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Title: Defining the genetic basis of three novel neurodevelopmental disorders identified in families from Oman
Author: Ahmed, Mustafa Yaseen
ISNI:       0000 0004 7427 0505
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2017
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The recognition of the clinical burden arising from otherwise rare inherited neurological conditions in Oman, arising largely due to the historical practice of tribal community isolation, led to collaborative international research programs aimed at investigating the causes of these conditions to improve diagnosis and aid early intervention, clinical care and genetic screening and counselling efforts. The studies detailed in this thesis describe the investigations undertaken to identify the genetic basis of three rare inherited conditions in extended Omani families. In addition, the interconnectivity between this program, and other international consortia also administered through UEMS, enabled the simultaneous identification and investigation of families from India and Iran with the same genetic disorders. This opportunity enabled robust genetic, clinical and functional descriptions of three previously undescribed inherited conditions. The investigations undertaken on the first condition defined through studies of two interlinking families with individuals with pontocerebellar hypoplasia type 3 led to the identification of the first human disease causing mutation in the PCLO gene, encoding a presynaptic active zone scaffolding molecule. Functional studies in zebrafish determined that loss of PCLO function results in severe brain malformations in this animal model which resemble those observed in the human disorder. The second study identified mutations in the PRUNE1 gene as being responsible for a new microcephaly syndrome identified in families from Oman, as well as other families from India, Iran and Italy. Functional studies of prune also defined an important new and previously unrecognised role for the molecule in microtubule polymerization, a process essential for the cytoskeletal rearrangements that occur during cellular division and proliferation. This provides a functional link between prune mutation and other known causes of microcephaly. The third study led to the documentation of the first human disease arising through abnormalities in the ethanolamine branch of the Kennedy pathway, by the identification of loss of function mutation in EPT1 in a single nuclear Omani family in individuals with complex hereditary spastic paraplegia. Together, these studies define three new molecules responsible for new inherited neurodevelopmental disorders, and the clinical and biological outcomes of these gene mutations. As well as aiding scientific knowledge of the biological basis of neurodevelopmental disease, these findings will have substantial clinical impacts and not only aid diagnosis of these phenotypes in regional populations, but also enable genetic counselling, informed family planning and early treatment and clinical intervention for affected families globally.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available