2 NF1 MUTATIONS - FRAMESHIFT IN THE GAP-RELATED DOMAIN, AND LOSS OF 2CODONS TOWARD THE 3' END OF THE GENE

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dom inant disorders, and is due to mutations within the NF1 gene on chromo some 17q11.2. Only the middle 400 amino acids of the associated protei n (neurofibromin) have a known function, comprising a GTPase-activatin g-protein (GAP) domain. The large gene size and the fact that approxim ately half of cases are due to new mutation render mutation analysis d ifficult. NF1 direct mutation characterization is important for develo pment of DNA diagnostic procedures, analysis of phenotype/genotype cor relations, and delineation of functions for specific domains of neurof ibromin. We report two mutations detected using PCR amplification of i ndividual exons followed by heteroduplex analysis. One is a single bas e deletion in exon 24 which is predicted to result in a protein trunca ted early in the GAP-related domain. The other is a 6-bp deletion in e xon 39 which is predicted to result in loss of two amino acids in the mature protein near the carboxy-terminus. The exon 24 mutant allele wa s shown to be expressed by RNA PCR analysis. The exon 39 mutation sugg ests that those two amino acids are important in neurofibromin functio n, perhaps indicating a functional domain. (C) 1994 Wiley-Liss, Inc.