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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
Author(s) -
Nordin Angelica,
Larsson Elin,
Holmberg Monica
Publication year - 2012
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22002
Subject(s) - rna splicing , intron , biology , polypyrimidine tract , splice site mutation , exon , genetics , lactic acidosis , mutation , mutant , microbiology and biotechnology , rna binding protein , gene , rna , biochemistry
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. Hum Mutat 33:467–470, 2012. © 2011 Wiley Periodicals, Inc.