title: 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.
authors.affiliation: Laboratory of Laboratory Animal Science and Medicine, Co-Department of Veterinary Medicine, Faculty of Agriculture, Iwate University, 3-18-8 Ueda, Morioka, Iwate 020-8550, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kimura
authors.affiliation: Laboratory of Laboratory Animal Science and Medicine, Co-Department of Veterinary Medicine, Faculty of Agriculture, Iwate University, 3-18-8 Ueda, Morioka, Iwate 020-8550, Japan.
authors.forename: Satoki
authors.initials: S
authors.lastname: Ichimura
authors.affiliation: Technical Division, Iwate University, 3-18-8 Ueda, Morioka, Iwate 020-8550, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Sasaki
authors.affiliation: Technology and Development Unit for Knowledge Base of Mouse Phenotype, RIKEN Bioresource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Masuya
authors.affiliation: Technology and Development Team for Mouse Phenotype Analysis, Japan Mouse Clinic, RIKEN Bioresource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Technology and Development Team for Mouse Phenotype Analysis, Japan Mouse Clinic, RIKEN Bioresource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Wakana
authors.affiliation: Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
authors.affiliation: Laboratory of Laboratory Animal Science and Medicine, Co-Department of Veterinary Medicine, Faculty of Agriculture, Iwate University, 3-18-8 Ueda, Morioka, Iwate 020-8550, Japan. Electronic address: furuichi@iwate-u.ac.jp.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Furuichi
mesh_terms: D000818:Animals; D017209:Apoptosis; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D024043:Collagen Type II / Q000235:genetics*; D059865:Endoplasmic Reticulum Stress; D005260:Female; D006132:Growth Plate / Q000002:abnormalities / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D012863:Skeleton / Q000002:abnormalities; D013796:Thanatophoric Dysplasia / Q000235:genetics* / Q000473:pathology; D056811:Unfolded Protein Response
chemical_list: C499177:COL2A1 protein, human; D024043:Collagen Type II
keywords: Apoptosis; COL2A1; Chondrocyte; ER stress; PLSD-T