsyndromic CRD proband. Extensive functional analyses of the missense variant in cell culture and zebrafish strongly suggests its pathogenic nature. Loss of IFT81 impairs ciliogenesis and, interestingly, the missense variant displayed significantly reduced rescue of ciliogenesis in the IFT81 knockdown in vitro system. Consistently, dramatic reduction of rescue efficiency of the ift81 mutant zebrafish embryo by mRNA with the missense variant was observed, further supporting its pathogenicity.CONCLUSIONS: Consistent with the function of the IFT-B complex in the maintenance of photoreceptor cilium, we report a case of mutations in a core IFT-B protein, IFT81. This represents the first report of mutations in IFT81 as a candidate gene for nonsyndromic retinal dystrophy, hence expanding the phenotype spectrum of IFT-B components.

Alternate JournalInvest Ophthalmol Vis Sci
PubMed ID28460050
PubMed Central IDPMC5413215
Grant ListP30 EY002520 / EY / NEI NIH HHS / United States
R01 EY018571 / EY / NEI NIH HHS / United States
R01 EY022356 / EY / NEI NIH HHS / United States
S10 RR026550 / RR / NCRR NIH HHS / United States

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