Human Molecular Genetics, Vol 7, 1261-1268, Copyright © 1998 by Oxford University Press
A Klose, MR Ahmadian, M Schuelke, K Scheffzek, S Hoffmeyer, A Gewies, F Schmitz, D Kaufmann, H Peters, A Wittinghofer and P Nurnberg
Neurofibromatosis type 1 (NF1) is a common familial tumour syndrome with
multiple clinical features such as neurofibromas, cafe-au-lait spots (CLS),
iris Lisch nodules, axillary freckling, optic glioma, specific bone lesions
and an increased risk of malignant tumours. It is caused by a wide spectrum
of mutations affecting the NF1 gene. Most mutations result in the loss of
one allele at the DNA, mRNA or protein level and thus in the loss of any
function of the gene product neurofibromin. The idea of the simultaneous
loss of several different neurofibromin functions has been postulated to
explain the pleiotropic effects of its loss. However, we have identified a
novel missense mutation in a family with a classical multi-symptomatic NF1
phenotype, including a malignant schwannoma, that specifically abolishes
the Ras- GTPase-activating function of neurofibromin. In this family,
Arg1276 had mutated into proline. Based on complex biochemical studies as
well as the analysis of the crystal structure of the GTPase-activating
protein (GAP) domain of p120GAP in the presence of Ras, we unequivocally
identified this amino acid as the arginine finger of the neurofibromin
GAP-related domain (GRD)-the most essential catalytic element for RasGAP
activity. Here, we present data demonstrating that the mutation R1276P,
unlike previously reported missense mutations of the GRD region, does not
impair the secondary and tertiary protein structure. It neither reduces the
level of cellular neurofibromin nor influences its binding to Ras
substantially, but it does completely disable GAP activity. Our findings
provide direct evidence that failure of neurofibromin GAP activity is the
critical element of NF1 pathogenesis. Thus, therapeutic approaches aimed at
the reduction of Ras.GTP levels in neural crest-derived cells can be
expected to relieve most of the NF1 symptoms.
ARTICLES
Selective disactivation of neurofibromin GAP activity in neurofibromatosis type 1
Institut fur Medizinische Genetik, Universitatsklinikum Charite- Medizinische Fakultat der Humboldt-Universitat zu Berlin, Campus Charite Mitte, D-10098 Berlin, Germany.
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