Abstract
Human prenatal development is dependent upon the precise temporal and spatial control of cellular processes, regulated by a diverse array of molecules. Progressively, the genes and gene families critical in human embryogenesis are being ascertained and mutations in any one of these could potentially give rise to inherited developmental disorders. Studying the molecular genetic aetiology of such disorders leads to an increased awareness and understanding of the pathways and mechanisms that are crucial in developmental programming.The initial aim of this research was to perform genetic mapping studies in a number of families with developmental disorders, to identify specific chromosomal segments harbouring the disease genes. The conditions studied include disorders of skeletal, parathyroid, and central nervous system development, namely spondyloepimetaphyseal dysplasia with abnormal dentition (SEMDAD), familial isolated hypoparathyroidism, and hereditary spastic paraplegia with thin corpus callosum (HSP-TCC), as well as the eye disorders autosomal dominant anophthalmia-microphthalmia and X-linked idiopathic congenital nystagmus (ICN). Genetic mapping techniques employed standard statistics-based linkage analysis and autozygosity mapping, a unique method of mapping autosomal recessive disease genes in consanguineous families.
Following elucidation of putative disease gene intervals, functional candidate genes were analysed to detect pathogenic variants using a range of screening techniques, including direct DNA sequencing, comparative genomic hybridisation and multiplex ligation-dependent probe amplification. Identified mutations were interrogated further using in vitro functional studies and the model organism, Danio rerio (zebrafish). This study has successfully detected novel mutations in two previously characterised genes (GCM2 and OTX2) and provided independent confirmation of KIAA1840 as the gene underlying SPG11-linked HSP-TCC. In addition, autozygosity mapping has isolated a potentially novel locus for SEMDAD, whilst refinement of the major NYS1 locus has led to identification of the first gene causing X-linked ICN. This work offers a substantial advance in elucidation of the biological processes underlying this group of disorders.
| Date of Award | 1 Apr 2009 |
|---|---|
| Original language | English |
| Awarding Institution |
|
| Supervisor | Richard Trembath (Supervisor) |