Hallam, Paula Jane; (1994) The molecular genetics of Charcot-Marie-Tooth disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Charcot Marie Tooth disease is the commonest of the inherited peripheral neuropathies, with an incidence of 1/2500. The most frequent form of inheritance is one of autosomal dominance. The majority of families showing this mode of inheritance have shown linkage to probes from the pericentric region of chromosome 17 although genetic heterogeneity does exist, with some families showing linkage to chromosome 1 probes. Eight large families, six of whom had previously shown linkage to probes from the pericentric region of chromosome 17 were examined with probes from the short arm of chromosome 17. Two-point and multi-point linkage analyses were used further to localise the genetic location of the disease gene to the 12cM region between probes pl0.41 and EW503 on 17pll.2-12. Multi-point analysis gave a maximum lod score of 9.97 for the interval between these two probes. Cross-overs still remained, in different families, between the disease locus and both flanking probes. Following the identification of sub-microscopic duplication of part of 17pll.2 in patients with CMT1a from two other groups, the families in our study group were analyzed for evidence of this duplication. The duplication was detected in all eight families, as well as in twenty-seven smaller families previously too small for conventional linkage analysis and numerous sporadic cases. The region of duplication seems consistent in the eight families studied in detail, including probes VAW409R3 (D17S122), VAW412R3 (D17S125) and pEW401 (D17S61), a region thought to be approximately 1Mb. Cross-overs still exist within the duplicated region, with probes VAW409R3 and pEW401 (VAW412R3 being uninformative), although there is complete concordance of the duplication with the disease phenotype. No duplication of this region was seen in individuals with CMT2.

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