These results are the first to document double inactivation of NF1 in PA tissue and suggest that the neurofibromin-Ras signal transduction pathway is involved in this bone dysplasia in NF1.
Inherited mutations of the p53 and neurofibromin genes are thought to cause two distinct neoplastic disorders in which gliomas occur, the Li-Fraumeni syndrome and neurofibromatosis type 1.
Analysis of benign and malignant tumors commonly associated with NF1 patients, as well as those with high NF1 gene mutation frequency, reveals an antagonistic role for NF1 heterozygosity in tumor initiation and malignant transformation and helps to reconciliate the role of the NF1 gene in both NF1 and non-NF1 patient contexts.
Although a mutation in the NF1 gene is the only factor required to initiate the neurocutaneous-skeletal neurofibromatosis 1 (NF1) syndrome, the pathoetiology of the multiple manifestations of this disease in different organ systems seems increasingly complex.
Linkage analysis with a polymorphism in the bovine NF1 gene confirmed that two affected animals from the same sire inherited the same paternal NF1 allele.
As such, individuals with NF1 are born with a germline mutation in the NF1 gene, but may develop numerous distinct neurological problems, ranging from autism and attention deficit to brain and peripheral nerve sheath tumors.
Loss of function mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin, leads to accelerated p21(Ras) activity and phosphorylation of multiple downstream kinases, including Erk and Akt.
A further understanding of neurofibromin function will help to elucidate the pathophysiology of NF1 and will also lead to a better understanding of cell cycle regulation and ras pathways in specific cell types.
Coinactivation of the TP53 gene by deletion, or by point mutation along with NF1 gene inactivation, is known to exacerbate disease symptoms in NF1, therefore TP53 gene inactivation was screened.
Children with neurofibromatosis type 1 (NF1) carry germline mutations in one allele of the NF1 gene and are predisposed to myeloid malignancies, particularly juvenile myelomonocytic leukemia (JMML).
(2008) demonstrate that mast cells heterozygous for the Nf1 gene promote the growth of neurofibromas in a mouse model of neurofibromatosis and that genetic and pharmacological inhibition of these cells is sufficient to block tumor growth.
Despite the reduced level of neurofibromin cellular GAP activity was normal, which suggests that defects in other functions of the neurofibromin molecule may be important in the pathogenesis of NF1.
We propose that the symptoms leading to the diagnosis of NF1 in our patient could be attributed to mosaic hemizygosity for the NF1 gene in some of her somatic cells.