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Do you find it as confusing as I do that when geneticists refer to the gene for a disease they mean the gene which stops you having the disease not the mutation that causes it? Thus the gene for neurofibromatosis type 1 (NF1) encodes neurofibromin, a protein that acts on oncogenic Ras proteins to produce a tumour suppressor effect but the mutant gene which causes NF1 results in the production of inactive neurofibromin. In theory though, it takes the inactivation of both tumour suppressor gene alleles in somatic cells to produce malignant change and, NF1 being dominantly inherited, people with NF1 have a normal and an abnormal gene. They are predisposed to develop tumours of neural tissue and young children with the condition have a 200 to 500 fold increase in risk of myeloid malignancy. So why this predisposition to malignancy in heterozygotes who ought to be protected by their normal gene? Workers in California (Lucy Side and colleagues, New England Journal of Medicine1997;336:1713-20) examined bone marrow cells from 18 children with NF1 and malignant myeloid disorders. They found abnormal neurofibromin peptides in nine and truncating mutations of the NF1 gene in eight. In five specimens the cells contained no normal NF1 gene. Examination of affected parents showed that the abnormal genes in leukaemic cells were inherited and not somatic mutations. It is suggested, therefore, that malignancy occurs when the normal NF1 allele in somatic cells is inactive. Other factors favouring malignant change are male sex, maternal inheritance, and loss of chromosome 7. Work on mice suggests that it may be possible to develop anti-Ras protein drugs which could prove effective against some malignancies.
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