| Summary: | <p>Abstract</p> <p>Background</p> <p>Inherited retinal dystrophies, including Retinitis Pigmentosa and Leber Congenital Amaurosis among others, are a group of genetically heterogeneous disorders that lead to variable degrees of visual deficits. They can be caused by mutations in over 100 genes and there is evidence for the presence of as yet unidentified genes in a significant proportion of patients. We aimed at identifying a novel gene for an autosomal recessive form of early onset severe retinal dystrophy in a patient carrying no previously described mutations in known genes.</p> <p>Methods</p> <p>An integrated strategy including homozygosity mapping and whole exome sequencing was used to identify the responsible mutation. Functional tests were performed in the medaka fish (<it>Oryzias latipes</it>) model organism to gain further insight into the pathogenic role of the <it>ADAMTS18</it> gene in eye and central nervous system (CNS) dysfunction.</p> <p>Results</p> <p>This study identified, in the analyzed patient, a homozygous missense mutation in the <it>ADAMTS18</it> gene, which was recently linked to Knobloch syndrome, a rare developmental disorder that affects the eye and the occipital skull. <it>In vivo</it> gene knockdown performed in medaka fish confirmed both that the mutation has a pathogenic role and that the inactivation of this gene has a deleterious effect on photoreceptor cell function.</p> <p>Conclusion</p> <p>This study reveals that mutations in the <it>ADAMTS18</it> gene can cause a broad phenotypic spectrum of eye disorders and contribute to shed further light on the complexity of retinal diseases.</p>
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