Rousseau, Karine; (2004) Genetically determined variation of secreted mucins. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Mucins are the major components of the mucus that protects all major epithelia such as the respiratory and gastro-intestinal tracts. Mucins (gene symbol MUC followed by a number) are heavily glycosylated proteins characterised by a large central domain composed of a tandemly repeated sequence. This central domain is encoded by a single exon and exhibits VNTR (Variable Number Tandem Repeat) type polymorphism. This feature has been examined in association studies and suggested that MUC7 and MUC2 mucins could play a role in predisposition to or protection from respiratory disease. However, the alleles involved would generate a relatively small change in the size of the total protein, suggesting that the effect observed might not be due to differences in the VNTR length itself but be due to one or more linked polymorphisms. The first aim of this thesis was to study the MUC7 gene and protein. Monoclonal antibodies against MUC5B and MUC7 were produced and qualitative as well as quantitative differences in the mucin production were found between and within individuals. In parallel, the genetic variation of MUC7 was characterised and haplotype diversity examined. This was then used to re-examine the allelic association previously found with respiratory disease and an additional locus was found to asscociate with asthma. The second objective of this thesis was to further investigate the association reported between MUC2 and asthma. MUC2 is expressed at low levels in the respiratory epithelium but the MUC2 gene is located in a mucin gene complex on chromosome 11 with MUC6, MUC5AC and MUC5B genes. This chromosomal region and patterns of linkage disequilibrium (LD) were characterised. It was found that MUC2 and MUC5AC are in LD and flanked by two recombination hot-spots. This could explain the association with respiratory disease and suggests a possible role of MUC5 AC, which is strongly expressed in the airways.

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