Spinal Neurofibromatosis without Café-au-Lait Macules in Two Families with Null Mutations of the NF1 Gene

Abstract

Spinal neurofibromatosis (SNF) is considered to be an alternative form of neurofibromatosis, showing multiple spinal tumors and café-au-lait macules. Involvement of the neurofibromatosis type 1 (NF1) locus has been demonstrated, by linkage analysis, for three families with SNF. In one of them, a cosegregating frameshift mutation in exon 46 of the NF1 gene was identified. In the present study, we report four individuals from two families who carry NF1 null mutations that would be expected to cause NF1. Three patients have multiple spinal tumors and no café-au-lait macules, and the fourth has no clinical signs of NF1. In the first family, a missense mutation (Leu2067Pro) in NF1 exon 33 was found, and, in the second, a splice-site mutation (IVS31-5A-->G) enlarging exon 32 by 4 bp at the 5' end was found. The latter mutation has also been observed in an unrelated patient with classical NF1. Both NF1 mutations cause a reduction in neurofibromin of approximately 50%, with no truncated protein present in the cells. This demonstrates that typical NF1 null mutations can result in a phenotype that is distinct from classical NF1, showing only a small spectrum of the NF1 symptoms, such as multiple spinal tumors, but not completely fitting the current clinical criteria for SNF. We speculate that this phenotype is caused by an unknown modifying gene that compensates for some, but not all, of the effects caused by neurofibromin deficiency.

Genetic Factors that Affect Tumorigenesis in NF1

“…9 Our data extend these reports by demon-"strating clonal proliferation of malignant T-lymphoid lineage cells Nfl) confers a proliferative advantage that is predominately expressed in the myeloid lineage. As suggested by a previous report 20 showing polyclonality in the T-lymphoid lineage in a child the corresponding maternal 17q region carrying the NF1 allele. This putative progenitor cell would carry 2 maternal NF1 alleles, 2 maternal alleles for the additional approximately 500 genes in the Acknowledgment LOH region, and a single maternal and paternal allele for the remaining chromosome 17 loci.…”

“…The majority of NF1 microdeletion patients in the in ref. 20), this is only the second to be analyzed at the nucleotide current study were selected by phenotype. To date, available level.…”

Next-generation sequencing identifies rare variants associated with Noonan syndrome

“…1D). These results suggest that the p.L1361R mutation decreases protein stability, as seen with other NF1 missense mutations (19). Accordingly, the mutant NF1-GRD construct was defective in suppressing basal and epidermal growth factor (EGF)-evoked ERK activation, as assessed by immunoblotting with anti-phosphorylated-ERK (p-ERK) antibodies (Fig.…”

“…NF1 encodes neurofibromin, a RAS-GTPase-activating protein (RAS-GAP). Although most causative NF1 point mutations result in premature translation termination (18), some disease-associated missense mutations encode unstable NF1 proteins without affecting NF1 mRNA levels (19), and others impair RAS-GAP activity (20)(21)(22). The leucine at position 1361 of NF1 is located in the GAP-related domain (NF1-GRD) and is highly conserved (Fig.…”

Clinical and genetic aspects of neurofibromatosis 1

“…A few families have been reported in which affected individuals have NF1 mutations and multiple spinal neurofibromas but few, if any, cutaneous manifestations of the disease. [115][116][117] Other examples include a human with an NF1 mutation and an optic pathway glioma but no other diagnostic features of NF1 161 and a child with an NF1 mutation and encephalocraniocutaneous lipomatosis. 162 The relationship of the NF1 mutations to the unusual phenotypes in these individuals is not understood.…”