Multiple cryptic splice sites can be activated by IDS point mutations generating misspliced transcripts

Susanna Lualdi, Maria G. Pittis, Stefano Regis, Rossella Parini, Anna E. Allegri, Francesca Furlan, Bruno Bembi, Mirella Filocamo

Research output: Contribution to journalArticlepeer-review


Mutations in the gene encoding the enzyme iduronate-2-sulfatase (IDS) were reported as the cause of the X-linked recessive lysosomal disease, mucopolysaccharidosis II (MPS II). Amongst the different mutations, it emerges that nearly 10% are nucleotide substitutions causing splicing mutations. We now report the molecular characterisation of three MPS II patients with multiple aberrant transcripts due to three different point mutations. The c.418+1G>C that occurred in the invariant splice-site motif, produced only aberrantly spliced transcripts. Whilst the mutations affecting variant motifs (c.419G>T) or coding regions (c.245C>T) led to aberrantly spliced transcripts in addition to correctly spliced transcripts with the respective predicted missense mutation, p.G140V or p.A82V. A combination of experimental tests and computational approaches were used to understand the molecular basis underlying the altered transcription patterns. In addition, by using real-time reverse transcriptase polymerase chain reaction, the reduction of mRNA amount in two patients observed was likely due to nonsense-mediated mRNA decay pathway. Overall, our results further emphasised the importance of cloning and sequencing independent transcripts to reveal less abundant, aberrant products, which often could not be detected by direct sequencing. Moreover, the different splicing patterns observed in the three patients as a consequence of point mutations show how sensitive the balance is between constitutive and cryptic splice sites in the IDS gene. The generation of such diverse transcripts, together with their level of expression, could contribute to the profound phenotypic variability reported in MPS II.

Original languageEnglish
Pages (from-to)692-700
Number of pages9
JournalJournal of Molecular Medicine
Issue number8
Publication statusPublished - Aug 2006


  • Cryptic splice sites
  • mRNA decay
  • Multiple transcripts
  • Real-time RT-PCR
  • Splicing mutations

ASJC Scopus subject areas

  • Medicine(all)


Dive into the research topics of 'Multiple cryptic splice sites can be activated by IDS point mutations generating misspliced transcripts'. Together they form a unique fingerprint.

Cite this