Human Genetics

, Volume 113, Issue 6, pp 551–554 | Cite as

NF1 exon 7 skipping and sequence alterations in exonic splice enhancers (ESEs) in a neurofibromatosis 1 patient

  • Patrizia Colapietro
  • Cristina Gervasini
  • Federica Natacci
  • Livia Rossi
  • Paola Riva
  • Lidia LarizzaEmail author
Short Report


The underestimates of NF1 gene mutations in neurofibromatosis 1 (NF1) have been attributed to the large size of the NF1 gene, the considerable frequency of gross deletions and the common occurrence of splicing defects that are only detectable by cDNA analysis. We here report on a patient with severe NF1 showing at RT-PCR analysis the expected fragment from exon 4b to 8 together with a shortened one with the in-frame skipping of exon 7. Sequencing of the corresponding genomic fragment revealed a G→A transition and a C→A transversion at nucleotide positions 57 and 58 of the 174-bp long exon 7, neither of which was present in the proband's parents or 50 healthy controls. No other variation was found in the entire NF1 coding sequence. The use of previously established sequence matrices for the scoring of putative ESE motifs showed that the adjacent silent and missense mutations are located within highly conserved overlapping stretches of seven nucleotides with a close similarity to the ESE-specific consensus sequences recognised by the SC35 and SF2/ASF SR proteins. The combined occurrence of both consecutive alterations decreases the motif score for both SF2/ASF and SC35 below their threshold levels. As the aberrant transcript is consistently expressed, a protein lacking 58 amino acids is predicted. Thus the contiguous internal exon 7 mutations are suggested to cause exon 7 skipping as a result of the mis-splicing caused by abrogation of functional ESEs.


Exonic Splice Enhancer Aberrant Transcript Exonic Splice Enhancer Motif Putative Exonic Splice Enhancer Occipitofrontal Head Circumference 
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We thank the family that participated in this study. This work was supported by a grant from Italian Ministry of Health on neurofibromatosis 1 and by a 2002 AIRC (Associazione Italiana per la Ricerca sul Cancro) grant (to L.L.) and a 2002 FIRST grant (to P.R).


  1. Ars E, Serra E, Garcia J, Kruyer H, Gaona A, Lazaro C, Estivill X (2000) Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1. Hum Mol Genet 9:237–247PubMedGoogle Scholar
  2. Cartegni L, Chew SL, Krainer AR (2002) Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev 3:285–298CrossRefPubMedGoogle Scholar
  3. Fahsold R, Hoffmeyer S, Mischung C, Gille C, Ehlers C, Kücükceylan N, Abdel-Nour M, Gewies A, Peters H, Kaufmann D, Buske A, Tinschert S, Nürmberg P (2000) Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet 66:790–818PubMedGoogle Scholar
  4. Fairbrother WG, Yeh RF, Sharp PA, Burge CB (2002) Predictive identification of exonic splicing enhancers in human genes. Science 297:1007–1013CrossRefPubMedGoogle Scholar
  5. Hoffmeyer S, Nürmberg P, Ritter H, Fahsold R, Leistner W, Kaufmann D, Krone W (1998) Nearby stop codons in exons of the neurofibromatosis type 1 gene are disparate splice effectors. Am J Hum Genet 62:269–277PubMedGoogle Scholar
  6. Liu H-X, Zhang M, Krainer AR (1998) Identification of functional exonic splicing enhancer motifs recognized by individual SR proteins. Genes Dev 12:1998–2012PubMedGoogle Scholar
  7. Liu H-X, Cartegni L, Zhang MQ, Krainer AR (2001) A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes. Nat Genet 27:55–58PubMedGoogle Scholar
  8. Messiaen L, Callens T, De Paepe A, Craen M, Mortier G (1997) Characterisation of two different nonsense mutations, C6792A and C6792G, causing skipping of exon 37 in the NF1 gene. Hum Genet 101:75–80PubMedGoogle Scholar
  9. Messiaen L, Callens T, Mortier G, Beyesn D, Vandenbroucke I, Van Roy N, Speleman F, De Paepe A (2000) Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mut 15:541–555PubMedGoogle Scholar
  10. Riva P, Corrado L, Natacci F, Castorina P, Wu BL, Schneider GH, Clementi M, Tenconi R, Korf BR, Larizza L (2000) NF1 microdeletion syndrome: refined FISH characterization of sporadic and familial deletions with locus-specific probes. Am J Hum Genet. 66:100–109Google Scholar
  11. Thomson SAM, Wallace MR (2002) RT-PCR splicing analysis of the NF1 open reading frame. Hum Genet 110:495–502CrossRefPubMedGoogle Scholar
  12. Upadhyaya M and Cooper DM (1998) The mutational spectrum in neurofibromatosis 1 and its underlying mechanisms. In: Upadhyaya M, Cooper M (eds) Neurofibromatosis type 1: from genotype to phenotype. BIOS Scientific, Oxford, pp 65–88Google Scholar
  13. Vandenbroucke I, Vandesompele J, De Paepe A, Messiaen L (2002) Quantification of NF1 transcripts reveals novel highly expressed splice variants. FEBS Lett 522:71–76CrossRefPubMedGoogle Scholar
  14. Wimmer K, Eckart M, Rehder H, Fonatsch C (2000) Illegitimate splicing of the NF1 gene in healthy individuals mimics mutation-induced splicing alterations in NF1 patients. Hum Genet 106:311–313PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Patrizia Colapietro
    • 1
  • Cristina Gervasini
    • 1
  • Federica Natacci
    • 2
  • Livia Rossi
    • 3
  • Paola Riva
    • 1
  • Lidia Larizza
    • 1
    Email author
  1. 1.Department of Biology and Genetics for Medical SciencesUniversity of MilanMilanItaly
  2. 2.Medical Genetics ServiceIstituti Clinici di PerfezionamentoMilanItaly
  3. 3.II Pediatrics DepartmentMilanItaly

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