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Sci Rep. 2017 Sep 15;7(1):11717. doi: 10.1038/s41598-017-10343-9.

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

Author information

1
Division of Periodontology, Department of Oral Biological Science, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan. koichi@dent.niigata-u.ac.jp.
2
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. koichi@dent.niigata-u.ac.jp.
3
Division of Medical Genetics, Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
4
Division of Periodontology, Department of Oral Biological Science, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan.
5
Research Center for Advanced Oral Science, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
6
Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
7
Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRS, 13288, Marseille, France.
8
Division of Bio-Prosthodontics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
9
Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, United States of America.
10
Division of Neurogenetics, Center for Neurological Diseases and Cancer Nagoya University Graduate School of Medicine, Nagoya, Japan.
11
Laboratory of Periodontology and Immunology, Department of Oral Health and Welfare, Faculty of Dentistry, Niigata University, Niigata, Japan.
12
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
13
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. Bruce.Beutler@UTSouthwestern.edu.

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."

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