Characterization of NF1 allele containing two nonsense mutations in exon 37 that segregates with neurofibromatosis type 1

Abstract

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disease caused by mutations in the NF1 gene. The mutation rate of NF1 is one of the highest known for human genes and the mutational analysis has revealed a wide variety of changes, a significant proportion of which affect normal pre-mRNA splicing. Here, we describe two truncating mutations in exon 37 of NF1, the recurrent c.6792C>A and the novel c.6799C>T change, that occur in cis and segregate with NF1 in a large family. The double mutation induces defective splicing of exon 37 and thus, we performed quantitative comparisons of transcripts harboring single (c.6792C>G or c.6792C>A) and double (c.6792C>A and c.6799C>T) mutations to assess their effects on exon 37 splicing. Skipping of exon 37 was greater and there were fewer mutant full-length transcripts in samples with the double mutation than in those carrying single mutations. Thus, the combination of the c.6792C>A and c.6799C>T mutations augmented exon 37 skipping. These findings suggest that, in addition to the previously described exonic splicing enhancer in the c.6791_6795 region, c.6799 lies within an additional regulatory element that influences the splicing of exon 37.

Functional imaging of RAS pathway targeting in malignant peripheral nerve sheath tumor cells and xenografts

“…Two cell lines, sNF96.2 and 26T, had relatively high expression of MET ; this is interesting because high MET expression drives MPNST formation in a mouse model, 56 and evidence for MET activation has correlated with poorer survival in a retrospective analysis 57 . Missense, frame‐shift, or nonsense mutations with an alternative allele frequency of ∼0.5 or higher were found in NF1 in four of five MPNST lines (Supporting Information Figure Table S1); S462 and S462TY are derived from the same patient sample 58 with the same nonsense mutation SNV with a high allele frequency, 0.955 and 1, respectively, which has previously been identified as pathogenic 59,60 . Additional missense mutations present at lower frequency (∼0.1) were identified and predicted to be deleterious using the SIFT algorithm 61 (bolded SNVs, Table 1).…”

Case Report: A Synonymous Mutation in NF1 Located at the Non-canonical Splicing Site Leading to Exon 45 Skipping

“…NF1 is one of the most common genetic disease with multisystem abnormalities involving the changes in the skin, muscle, neuronal system and other tissues derived from embryonic neuronal crest (Ferner et al, 2007;Sabbagh et al, 2009;Hernández-Imaz et al, 2013;Monroe et al, 2017). Generally, NF1 presents a high degree of variability because approximately 50% of mutations in the NF1 gene were associated with splicing (Ars et al, 2000;Monroe et al, 2017).…”

“…Neurofibromatosis type I (NF1, MIM 162200) is an autosomal dominant disease caused by mutations in the NF1 gene (Stevenson and Viskochil, 2009), with the manifestations of cafe' au lait macules, neurofibromas, Lisch nodules and bony dysplasia (Ferner et al, 2007;Sabbagh et al, 2009;Hernández-Imaz et al, 2013;Monroe et al, 2017). Over 3,000 mutations were recorded in the Human Gene Mutation Database (HGMD), among which, 583 lead to abnormal splicing.…”

An unusual case of pediatric embryonal rhabdomyosarcoma with subsequent diagnosis of neurofibromatosis type 1

“…Despite neither parent having clinical features of neurofibromatosis type 1 (NF1), genetic testing for the patient was pursued. The patient was heterozygous for the pathogenic variant, c.6792C>A, (p.Tyr2264*), in the NF1 gene, supporting a clinical diagnosis of NF1 1 . Parental genetic testing will be completed.…”

“…The patient was heterozygous for the pathogenic variant, c.6792C>A, (p.Tyr2264*), in the NF1 gene, supporting a clinical diagnosis of NF1. 1 Parental genetic testing will be completed.…”