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Tamar Ben-Yosef, Osnat Eidinger, Rina Leibu, Hadas Newman, Leah Rizel, Ido Perlman; An intronic deletion in the PROM1 gene leads to autosomal recessive cone-rod dystrophy . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2898.
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To investigate the genetic basis for autosomal recessive cone-rod dystrophy (CRD) in a consanguineous Israeli Jewish family.
Patients underwent a detailed ophthalmic examination, including funduscopy, electroretinography (ERG), visual field testing and optical coherence tomography (OCT). Genome-wide homozygosity mapping using a SNP array was performed to identify homozygous regions shared among two of the affected individuals. Mutation screening of the underlying gene was carried out by direct sequencing. In silico and in vitro analyses were used to predict the effect of the identified mutation on splicing.
The affected family members are three siblings suffering from progressive visual deterioration, glare, deficient color vision and night vision abnormalities. Visual field tests revealed central scotomas of different extension. Both cone and rod ERG responses were reduced, with cones being more severely affected. Homozygosity mapping revealed several homozygous intervals shared among two of the affected individuals. One of them included the PROM1 gene. Sequence analysis of the 26 coding exons of PROM1 in one affected individual revealed no mutations in the coding sequence or in intronic splice-sites. However, in intron 21, proximate to the intron-exon junction, we observed a homozygous10 bp deletion between positions -26 and -17 (c.2281-26_-17del). This deletion co-segregated with the disease in the family, and was not detected in public databases nor in 101 ethnically-matched control individuals. In silico analysis predicted that this deletion would lead to altered intron 21 splicing. Bioinformatic analysis predicted that a recognition site for the SRSF2 splicing factor is located within the deleted sequence.<br />
Here we report a novel and unique intronic mutation of PROM1, underlying autosomal recessive CRD in a consanguineous Israeli family. Altered splicing probably results from deletion of a recognition site for the SRSF2 splicing factor. This report expands the spectrum of pathogenic mutations of PROM1 and further demonstrates the importance of intronic mutations.
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