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Methods for investigating the molecular bases of complement terminal component deficiency

Thomas, Andrew David 2012. Methods for investigating the molecular bases of complement terminal component deficiency. MPhil Thesis, Cardiff University.
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The purpose of this thesis is to identify and examine the molecular mechanisms which result in deficiency of the complement terminal pathway, a part of the innate immune system which can destroy pathogens by lysis through formation of the membrane attack complex (MAC). Patient samples with mutations in components C5, C7 and C8 were available and methods to study these mutations in either genomic, RNA or protein were developed. Work on C5 Deficiency focused on a young African Xhosa woman with C5 deficiency, and identified a known nonsense mutation in exon 1 [c.84C>T; p.Q28X] and a novel missense mutation in exon 7 [c.754G>A] that leads to a conservative change [p.A252T]. Three intronic sequence variations were also identified. An in silico analysis of these mutations was made and a method for amplifying full length cDNA was developed. C7 Deficiency studies focused on four Irish families for which a large genomic deletion was thought to be present. Mapping of the breakpoints and PCR across the deletion identified a 6.4kb deletion together with the insertion of a novel 8bp sequence [c.739+1262_1270-2387delinsGCAGGCCA]. A method for carrier detection was developed. Bioinformatics analysis indicated that the initial DNA breakage was Alu-mediated. C8 Deficiency was investigated in three patients with C8 deficiency. Genomic studies revealed that two patients were shown to be homozygous for the common nonsense mutation in exon 9 [1282C > T; p.A428X. The other was a compound heterozygote for a novel duplication in exon 7 [c.1047_1053 dupGGCTGTG], and a previously reported nonsense mutation [c.298C > T; p.G91X] in exon 3

Item Type: Thesis (MPhil)
Status: Unpublished
Schools: Medicine
Subjects: Q Science > QH Natural history > QH426 Genetics
Q Science > QR Microbiology > QR180 Immunology
R Medicine > R Medicine (General)
Date of First Compliant Deposit: 30 March 2016
Last Modified: 04 Jun 2017 04:21

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