Mutations affecting mRNA splicing are the most common molecular defects inpatients with neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is one of the most common inherited disorder s in humans and is caused by mutations in the NFI gene. To date, the majori ty of the reported NFI mutations are predicted to result in protein truncat ion, but very few studies have correlated the causative NFI mutation with i ts effect at the mRNA level. We have applied a whole NFI cDNA screening met hodology to the study of 80 unrelated NF1 patients and have identified 44 d ifferent mutations, 32 being novel, in 52 of these patients. Mutations were detected in 87% of the familial cases, but in 51% of the sporadic ones, At least 15 of the 80 NF1 patients (19%) had recurrent mutations. The study s hows that in 50% of the patients in whom the mutations were identified, the se resulted in splicing alterations. Most of the splicing mutations did not involve the conserved AG/GT dinucleotides of the splice sites. One framesh ift, two nonsense and two missense mutations were also responsible for alte rations in mRNA splicing. The location and type of mutation within the NFI gene, and its putative effect at the protein level, do not indicate any rel ationship to any specific clinical feature of NF1, The high proportion of a berrant spliced transcripts detected in NF1 patients stresses the importanc e of studying mutations at both the genomic and RNA level, It is possible t hat part of the clinical variability in NF1 could be due to mutations affec ting mRNA splicing, which is the most common molecular defect in NF1.