Leber congenital amaurosis associated with AIPL1: challenges in ascribing disease causation, clinical findings, and implications for gene therapy
Autor: | Hoai Viet Tran, Jill A. Cowing, Robert H. Henderson, Andrew R. Webster, Michael E. Cheetham, Robin R. Ali, Genevieve A. Wright, Alexander J. Smith, Arundhati Dev-Borman, Robert E MacLaren, Anthony G. Robson, Donna S. Mackay, Dorothy A. Thompson, Phillip Moradi, Isabelle Russell-Eggitt, Anthony T. Moore, Michel Michaelides, Mei Hong Tan |
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Jazyk: | angličtina |
Rok vydání: | 2012 |
Předmět: |
Adult
Retinal Disorder Microarray Adolescent Nonsense mutation Leber Congenital Amaurosis lcsh:Medicine Biology Bioinformatics Young Adult Genetic Mutation medicine Genetics Humans Allele Fluorescein Angiography lcsh:Science Child Eye Proteins Adaptor Proteins Signal Transducing Clinical Genetics Multidisciplinary medicine.diagnostic_test Genetic heterogeneity Gene Expression Profiling lcsh:R Case-control study Computational Biology Genomics Genetic Therapy Gene expression profiling Ophthalmology Case-Control Studies Child Preschool Mutation Medicine lcsh:Q RNA Splice Sites Carrier Proteins Population Genetics Electroretinography Research Article |
Zdroj: | PLoS ONE PLoS ONE, Vol 7, Iss 3, p e32330 (2012) |
ISSN: | 1932-6203 |
Popis: | Leber Congenital Amaurosis (LCA) and Early Childhood Onset Severe Retinal Dystrophy are clinically and genetically heterogeneous retinal disorders characterised by visual impairment and nystagmus from birth or early infancy. We investigated the prevalence of sequence variants in AIPL1 in a large cohort of such patients (n = 392) and probed the likelihood of disease-causation of the identified variants, subsequently undertaking a detailed assessment of the phenotype of patients with disease-causing mutations. Genomic DNA samples were screened for known variants in the AIPL1 gene using a microarray LCA chip, with 153 of these cases then being directly sequenced. The assessment of disease-causation of identified AIPL1 variants included segregation testing, assessing evolutionary conservation and in silico predictions of pathogenicity. The chip identified AIPL1 variants in 12 patients. Sequencing of AIPL1 in 153 patients and 96 controls found a total of 46 variants, with 29 being novel. In silico analysis suggested that only 6 of these variants are likely to be disease-causing, indicating a previously unrecognized high degree of polymorphism. Seven patients were identified with biallelic changes in AIPL1 likely to be disease-causing. In the youngest subject, electroretinography revealed reduced cone photoreceptor function, but rod responses were within normal limits, with no measurable ERG in other patients. An increasing degree and extent of peripheral retinal pigmentation and degree of maculopathy was noted with increasing age in our series. AIPL1 is significantly polymorphic in both controls and patients, thereby complicating the establishment of disease-causation of identified variants. Despite the associated phenotype being characterised by early-onset severe visual loss in our patient series, there was some evidence of a degree of retinal structural and functional preservation, which was most marked in the youngest patient in our cohort. This data suggests that there are patients who have a reasonable window of opportunity for gene therapy in childhood. |
Databáze: | OpenAIRE |
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