Limited contribution of interchromosomal gene conversion to NF1 gene mutation

Editor—Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders with a population frequency of 1 in 3500.1 The disease is clinically characterised by multiple neurofibromas, cafe au lait spots and Lisch nodules of the iris. The NF1 gene, a tumour suppressor gene, resides on the proximal long arm of chromosome 17 (17q11.2). It spans approximately 350 kb of genomic DNA and, comprising 60 exons, encodes the protein neurofibromin.2 This protein, consisting of 2818 amino acids, contains a central domain that has homology with GTPase activating proteins (GAPs).3 A distinct feature of the NF1 gene is the very high spontaneous mutation rate (1 × 10-4 per gamete per generation), which is about 100-fold higher than the usual mutation rate for a single locus.1 Up to 50% of all NF1 cases are thought to result from de novo mutations. The NF1 gene provides a large target for mutations because of its relatively large size, but this may only account for a factor of 10 in terms of increase in mutation rate.4 The presence of numerous NF1 pseudogenes has been proposed as an explanation for the high mutation rate in NF1.5 In the human genome, at least 12 different NF1 related sequences have been identified on chromosomes 2, 12, 14, 15, 18, 21, and 22.5-13 Most of the NF1 pseudogenes have been mapped in pericentromeric regions. The chromosome 2 NF1 pseudogene has been localised to region 2q21, which is known to contain the remnant of an ancestral centromere.14 Owing to the absence of selective pressure, mutations may accumulate in the NF1 pseudogenes. Consequently, the pseudogenes could act as reservoirs of mutations, which might be crossed into the functional NF1 gene by interchromosomal gene conversion.5 Gene conversion, the …