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Endoplasmic reticulum stress-mediated apoptosis contributes to a skeletal dysplasia resembling platyspondylic lethal skeletal dysplasia, Torrance type, in a novel Col2a1 mutant mouse line.

Abstract
In humans, mutations in the COL2A1 gene encoding the α1(II) chain of type II collagen, create many clinical phenotypes collectively termed type II collagenopathies. However, the mechanisms generating this diversity remain to be determined. Here we identified a novel Col2a1 mutant mouse line by screening a large-scale N-ethyl-N-nitrosourea mutant mouse library. This mutant possessed a p.Tyr1391Ser missense mutation in the C-propeptide coding region, and this mutation was located in positions corresponding to the human COL2A1 mutation responsible for platyspondylic lethal skeletal dysplasia, Torrance type (PLSD-T). As expected, p.Tyr1391Ser homozygotes exhibited lethal skeletal dysplasias resembling PLSD-T, including extremely short limbs and severe dysplasia of the spine and pelvis. The secretion of the mutant proteins into the extracellular space was disrupted, accompanied by an abnormally expanded endoplasmic reticulum (ER) and the up-regulation of ER stress-related genes in chondrocytes. Chondrocyte apoptosis was severely induced in the growth plate of the homozygotes. These findings strongly suggest that ER stress-mediated apoptosis caused by the accumulated mutant proteins in ER contributes to skeletal dysplasia in Co12a1 mutant mice and PLSD-T patients.
AuthorsMakoto Kimura, Satoki Ichimura, Kuniaki Sasaki, Hiroshi Masuya, Tomohiro Suzuki, Shigeharu Wakana, Shiro Ikegawa, Tatsuya Furuichi
JournalBiochemical and biophysical research communications (Biochem Biophys Res Commun) 2015 Dec 4-11 Vol. 468 Issue 1-2 Pg. 86-91 ISSN: 1090-2104 [Electronic] United States
PMID26545783 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier Inc. All rights reserved.
Chemical References
  • COL2A1 protein, human
  • Collagen Type II
Topics
  • Animals
  • Apoptosis
  • Chondrocytes (metabolism, pathology)
  • Collagen Type II (genetics)
  • Endoplasmic Reticulum Stress
  • Female
  • Growth Plate (abnormalities, pathology)
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation, Missense
  • Skeleton (abnormalities)
  • Thanatophoric Dysplasia (genetics, pathology)
  • Unfolded Protein Response

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