Novel homozygous splicing mutations in ARL2BP cause autosomal recessive retinitis pigmentosa

Mutations in encoding ADP-ribosylation factor-like 2 binding protein, have recently been implicated as a cause of autosomal recessive retinitis pigmentosa (arRP), with three homozygous variants identified to date. In this study, we performed next-generation sequencing to reveal additional arRP cases...

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Bibliographic Details
Published in:Molecular vision 2018-08, Vol.24, p.603-612
Main Authors: Fiorentino, Alessia, Yu, Jing, Arno, Gavin, Pontikos, Nikolas, Halford, Stephanie, Broadgate, Suzanne, Michaelides, Michel, Carss, Keren J, Raymond, F Lucy, Cheetham, Michael E, Webster, Andrew R, Downes, Susan M, Hardcastle, Alison J
Format: Article
Language:English
Subjects:
ADP-ribosylation factor
Adult
Carrier Proteins - genetics
DNA Mutational Analysis
Electroretinography
Exome
Female
Genes, Recessive
Genetic Association Studies
Genomes
Genotypes
High-Throughput Nucleotide Sequencing
History, 16th Century
Homozygote
Humans
Introns
Male
Mutation
Next-generation sequencing
Pedigree
Phenotype
Phenotypes
Phenotyping
Photography
Rare diseases
Retina
Retinal degeneration
Retinitis
Retinitis pigmentosa
Retinitis Pigmentosa - genetics
Reverse Transcriptase Polymerase Chain Reaction
RNA Splicing
RNA-directed DNA polymerase
Splicing
Tomography, Optical Coherence
Transcription
Transcription Factors
Whole Genome Sequencing
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Summary:Mutations in encoding ADP-ribosylation factor-like 2 binding protein, have recently been implicated as a cause of autosomal recessive retinitis pigmentosa (arRP), with three homozygous variants identified to date. In this study, we performed next-generation sequencing to reveal additional arRP cases associated with variants. Whole-genome sequencing (WGS) or whole-exome sequencing (WES) was performed in 1,051 unrelated individuals recruited for the UK Inherited Retinal Disease Consortium and NIHR-BioResource Rare Diseases research studies. Sanger sequencing was used to validate the next-generation sequencing data, and reverse transcriptase (RT)-PCR analysis was performed on RNA extracted from blood from affected individuals to test for altered splicing of . Detailed phenotyping was performed, including clinical evaluation, electroretinography, fundus photography, fundus autofluorescence imaging, and spectral-domain optical coherence tomography. Homozygous variants in (NM_012106.3) were identified in two unrelated individuals with RP. The variants, c.207+1G>A and c.390+5G>A, at conserved splice donor sites for intron 3 and intron 5, respectively, were predicted to alter the pre-mRNA splicing of . RT-PCR spanning the affected introns revealed that both variants caused abnormal splicing of in samples from affected individuals. This study identified two homozygous variants in as a rare cause of arRP. Further studies are required to define the underlying disease mechanism causing retinal degeneration as a result of mutations in and any phenotype-genotype correlation associated with residual levels of the wild-type transcript.
ISSN:1090-0535
1090-0535