PUBLICATION

IFT81 as a Candidate Gene for Nonsyndromic Retinal Degeneration

Authors
Dharmat, R., Liu, W., Ge, Z., Sun, Z., Yang, L., Li, Y., Wang, K., Thomas, K., Sui, R., Chen, R.
ID
ZDB-PUB-170502-1
Date
2017
Source
Investigative ophthalmology & visual science   58: 2483-2490 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Zebrafish
  • Female
  • Retina/metabolism*
  • Retina/pathology
  • DNA Mutational Analysis
  • Muscle Proteins/genetics*
  • Muscle Proteins/metabolism
  • DNA/genetics*
  • Male
  • Mutation*
  • Animals
  • Codon, Nonsense
  • Humans
  • Phenotype
  • Retinal Degeneration/genetics*
  • Retinal Degeneration/metabolism
  • Retinal Degeneration/pathology
  • Disease Models, Animal
  • Cells, Cultured
(all 19)
PubMed
28460050 Full text @ Invest. Ophthalmol. Vis. Sci.
Abstract
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.
Genes / Markers
Figures
Figure Gallery (1 images)
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Expression
No data available
Phenotype
Fish Conditions Stage Phenotype Figure
ift81hi409Tg/hi409Tgstandard conditionsProtruding-mouth
ift81hi409Tg/hi409Tgstandard conditionsProtruding-mouth
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hi409TgTransgenic Insertion
1 - 1 of 1
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Human Disease / Model
Human Disease Fish Conditions Evidence
cone-rod dystrophyTAS
1 - 1 of 1
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Sequence Targeting Reagents
No data available
Fish
Fish
ift81hi409Tg/hi409Tg
1 - 1 of 1
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Antibodies
Name Type Antigen Genes Isotypes Host Organism
Ab1-mycmonoclonal
    		IgG1Mouse
    1 - 1 of 1
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    Orthology
    No data available
    Engineered Foreign Genes
    No data available
    Mapping
    No data available
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    Citation
    Dharmat, R., Liu, W., Ge, Z., Sun, Z., Yang, L., Li, Y., Wang, K., Thomas, K., Sui, R., Chen, R. (2017) IFT81 as a Candidate Gene for Nonsyndromic Retinal Degeneration. Investigative ophthalmology & visual science. 58:2483-2490.