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Title: A positional cloning strategy to identify candidate genes for X-linked mental retardation
Author: Cox, J. J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2006
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Twenty-one genes are known that when mutated cause non-syndromic X-linked mental retardation (NS-XLMR), a condition in which learning disability is the only consistent clinical feature among affected individuals. The principal aim of this project was to identify further NS-XLMR genes. To achieve this aim we characterized X chromosomal breakpoints in rare patients with apparently balanced X;autosome translocations and learning disability to identify disrupted candidate NS-XLMR genes. In patient LPW, a female with a translocation involving chromosomes X and 8, we identified a small 650 kb duplication at the X chromosome breakpoint that was likely to be responsible for the patient’s learning disability. In patient AGO819, the CLCN5 gene was found to be disrupted by the X chromosomal breakpoint. As CLCN5 is a gene mutated in a familial renal disease not associated with learning disability then expression analysis of genes adjacent to CLCN5 was performed. A position effect disrupting the expression of a neighbouring gene, CCNB3, was detected indicating that the expression of one or more genes surrounding the X chromosome breakpoint was disrupted. One of these genes, KIAA1202, has recently been reported to be mutated in familial learning disability. In a third patient with a balanced translocation, KD, no gene was found disrupted by the X chromosome breakpoint and further analysis indicated that this patient’s learning disability was likely to be related to abnormalities at the autosomal breakpoint. The project was concluded by characterizing two mutations identified in DLG3. We proved that the genomic mutations disrupted splicing of DLG3 at the mRNA level, confirming that the mutations were likely to be disease-causing in the two families.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available