The molecular genetics of multiple sclerosis in Southampton and the Channel Isles : an analysis of the major myelin-associated protein genes

Sharpe, Geoffrey (1997) The molecular genetics of multiple sclerosis in Southampton and the Channel Isles : an analysis of the major myelin-associated protein genes. University of Southampton, Doctoral Thesis.

Abstract

Multiple Sclerosis (MS) is a major cause of neurological disability worldwide, but despite over 150 years of study its aetiology remains unclear.

It is now however generally accepted that there is a genetic component determining susceptibility to the disease. This thesis tests the hypothesis that the MS susceptibility genes include those encoding the major myelin - associated proteins, namely Proteolipid Protein (PLP), Myelin Basic Protein (MBP), 2', 3' cyclic nucleotide-3'-phosphohydrolase (CNP) and Myelin-Associated Glycoprotein (MAG).

The first ever epidemiological survey of the Channel Island for MS revealed standardised prevalence rates which seem to support the existence of a north-south latitudinal gradient of the disease throughout the British Isles. Differences between the two Bailiwicks in the rates for female sufferers were however identified. This survey together with a previously reported study in the Southampton area, allowed identification of persons with MS and of informative families for inclusion in the subsequent molecular analysis. DNA from these groups, together with a control population were examined for mutations in all mutations in all four genes using the restriction fragment length polymorphism (RFLP) technique, utilising probes isolated from both bovine and human cDNA libraries. Despite extensive examination, no novel mutations were detected. Because of the relative lack of sensitivity inherent in the RFLP technique, a further method, that of single strand conformation polymorphism (SSCP), was used to analyse the entire coding region of the PLP gene in both the MS and control groups. Analysis of the seven exons and the splice junctions revealed a polymorphism which was identified as a silent T → C transition in exon 4 and which was not MS specific.

These results demonstrate that mutations within the genes encoding the major myelin - associated proteins, particularly PLP, are unlikely to confer the genetic susceptibility in MS.

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