RGD Reference Report - ENU-induced missense mutation in the C-propeptide coding region of Col2a1 creates a mouse model of platyspondylic lethal skeletal dysplasia, Torrance type. - Rat Genome Database

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ENU-induced missense mutation in the C-propeptide coding region of Col2a1 creates a mouse model of platyspondylic lethal skeletal dysplasia, Torrance type.

Authors: Furuichi, Tatsuya  Masuya, Hiroshi  Murakami, Tomohiko  Nishida, Keiichiro  Nishimura, Gen  Suzuki, Tomohiro  Imaizumi, Kazunori  Kudo, Takashi  Ohkawa, Kiyoshi  Wakana, Shigeharu  Ikegawa, Shiro 
Citation: Furuichi T, etal., Mamm Genome. 2011 Jun;22(5-6):318-28. doi: 10.1007/s00335-011-9329-3. Epub 2011 May 3.
RGD ID: 11667102
Pubmed: PMID:21538020   (View Abstract at PubMed)
DOI: DOI:10.1007/s00335-011-9329-3   (Journal Full-text)

The COL2A1 gene encodes the α1(II) chain of the homotrimeric type II collagen, the most abundant protein in cartilage. In humans, COL2A1 mutations create many clinical phenotypes collectively termed type II collagenopathies; however, the genetic basis of the phenotypic diversity is not well elucidated. Therefore, animal models corresponding to multiple type II collagenopathies are required. In this study we identified a novel Col2a1 missense mutation--c.44406A>C (p.D1469A)--produced by large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis in a mouse line. This mutation was located in the C-propeptide coding region of Col2a1 and in the positions corresponding to a human COL2A1 mutation responsible for platyspondylic lethal skeletal dysplasia, Torrance type (PLSD-T). The phenotype was inherited as a semidominant trait. The heterozygotes were mildly but significantly smaller than wild-type mice. The homozygotes exhibited lethal skeletal dysplasias, including extremely short limbs, severe spondylar dysplasia, severe pelvic hypoplasia, and brachydactyly. As expected, these skeletal defects in the homozygotes were similar to those in PLSD-T patients. The secretion of the mutant proteins into the extracellular space was disrupted, accompanied by abnormally expanded rough endoplasmic reticulum (ER) and upregulation of ER stress-related genes, such as Grp94 and Chop, in chondrocytes. These findings suggested that the accumulation of mutant type II collagen in the ER and subsequent induction of ER stress are involved, at least in part in the PLSD-T-like phenotypes of the mutants. This mutant should serve as a good model for studying PLSD-T pathogenesis and the mechanisms that create the great diversity of type II collagenopathies.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Torrance type platyspondylic dysplasia  ISOCol2a1 (Mus musculus)11667102; 11667102DNA:mutation:cds:c.44406A>C (p.D1469A)(mouse)RGD 
Torrance type platyspondylic dysplasia  IMP 11667102DNA:mutation:cds:c.44406A>C (p.D1469A)(mouse)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Col2a1  (collagen type II alpha 1 chain)

Genes (Mus musculus)
Col2a1  (collagen, type II, alpha 1)

Genes (Homo sapiens)
COL2A1  (collagen type II alpha 1 chain)


Additional Information