MUTATIONAL AND FUNCTIONAL-ANALYSIS OF THE NEUROFIBROMATOSIS TYPE-1 (NF1) GENE

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dom inant disorders. It is caused by mutations in the NF1 gene which compr ises 60 exons and is located on chromosome 17q. The NF1 gene product, neurofibromin, displays partial homology to GTPase-activating protein (GAP). The GAP-related domain (GRD), encoded by exons 20-27a, is the o nly region of neurofibromin to which a biological function has been as cribed. A total of 320 unrelated NF1 patients were screened for mutati ons in the GRD-encoding region of the NF1 gene. Sixteen different lesi ons in the NF1 GRD region were identified in a total of 20 patients. O f these lesions, 14 are novel and together comprise three missense, tw o nonsense and three splice site mutations plus six deletions of betwe en 1 and 4 bp. The effect of one of the missense mutations (R1391S) wa s studied by in vitro expression of a site-directed mutant and GAP act ivity assay. The mutant protein, R1391S, was found to be some 300-fold less active than wild-type NF1 GRD. The mutations reported in this st udy therefore provide further material for the functional analysis of neurofibromin as well as an insight into the mutational spectrum of th e NF1 GRD.