Abstract:
The terminal cytogenetic band of the human X chromosome, Xq28, has been intensively studied by human geneticists because of the high gene density of this region. Included in this region are the genes implicated in Adrenoleukodystrophy (ALD) and Emery-Dreifuss Muscular Dystrophy (EDMD). This thesis describes molecular studies of these two devastating disorders. ALD is a neurological disorder, that manifests with differing clinical phenotypes, even within the same kindred. The disease is characterised biochemically by an accumulation of very long chain fatty acids (VLCFAs), primarily in cerebral white matter and the adrenal gland. EDMD is a heterogeneous disorder that is characterised by early contractures of the elbows, Achilles tendons and postcervical muscles; slowly progressive muscle wasting and weakness; and cardiomyopathy. There are no significant intellectual defects reported in EDMD patients. The genes involved in ALD (ALD) and EDMD (EDMD) have both been characterised. In addition, the murine homologue of ALD (Aldgh) has recently been isolated and characterised by the author's laboratory. This thesis is divided into four parts. The first describes the development of monoclonal antibodies which recognise the ALD protein (ALDP) and the EDMD protein (emerin). These antibodies have allowed molecular studies of ALD and EDMD at the protein level. The second part of this thesis details the isolation and characterisation of the murine homologue of the EDMD gene (Edmd). In so far as animal models of inherited human disorders provide a manipulative system in which a number of aspects of human disease can be analysed, the studies described in this thesis provide the foundation for the development of a mouse model of EDMD. The third part of this thesis describes physical mapping studies of the Aldgh and Edmd genes, and contrasts these maps with those of the human homologues. This comparative physical mapping study revealed gene rearrangements that have occurred during evolution. Finally, mutation studies of EDMD patients were undertaken in the hope that structure-function relationships of emerin could be determined, and to develop an efficient molecular-based approach for the identification of EDMD individuals.