Characterisation of the out cold mutations of Drosophila melanogaster

Lindsay, Helen Anne (2005) Characterisation of the out cold mutations of Drosophila melanogaster. PhD thesis, University of Glasgow.

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Out cold (Ocd) is an X-linked Drosophila gene, mutations in which lead to dominant cold- sensitive paralysis. Previous studies have suggested that Ocd may have some involvement in mitochondrial energy metabolism. The primary objective of this work was to identify the Ocd gene and gene product, and determine how mutations in it result in this complex phenotype. Two strategies were employed to narrow down the Ocd critical region: SNP mapping and P element mapping. From an original area of 1.5Mb, the critical region was reduced to less than 100kb and only six candidate genes. Complementation tests between Ocd and paralytic (para), a voltage-gated sodium channel gene, suggested the two are allelic. Subsequent sequencing of Ocd lines revealed mutations within highly conserved regions of para, both within transmembrane segment S6 of domain III (I1545M, T155II), and in the linker between domains III and IV (G1571R), the putative location of the channel inactivation gate. Further evidence for allelism between Ocd and para was obtained from electrophysiology and pesticide resistance experiments. In addition, a proteomics study was conducted which supports the notion of mitochondrial defects arising as a consequence of the Ocd mutations. The G1571R mutation is of particular interest as mutations of the orthologous residue in the human skeletal muscle sodium channel gene SCN4A, G1306, have been associated with cases of periodic paralysis and myotonia, including the cold-sensitive disorder paramyotonia congenita. The mechanisms by which sodium channel mutations lead to such phenotypes are not well understood. In the absence of a suitable vertebrate model system, Ocd provides a system in which genetic, molecular, physiological and behavioural tools can be exploited to determine mechanisms underlying sodium channel periodic paralyses.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Kevin O Dell
Keywords: Genetics
Colleges/Schools: College of Medical Veterinary and Life Sciences
Date of Award: 2005
Depositing User: Enlighten Team
Unique ID: glathesis:2005-74105
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 07 Aug 2019 15:01
Last Modified: 07 Aug 2019 15:03
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