Unusual splice site mutations disrupt FANCA exon 8 definition

Chiara Mattioli, Giulia Pianigiani, Daniela De Rocco, Anna Monica Rosaria Bianco, Enrico Cappelli, Anna Savoia, Franco Pagani

Research output: Contribution to journalArticlepeer-review


The pathological role of mutations that affect not conserved splicing regulatory sequences can be difficult to determine. In a patient with Fanconi anemia, we identified two unpredictable splicing mutations that act on either sides of FANCA exon 8. In patients-derived cells and in minigene splicing assay, we showed that both an apparently benign intronic c.710-5T>C transition and the nonsense c.790C>T substitution induce almost complete exon 8 skipping. Site-directed mutagenesis experiments indicated that the c.710-5T>C transition affects a polypyrimidine tract where most of the thymidines cannot be compensated by cytidines. The c.790C>T mutation located in position - 3 relative to the donor site induce exon 8 skipping in an NMD-independent manner and complementation experiments with modified U1 snRNAs showed that U1 snRNP is only partially involved in the splicing defect. Our results highlight the importance of performing splicing functional assay for correct identification of disease-causing mechanism of genomic variants and provide mechanistic insights on how these two FANCA mutations affect exon 8 definition.

Original languageEnglish
Pages (from-to)1052-1058
Number of pages7
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number7
Publication statusPublished - 2014


  • Fanconi anemia
  • Nonsense codon
  • Nonsense mediated mRNA decay
  • RNA splice sites
  • RNA splicing
  • U1 small nuclear ribonucleoprotein

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine


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