Padayachee, Munoreedevi; (1995) Molecular genetic analysis of X-linked hyperimmunoglobulinaemia M. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Prior to this study HIGM1 was shown to map to Xq24-27 by linkage to DXS42 using conventional RFLPs in family EsX. This study was extended to three other families using both conventional RFLP's and short tandem repeat polymorphisms. Six families were analysed for linkage to HPRT (Xq26) using a tetranucleotide tandem repeat polymorphism and a maximum lod score of 4.891 at Θ =0.05 was obtained. A multipoint analysis of the region assigned the gene to Xq26. The physiological ligand for CD40 (hCD40L) that is expressed on the surface of activated T cells, was assigned to Xq26.3-27.1. Crosslinking of CD40 on B cells induces, in the presence of lymphokines, Ig class switching from IgM to other Ig isotypes. Three patients, BW, TG and AT, in whom the defect mapped to Xq26, were subsequently shown to have defective expression of hCD40L and revealed point mutations on sequence analysis. This resulted in a disrupted conformation of hCD40L protein in BW and TG and a positive charge in the transmembrane domain of the protein in AT. Three patients, BS, CS and JP, with no definite history of the X-linked form of the disease but who showed defective expression of hCD40L on the surface of activated T cells, were studied. BS and CS showed changes in their mRNA using single stranded conformation polymorphism analysis. On cDNA sequence analysis, BS had an insertion of T at amino acid 133 and CS a frameshift deletion of 7bp at amino acid 107, thus confirming that spontaneous forms of the disease can also be associated with a defect inhCD40L. In the search for a polymorphism for use in prenatal diagnosis and carrier detection, an intragenic (CA)n repeat sequence which was tested in six families, was informative in four families. A maximum lod score of 6,976 at Θ =0, was obtained. A second reported A to T intragenic polymorphism tested on 50 chromosomes was not polymorphic in the population tested.

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