Mechanism of spreading of the highly related neurofibromatosis type 1 (NF1) pseudogenes on chromosomes 2, 14 and 22

Neurofibromatosis type 1 (NF1) is a frequent hereditary disorder that invol ves tissues derived from the embryonic neural crest. Besides the functional gene on chromosome arm 17q, NF1-related sequences (pseudogenes) are presen t on a number of chromosomes including 2, 12, 14 15, 18, 21, and 22. We elu cidated the complete nucleotide sequence of the NF1 pseudogene on chromosom e 22. Only the middle part of the functional gene but not exons 21-27a, enc oding the functionally important CAP-related domain of the NF1 protein, is presented in this pseudogene. In addition to the two known NF1 pseudogenes on chromosome 14 we identified two novel variants. A phylogenetic tree was constructed, from which we concluded that the NF1 pseudogenes on chromosome s 2, 14 and 22 are closely related to each other. Clones containing one of these pseudogenes cross-hybridised with the other pseudogenes in this subse t, but did not reveal any in situ hybridisation with the functional NF1 gen e or with NF1 pseudogenes on other chromosomes. This suggests that their hy bridisation specificity is mainly determined by homologous sequences flanki ng the pseudogenes. Strong support for this concept was obtained by sequenc e analysis of the flanking regions, which revealed more than 95% homology. We hypothesise that during evolution this subset of NF1 pseudogenes initial ly arose by duplication and transposition of the middle part of the functio nal NF1 gene to chromosome 2. Subsequently, a much larger fragment, includi ng flanking sequences, was duplicated and gave rise to the current NF1 pseu dogene copies on chromosomes 14 and 22.