Community genetic studies provide an important opportunity to discover the genetic basis of new inherited diseases, while at the same time providing impacting medical benefits for the communities involved. Discovering a disease gene provides important insights into the molecular genetic basis of an inherited disease. Once the genetic cause of a disorder is established, diagnostic testing may be performed to provide affected families the chance of early diagnosis and treatment intervention, support may be provided via premarital or prenatal counselling, and educational benefits may be provided regarding the causes and nature of inherited disease. This thesis involves the molecular genetic investigation of three novel neurological conditions. The first of these, a complex form of hereditary spastic paraplegia (HSP) associated with developmental delay (GM2 synthase deficiency), was found to be caused by mutations in the 84GALNTl gene. The disorder was discovered in families from Kuwait, ยท , : Canada and the Amish. The biochemical outcome of altered ganglioside biosynthesis, leading to GM2 synthase deficiency, was confirmed using HPLC and mass spectrometry. The second condition, neurodevelopmental delay associated with speech disorder in a large Amish kinship, was found to be caused by a missense mutation in the HERC2 gene. Encoded mutant HERC2 protein was found to have a reduced half-life compared with its wild-type counterpart, leading to a significant reduction in HERC2 levels in affected individuals. e The third genetic condition was found to be caused due to missense mutations at a mutation hotspot in the TFG gene leading to both pure and complex forms of HSP in a British-Pakistani consanguineous family, and an Indian family in which parents were not known to be related. Two different missense mutations resulting into two different amino acid outcomes at the same highly conserved amino acid residue in the TFG gene caused this condition. Thus, the molecular genetic investigations defined here identify new molecular causes of neurological disease and define genes which are essential for normal neuronal development. More in-depth investigation of the disease mechanisms underlying these conditions may in turn translate into providing treatment therapies for affected families in near future.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:676899 |
| Date | January 2015 |
| Creators | Harlalka, Gaurav Vijay |
| Publisher | St George's, University of London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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