TY - JOUR
T1 - An ENU-induced splice site mutation of mouse Col1a1 causing recessive osteogenesis imperfecta and revealing a novel splicing rescue
AU - Tabeta, Koichi
AU - Du, Xin
AU - Arimatsu, Kei
AU - Yokoji, Mai
AU - Takahashi, Naoki
AU - Amizuka, Norio
AU - Hasegawa, Tomoka
AU - Crozat, Karine
AU - Maekawa, Tomoki
AU - Miyauchi, Sayuri
AU - Matsuda, Yumi
AU - Ida, Takako
AU - Kaku, Masaru
AU - Hoebe, Kasper
AU - Ohno, Kinji
AU - Yoshie, Hiromasa
AU - Yamazaki, Kazuhisa
AU - Moresco, Eva Marie Y.
AU - Beutler, Bruce
N1 - Funding Information:
This work was supported by NIH grant AI 054523 to BB; Grant for promotion of Niigata University Research Projects and JSPS grant KAKENHI 23390476 to KT; JSPS grant KAKENHI 19390536 to KY; and JSPS grants KAKENHI 26293407, 15K15704 to MK.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.".
AB - 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.".
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U2 - 10.1038/s41598-017-10343-9
DO - 10.1038/s41598-017-10343-9
M3 - Article
C2 - 28916811
AN - SCOPUS:85029508637
SN - 2045-2322
VL - 7
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 11717
ER -