Spondyloperipheral dysplasia is caused by truncating mutations in the C-propeptide of COL2A1.

Details

Serval ID
serval:BIB_1F3764ED6581
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
Spondyloperipheral dysplasia is caused by truncating mutations in the C-propeptide of COL2A1.
Journal
American Journal of Medical Genetics. Part A
Author(s)
Zankl A., Zabel B., Hilbert K., Wildhardt G., Cuenot S., Xavier B., Ha-Vinh R., Bonafé L., Spranger J., Superti-Furga A.
ISSN
1552-4825
Publication state
Published
Issued date
08/2004
Peer-reviewed
Oui
Volume
129A
Number
2
Pages
144-148
Language
english
Notes
Publication types: Case Reports ; Journal Article
Abstract
The term "spondyloperipheral dysplasia" (SPD) has been applied to the unusual combination of platyspondyly and brachydactyly as observed in a small number of individuals. The reported cases show wide clinical variability and the nosologic status and spectrum of this condition are still ill defined. Zabel et al. [1996: Am J Med Genet 63(1):123-128] reported an individual with short stature and SPD who was heterozygous for a frameshift mutation in the C-propeptide domain of COL2A1. To explain the additional finding of brachydactyly that is not an usual feature of the type II collagenopathies, it was postulated that the nature of the mutation induced precocious calcification and premature fusion of metacarpal and phalangeal growth plates. The C-propeptide of collagen II had previously been found to promote calcification ("chondrocalcin"). We have ascertained two further individuals with clinical and radiological findings of a type II collagenopathy in infancy who developed brachydactyly type E like changes of fingers and toes in childhood. In both individuals, heterozygosity for novel, distinct mutations in the C-propeptide coding region of COL2A1 were found. Although all three mutations (the one previously reported and the two novel ones) predict premature termination, their location close to the 3'-end of the mRNA probably protects them from nonsense-mediated decay and allows for synthesis of mutant procollagen chains. However, loss of crucial cysteine residues or other sequences essential for trimerization prevents these chains from associating and participating in procollagen helix formation, and thus leads to accumulation in the ER-consistent with EM findings. The mechanism leading to precocious fusion of phalangeal epiphyses remains to be explored. The consistency of clinical, radiographic, and molecular findings in these three unrelated individuals confirms SPD as a distinct nosologic entity. The diagnosis of SPD is suggested by the appearance of brachydactyly in a child who has clinical and radiographic features of a collagen II disorder.
Keywords
Calcium-Binding Proteins/genetics, Collagen/genetics, Collagen Type II/genetics, DNA Primers, Endoplasmic Reticulum/metabolism, Female, Fingers/pathology, Fingers/radiography, Frameshift Mutation/genetics, Growth Plate/pathology, Heterozygote, Humans, Infant, Newborn, Male, Osteochondrodysplasias/genetics, Osteochondrodysplasias/pathology, Polymerase Chain Reaction, Procollagen/metabolism, Sequence Analysis, DNA, Toes/pathology, Toes/radiography
Pubmed
Web of science
Create date
21/01/2008 13:50
Last modification date
20/08/2019 13:55
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