Neurofibromatosis type 1 (NF1) is caused by deletions, insertions, 
translocations, and point mutations in the NF1 gene, which spans 350 kb on the 
long arm of human chromosome 17. Although several point mutations have been 
described, large molecular abnormalities have rarely been characterized in 
detail. We describe here the molecular breakpoints of a 12-kb deletion of the 
NF1 gene, which is responsible for the NF1 phenotype in a kindred with two 
children affected because of germline mosaicism in the unaffected father, who 
has the mutation in 10% of his spermatozoa. The mutation spans introns 31-39, 
removing 12,021 nt and inserting 30 bp, of which 19 bp are a direct repetition 
of a sequence located in intron 31, just 4 bp before the 5' breakpoint. The 5' 
and 3' breakpoints contain the sequence TATTTTA, which could be involved in the 
generation of the deletion. The most plausible explanation for the mechanism 
involved in the generation of this 12-kb deletion is homologous/nonhomologous 
recombination. Since sperm of the father does not contain the corresponding 
insertion of the 12-kb deleted sequence, this deletion could have occurred 
within the NF1 chromosome through loop formation. RNA from lymphocytes of one of 
the NF1 patients showed similar levels of the mutated and normal transcripts, 
suggesting that the NF1-mRNA from mutations causing frame shifts of the reading 
frame or stop codons in this gene is not degraded during its processing. The 
mutation was not detected in fresh lymphocytes from the unaffected father by PCR 
analysis, supporting the case for true germ-line mosaicism.