Central and peripheral forms of neurofibromatosis are closely related but discrete diseases which appear to have separate alterations in nerve growth factor activity.
A neurofibroma, a fibroma, a primary neurofibrosarcoma, and four neurofibrosarcoma metastases from a woman with hereditary neurofibromatosis who was heterozygous (GdB/GdA-) for the X-linked enzyme glucose-6-phosphate dehydrogenase were studied to determine the number of cells from which the tumors developed.
If disseminated NF is found to be heterogeneous at a molecular level, more families should be tested to further rule out any role for beta-NGF in this syndrome.
The analysis failed to confirm either the previously suggested linkage between NF and the plasma vitamin D-binding protein Gc or the possibility of linkage of NF to the secretor locus suggested by reports of two families segregating for NF and myotonic dystrophy.
In order to assess this possibility and to map the NF1 gene more precisely, we have used two polymorphic DNA markers from chromosome 17 to screen several pedigrees for linkage to NF1.
The maximum likelihood estimate of the recombination rate between the pHHH202 and NF1 loci was found to be O. Multilocus analysis suggested the following marker order: pA10-41-(p3-6, pHHH202); the NF1 gene fell with equal likelihood between either pA10-41-p3-6 or p3-6-pHHH202.
Four markers with varying degrees of linkage to NF1 have been physically localized and ordered by the panel: the loosely linked markers myosin heavy chain 2 (25 cM) to p12----13.105 and nerve growth factor receptor (14 cM) to q21.1----q23; the more closely linked pABL10-41 (D17S71, 5 cM) to p11.2; and the tightly linked pHHH202 (D17S33) to q11.2-q12.
However, crossovers with the VRNF locus suggest that a mutation in the nerve growth factor receptor gene itself is unlikely to be the fundamental defect responsible for the VRNF phenotype.
Here, we report strong evidence of linkage of NF1 to the centromeric marker D17Z1 (maximum lod = 4.42) and a weaker suggestion of linkage to the ERBA1 oncogene (maximum lod = 0.57), both at a recombination fraction of zero.
Linkage analysis with the human oncogene homolog erbA1, which maps to this region, suggests that this cancer-related gene is not the primary cause of NF1.
Four markers with varying degrees of linkage to NF1 have been physically localized and ordered by the panel: the loosely linked markers myosin heavy chain 2 (25 cM) to p12----13.105 and nerve growth factor receptor (14 cM) to q21.1----q23; the more closely linked pABL10-41 (D17S71, 5 cM) to p11.2; and the tightly linked pHHH202 (D17S33) to q11.2-q12.
NF1 did not recombine with either TH17.19 or HHH202 in any of the informative meioses surveyed (maximum lod scores of 17.04 and 7.21, respectively, at a recombination fraction of .00), indicating that these markers map very close to the NF1 gene.
To better localize the end points of these translocation events, and the NF1 gene (NF1) itself, human cosmids were isolated and mapped in the immediate vicinity of NF1.