Saunders, R.E.; (2008) Locus specific databases: integrating sequence, structural and clinical analysis in relation to disorders of the coagulation and complement systems. Doctoral thesis , University of London.

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Abstract

Following the success of the Human Genome Mutation Database, increasing numbers of locus-specific mutation databases are being compiled in order to present more detailed descriptions of the mutations in specific proteins and diseases. However, until now, many coagulation or complement disorders have no up-to-date, accurate repository of information. Structural analyses of disease-associated mutations can provide important new tools for identifying the underlying biochemical defect of disease. Type I mutations may affect the correct folding, secretion, expression or degradation of the protein. Alternatively, Type II mutations can disrupt the catalytic or substrate-binding functional site of the protein. Alternatively, mutations may not be the causative factor for disease. Including sequence and structural information to propose consensus domain structures can unravel these effects of mutations. Central repositories of data that combine structural, sequence and phenotypic information on mutations and proteins can facilitate the diagnosis and understanding of the associated diseases, and define the molecular consequences of disease. This thesis describes interactive web databases of genotypic, phenotypic, clinical and structural information on mutations associated with complement Factor H (FH) and coagulation Factor XI (FXI). Mutations within FH are associated with aHUS (atypical Haemolytic Uraemic Syndrome), MPGN (Membranoproliferative Glomerulonephritis) and AMD (Age-related Macular Degeneration), whereas mutations within FXI are associated with a FXI deficiency bleeding disorder. The methods used within the FH and FXI databases were extended and combined with a database management system to design a mutation database for the five Vitamin K dependent serine proteases of coagulation in order to study the effects of mutations within conserved domains. The database management system incorporates new tools that have been designed to automatically scan full length references to find text describing mutations. This significantly reduces the time and expertise required to maintain the databases.

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