Cundall, M.; (2004) Gene dosage and the molecular mechanisms of Pelizaeus-Merzbacher disease. Doctoral thesis , University of London.

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Abstract

Pelizaeus-Merzbacher disease (PMD) is an X-linked neurological disorder characterised by dysmyelination of the central nervous system. The major molecular defect involved in PMD is a variably sized duplication of Xq22 including the PLP1 gene. Determining the copy number of PLP1 is the first line of enquiry when trying to establish a molecular diagnosis of PMD. Multiplex amplifiable probe hybridisation is a quantitative technique that has been explored as a method for diagnosing PLP1 duplications in PMD patients and female carriers as part of this project. The rearrangements in a number of PMD families were investigated using FISH, PCR and sequencing of chromosome breakpoints. One tandem duplication and two more complex rearrangements were characterised during this study. A bioinformatic investigation of sequences present at the breakpoints in these families, and the genomic sequence throughout Xq22, has provided some insights into possible mechanisms causing duplications of this region. Increased dosage of Xq26-27 has been associated with pituitary hypoplasia and a mutation involving the SOX3 gene, located at Xq27.1, has been reported in a family with growth hormone deficiency. Characterisation of a duplication involving SOX3 in a family with X-linked hypopituitarism has been carried out using a similar strategy to the PLP1 duplications. This SOX3 duplication is the smallest yet reported and only contains two other genes. This provides strong evidence for increased dosage of SOX3 being involved in the aetiology of X-linked hypopituitarism. Gene dosage is increasingly being recognised as a cause for human genetic disorders, and it is important for diagnosis that changes in gene dosage can be reliably detected. As more cases of human genetic disease involving gene dosage become apparent, it is clear that duplications are frequent occurrences in the human genome, which may often be undetected as a cause of human genetic variation and disease.

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