Ellis, David; (1995) The molecular genetics of myelin genes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The aim of this project was to investigate the molecular defects associated with Charcot-Marie-Tooth disease and Pelizaeus-Merzbacher disease. Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy with an estimated population frequency of 1:2500. The disease displays genetic, clinical, and pathological heterogeneity, and is classified into a number of distinct sub-types. The most prevalent form is CMT1A which is commonly associated with a duplication of chromosome 17p11.2. The PMP-22. gene was reported to be mutated in a mouse model of CMT disease called Trembler. The PMP-22 gene maps within the duplicated region on chromosome 17p11.2 and there have been four reports of PMP-22 mutations in patients described as CMTI that did not carry the duplication. A separate form called CMT1B is associated with mutations of the Po gene on chromosome 1q22-23. CMTIII or Dejerine-Sottas disease has been described as an autosomal recessive condition that displays a more severe phenotype than the previous forms, but is caused by mutations of either PMP-22 or Po. Patients with CMT disease who did not carry the CMTIA duplication have been screened in this study for mutations in PMP-22 or Po. In addition, 50% of another myelin protein gene called PMP-2 has been screened. Three PMP-22 and a single Po gene mutation have been identified in CMTIII patients and no point mutation was identified in CMTI patients that did not carry the CMTIA duplication. In each case no other mutation within the same gene was identified, thereby suggesting dominant transmission of the disease which is in disagreement with the earlier proposal of autosomal recessive inheritance in CMTIII. However, it remains a possibility that these patients have developed the disease through the recessive inheritance of mutations in two different genes. The results demonstrate that in most cases, point mutations of PMP-22 cause CMTIII or severe CMTIA. CMT type II has been linked to a locus on chromosome 1 distinct from CMT1A and CMT1B. Linkage analysis in two CMTII families with three markers, showed an absence of close linkage to this locus, thereby demonstrating further genetic heterogeneity associated with CMT disease. Pelizaeus-Merzbacher (PMD) disease is a rare neurodegenerative disorder involving abnormal myelination of the central nervous system. The disease is caused by mutation of the PLP gene on the X-chromosome, but no PLP defect has been identified in many X-linked patients. The possibility that the same type of disease mechanism as that causing the CMTIA duplication was investigated, and a gene dosage effect of the PLP gene due to a sub-microscopic duplication of chromosome Xq22 was found in two unrelated boys with PMD, and their unaffected carrier mothers. The duplicated region spans at least 120kb and the level of increased dosage is greater in one boy with a more severe phenotype.

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