Dominant negative mutations in the C-propeptide of COL2A1 cause platyspondylic lethal skeletal dysplasia, torrance type, and define a novel subfamily within the type 2 collagenopathies

Details

Serval ID
serval:BIB_74DCE3145009
Type
Article: article from journal or magazin.
Publication sub-type
Case report (case report): feedback on an observation with a short commentary.
Collection
Publications
Institution
Title
Dominant negative mutations in the C-propeptide of COL2A1 cause platyspondylic lethal skeletal dysplasia, torrance type, and define a novel subfamily within the type 2 collagenopathies
Journal
American Journal of Medical Genetics. Part A
Author(s)
Zankl  A., Neumann  L., Ignatius  J., Nikkels  P., Schrander-Stumpel  C., Mortier  G., Omran  H., Wright  M., Hilbert  K., Bonafe  L., Spranger  J., Zabel  B., Superti-Furga  A.
ISSN
1552-4825
Publication state
Published
Issued date
02/2005
Peer-reviewed
Oui
Volume
133
Number
1
Pages
61-7
Notes
Case Reports
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Feb 15
Abstract
Platyspondylic lethal skeletal dysplasia (PLSD) Torrance type (PLSD-T) is a rare skeletal dysplasia characterized by platyspondyly, brachydactyly, and metaphyseal changes. Generally a perinatally lethal disease, a few long-term survivors have been reported. Recently, mutations in the carboxy-propeptide of type II collagen have been identified in two patients with PLSD-T, indicating that PLSD-T is a type 2 collagen-associated disorder. We studied eight additional cases of PLSD-T and found that all had mutations in the C-propeptide domain of COL2A1. The mutational spectrum includes missense, stop codon and frameshift mutations. All non-sense mutations were located in the last exon, where they would escape non-sense-mediated RNA-decay. We conclude that PLSD-T is caused by mutations in the C-propeptide domain of COL2A1, which lead to biosynthesis of an altered collagen chain (as opposed to a null allele). Similar mutations have recently been found to be the cause of spondyloperipheral dysplasia, a non-lethal dominant disorder whose clinical and radiographical features overlap those of the rare long-term survivors with PLSD-T. Thus, spondyloperipheral dysplasia and PLSD-T constitute a novel subfamily within the type II collagenopathies, associated with specific mutations in the C-propeptide domain and characterized by distinctive radiological features including metaphyseal changes and brachydactyly that set them apart from other type 2 collagenopathies associated with mutations in the triple-helical domain of COL2A1. The specific phenotype of C-propeptide mutations could result from a combination of diminished collagen fibril formation, toxic effects through the accumulation of unfolded collagen chains inside the chondrocytes, and alteration of a putative signaling function of the carboxy-propeptide of type 2 collagen.
Keywords
Child, Preschool Collagen Type II/*genetics Fatal Outcome Female Fetal Death Follow-Up Studies Foot Deformities, Congenital/pathology Hand Deformities, Congenital/pathology Humans Infant Infant, Newborn Male *Musculoskeletal Abnormalities *Mutation Osteochondrodysplasias/*genetics/pathology Phenotype
Pubmed
Web of science
Create date
21/01/2008 12:50
Last modification date
20/08/2019 14:32
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