A search for evidence of somatic mutations in the NF1 gene
Alison M Johna, Martino Ruggierib, Ros Fernerc, Meena Upadhyayaa
a Institute of Medical Genetics, University College of Medicine of Wales, Heath Park, Cardiff CF4 4XN, UK, b Department of Paediatric Neurology, Paediatric Clinic, University of Catania, Italy, c Department of Clinical Neurosciences, Guy's, King's, and St Thomas's School of Medicine, London, UK
Correspondence to: Dr Upadhyaya
Revised version received 8 June 1999;
Accepted for publication 5
August 1999
Neurofibromatosis type I (NF1) is an autosomal dominant
disorder affecting 1 in 3000 people. The NF1
gene is located on chromosome 17q11.2, spans 350 kb of genomic DNA, and
contains 60 exons. A major phenotypic feature of the disease is the
widespread occurrence of benign dermal and plexiform neurofibromas.
Genetic and biochemical data support the hypothesis that
NF1 acts as a tumour suppressor gene.
Molecular analysis of a number of NF1 specific tumours has shown the
inactivation of both NF1 alleles during
tumourigenesis, in accordance with Knudson's "two hit" hypothesis.
We have studied 82 tumours from 45 NF1 patients. Two separate
strategies were used in this study to search for the somatic changes
involved in the formation of NF1 tumours. First, evidence of loss of
heterozygosity (LOH) of the NF1 gene region
was investigated, and, second, a screen for the presence of sequence
alterations was conducted on a large panel of DNA derived from matched
blood/tumour pairs. In this study, the largest of its kind to date, we
found that 12% of the tumours (10/82) exhibited LOH; previous studies
have detected LOH in 3-36% of the neurofibromas examined. In addition, an SSCP/HA mutation screen identified five novel
NF1 germline and two somatic mutations. In a
plexiform neurofibroma from an NF1 patient, mutations in both
NF1 alleles have been characterised.
Keywords: neurofibromatosis; NF1 gene; somatic mutations
© 2000 by J Med Genet
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