The defective splicing caused by the ISCU intron mutation in patients with myopathy with lactic acidosis is repressed by PTBP1 but can be derepressed by IGF2BP1

Hum Mutat. 2012 Mar;33(3):467-70. doi: 10.1002/humu.22002. Epub 2011 Dec 29.


Hereditary myopathy with lactic acidosis (HML) is caused by an intron mutation in the iron-sulfur cluster assembly gene ISCU, which leads to the activation of cryptic splice sites and the retention of part of intron 4. This incorrect splicing is more pronounced in muscle than in other tissues, resulting in a muscle-specific phenotype. In this study, we identified five nuclear factors that interact with the sequence harboring the mutation and analyzed their effect on the splicing of the ISCU gene. The identification revealed three splicing factors, SFRS14, RBM39, and PTBP1, and two additional RNA binding factors, matrin 3 (MATR3) and IGF2BP1. IGF2BP1 showed a preference for the mutant sequence, whereas the other factors showed similar affinity for both sequences. PTBP1 was found to repress the defective splicing of ISCU, resulting in a drastic loss of mutant transcripts. In contrast, IGF2BP1 and RBM39 shifted the splicing ratio toward the incorrect splice form.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acidosis, Lactic / genetics*
  • Alternative Splicing / genetics
  • Heterogeneous-Nuclear Ribonucleoproteins / genetics
  • Heterogeneous-Nuclear Ribonucleoproteins / metabolism
  • Humans
  • Introns / genetics*
  • Iron-Sulfur Proteins / genetics*
  • Muscular Diseases / genetics*
  • Mutation
  • Nuclear Matrix-Associated Proteins / genetics
  • Nuclear Matrix-Associated Proteins / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Polypyrimidine Tract-Binding Protein / genetics
  • Polypyrimidine Tract-Binding Protein / metabolism
  • Protein Binding
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Serine-Arginine Splicing Factors


  • Heterogeneous-Nuclear Ribonucleoproteins
  • ISCU protein, human
  • Iron-Sulfur Proteins
  • MATR3 protein, human
  • Nuclear Matrix-Associated Proteins
  • Nuclear Proteins
  • PTBP1 protein, human
  • RNA-Binding Proteins
  • Polypyrimidine Tract-Binding Protein
  • Serine-Arginine Splicing Factors