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Severe retinal degeneration at an early age in Usher syndrome type 1B associated with homozygous splice site mutations in MYO7A gene.

ABSTRACT: Purpose:Usher syndrome is the most common cause of deafness associated with visual loss of a genetic origin. The purpose of this paper is to report very severe phenotypic features of type 1B Usher syndrome in a Saudi family affected by positive homozygous splice site mutation in MYO7A gene. Methods:Affected siblings went through detailed history. Complete ophthalmic examination was done. Imaging with colour fundus photography, fundus autofluorescence (AF), and optical coherence tomography (OCT) scans was performed. Full field electroretinogram (ffERG) was recorded. Molecular genetic testing was done using next-generation sequencing. Results:Visual acuity was more reduced (range 20/300-20/40) in older siblings (age>30 years), than in younger (age <30 years) siblings (range 20/70-20/25). OCT scans showed macular atrophy in all but one case that has cystoid macular edema (CME). AF demonstrated atrophy outside a small foveal area showing high signal. FfERG was flat in all cases. The homozygous splice site mutation c.470+1G>A in intron 5 of the MYO7A gene was detected in all affected siblings. Conclusions:This mutation manifested with advanced retinal degeneration at a young age. This may have implications regarding future gene therapy in Usher syndrome cases with this genotype.

SUBMITTER: Abdelkader E

PROVIDER: S-EPMC6010603 | biostudies-literature | 2018 Apr-Jun

REPOSITORIES: biostudies-literature

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Severe retinal degeneration at an early age in Usher syndrome type 1B associated with homozygous splice site mutations in MYO7A gene.

Abdelkader Ehab E Enani Lama L Schatz Patrik P Safieh Leen L

Saudi journal of ophthalmology : official journal of the Saudi Ophthalmological Society 20171026 2

<h4>Purpose</h4>Usher syndrome is the most common cause of deafness associated with visual loss of a genetic origin. The purpose of this paper is to report very severe phenotypic features of type 1B Usher syndrome in a Saudi family affected by positive homozygous splice site mutation <i>in MYO7A</i> gene<i>.</i><h4>Methods</h4>Affected siblings went through detailed history. Complete ophthalmic examination was done. Imaging with colour fundus photography, fundus autofluorescence (AF), and optica ...[more]

PMID: 29942180

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Project description:The first goal of the study was to find the genes that explain the difference in progression of age-related retinal degeneration (ageRD) between the inbred strains C57BL/6J-c2J (B6a) and BALB/cByJ (C). The specific goal was to find the candidate genes that explain the chromosome 6 and chromosome 10 quantitative trait loci (QTL) found in a previous study. Genes differentially expressed in retina between both strains and that map to the QTL are candidate genes. By integrating different approaches: microarray study, knowledge-based candidate gene search and screening of genetic variants, we found 35 candidate genes for chromosome 6 QTL and 14 candidate genes for chromosome 10 QTL. Five genes for each QTL were selected for sequencing and qPCR analysis. One gene, Tnfaip3 was selected for phenotypic testing and was excluded as the quantitative trait gene for chr10 QTL. The second goal of the study was to find biological processes and pathways associated with ageRD by Gene Ontology analysis of the microarray data. We concentrated on GO terms overrepresented in either strain at 8 months; the age when there is a difference in the phenotype (outer nuclear layer thickness). The GO analysis revealed that transcripts associated with inflammation, mitochondrial envelope, DNA repairing and oxidative stress were increased in the ageRD sensitive C strain with age (8 months). In the ageRD resistant B6a strain transcripts associated with antioxidant response, regulation of blood vessel size and growth factor activity were increased with age. Transcripts associated with cell remodeling and lipid metabolism were increased in either strain with age. This study aims to identify gene expression differences in posterior eyecups between the strains C and B6a at 4 months and at 8 months. Twelve animals were used per strain and time point for a total of 48 mice. Total RNA for 3 animals (6 eyes) were pooled giving a total of 4 biological replicates per strain and time point. The 4-month C samples labeled with Cy5 were hybridized with the 4-month B6a samples labeled with Cy3 (4 biological replicates); the 8-month C samples labeled with Cy5 were hybridized with the 8-month B6a samples labeled with Cy3, for 8 arrays (4 biological replicates). A second set of eight arrays were used to analyzed the same RNA samples but with the dye orientation reversed, yielding a total of 16 arrays in the experiment. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc.

Dataset Information

Severe retinal degeneration at an early age in Usher syndrome type 1B associated with homozygous splice site mutations in MYO7A gene.

Publications

Severe retinal degeneration at an early age in Usher syndrome type 1B associated with homozygous splice site mutations in MYO7A gene.

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