title: NF1 mutation rather than individual genetic variability is the main determinant of the NF1-transcriptional profile of mutations affecting splicing.
abstract: A significant number of neurofibromatosis type 1 (NF1) mutations result in exon skipping. The majority of these mutations do not occur in the canonical splice sites and can produce different aberrant transcripts whose proportions have not been well studied. It has been hypothesized that differences in the mutation-determined NF1-transcriptional profile could partially explain disease variability among patients bearing the same NF1 splice defect. In order to gain insight into these aspects, we analyzed the proportion of the different transcripts generated by nine NF1-splicing mutations in 30 patients. We assessed the influence of the mutation in the NF1-related transcriptional profiles and investigated the existence of individual differences in a global manner. We analyzed potential differences in tissue-specific transcriptional profiles and evaluated the influence of sample processing and mRNA nonsense-mediated decay (NMD). Small transcriptional differences were found in neurofibromas and neurofibroma-derived Schwann cells (SC) compared to blood. We also detected a higher cell culture-dependent NMD. We observed that mutation per se explains 93.5% of the profile variability among mutations studied. However, despite the importance of mutation in determining the proportion of NF1 transcripts generated, we found certain variability among patients with the same mutation. From our results, it seems that genetic factors influencing RNA processing play a minor role in determining the NF1-transcriptional profile. Nevertheless neurofibromin studies would clarify whether these small differences translate into significant functional changes that could explain the great clinical expressivity observed in the disease or any of the disease-related traits.
authors.affiliation: Centre de Genètica Mèdica i Molecular-Institut de Recerca Oncològica--Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Pros
authors.forename: Sara
authors.initials: S
authors.lastname: Larriba
authors.forename: Eva
authors.initials: E
authors.lastname: López
authors.forename: Anna
authors.initials: A
authors.lastname: Ravella
authors.forename: M Lluïsa
authors.initials: ML
authors.lastname: Gili
authors.forename: Helena
authors.initials: H
authors.lastname: Kruyer
authors.forename: Joan
authors.initials: J
authors.lastname: Valls
authors.forename: Eduard
authors.initials: E
authors.lastname: Serra
authors.forename: Conxi
authors.initials: C
authors.lastname: Lázaro
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D002478:Cells, Cultured; D016000:Cluster Analysis; D018389:Codon, Nonsense / Q000032:analysis; D004252:DNA Mutational Analysis; D005347:Fibroblasts / Q000473:pathology; D020869:Gene Expression Profiling; D005820:Genetic Testing / Q000379:methods; D014644:Genetic Variation; D006801:Humans; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000473:pathology; D025542:Neurofibromin 1 / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D018807:Polymorphism, Single-Stranded Conformational; D022821:RNA Splice Sites / Q000235:genetics; D020871:RNA Stability / Q000235:genetics; D013048:Specimen Handling; D014018:Tissue Distribution; D014158:Transcription, Genetic
chemical_list: D018389:Codon, Nonsense; D050505:Mutant Proteins; D025542:Neurofibromin 1; D022821:RNA Splice Sites