An ENU-induced splice site mutation of mouse Col1a1 causing recessive osteogenesis imperfecta and revealing a novel splicing rescue

Koichi Tabeta, Xin Du, Kei Arimatsu, Mai Yokoji, Naoki Takahashi, Norio Amizuka, Tomoka Hasegawa, Karine Crozat, Tomoki Maekawa, Sayuri Miyauchi, Yumi Matsuda, Takako Ida, Masaru Kaku, Kasper Hoebe, Kinji Ohno, Hiromasa Yoshie, Kazuhisa Yamazaki, Eva Marie Y. Moresco, Bruce Beutler

Research output: Contribution to journalArticle

Abstract

GU-AG consensus sequences are used for intron recognition in the majority of cases of pre-mRNA splicing in eukaryotes. Mutations at splice junctions often cause exon skipping, short deletions, or insertions in the mature mRNA, underlying one common molecular mechanism of genetic diseases. Using N-ethyl-N-nitrosourea, a novel recessive mutation named seal was produced, associated with fragile bones and susceptibility to fractures (spine and limbs). A single nucleotide transversion (T → A) at the second position of intron 36 of the Col1a1 gene, encoding the type I collagen, α1 chain, was responsible for the phenotype. Col1a1 seal mRNA expression occurred at greatly reduced levels compared to the wild-type transcript, resulting in reduced and aberrant collagen fibers in tibiae of seal homozygous mice. Unexpectedly, splicing of Col1a1 seal mRNA followed the normal pattern despite the presence of the donor splice site mutation, likely due to the action of a putative intronic splicing enhancer present in intron 25, which appeared to function redundantly with the splice donor site of intron 36. Seal mice represent a model of human osteogenesis imperfecta, and reveal a previously unknown mechanism for splicing "rescue.".

Original languageEnglish (US)
Article number11717
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'An ENU-induced splice site mutation of mouse Col1a1 causing recessive osteogenesis imperfecta and revealing a novel splicing rescue'. Together they form a unique fingerprint.

  • Cite this

    Tabeta, K., Du, X., Arimatsu, K., Yokoji, M., Takahashi, N., Amizuka, N., Hasegawa, T., Crozat, K., Maekawa, T., Miyauchi, S., Matsuda, Y., Ida, T., Kaku, M., Hoebe, K., Ohno, K., Yoshie, H., Yamazaki, K., Moresco, E. M. Y., & Beutler, B. (2017). An ENU-induced splice site mutation of mouse Col1a1 causing recessive osteogenesis imperfecta and revealing a novel splicing rescue. Scientific reports, 7(1), [11717]. https://doi.org/10.1038/s41598-017-10343-9