Titre
A diastrophic dysplasia sulfate transporter (SLC26A2) mutant mouse: morphological and biochemical characterization of the resulting chondrodysplasia phenotype.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Forlino, A.
Auteure/Auteur
Piazza, R.
Auteure/Auteur
Tiveron, C.
Auteure/Auteur
Della Torre, S.
Auteure/Auteur
Tatangelo, L.
Auteure/Auteur
Bonafè, L.
Auteure/Auteur
Gualeni, B.
Auteure/Auteur
Romano, A.
Auteure/Auteur
Pecora, F.
Auteure/Auteur
Superti-Furga, A.
Auteure/Auteur
Cetta, G.
Auteure/Auteur
Rossi, A.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
0964-6906[print], 0964-6906[linking]
Statut éditorial
Publié
Date de publication
2005-03
Volume
14
Numéro
6
Première page
859
Dernière page/numéro d’article
871
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
Mutations in the diastrophic dysplasia sulfate transporter (DTDST or SLC26A2) cause a family of recessively inherited chondrodysplasias including, in order of decreasing severity, achondrogenesis 1B, atelosteogenesis 2, diastrophic dysplasia (DTD) and recessive multiple epiphyseal dysplasia. The gene encodes a widely distributed sulfate/chloride antiporter of the cell membrane whose function is crucial for the uptake of inorganic sulfate, which is needed for proteoglycan sulfation. To provide new insights in the pathogenetic mechanisms leading to skeletal and connective tissue dysplasia and to obtain an in vivo model for therapeutic approaches to DTD, we generated a Dtdst knock-in mouse with a partial loss of function of the sulfate transporter. In addition, the intronic neomycine cassette in the mutant allele contributed to the hypomorphic phenotype by inducing abnormal splicing. Homozygous mutant mice were characterized by growth retardation, skeletal dysplasia and joint contractures, thereby recapitulating essential aspects of the DTD phenotype in man. The skeletal phenotype included reduced toluidine blue staining of cartilage, chondrocytes of irregular size, delay in the formation of the secondary ossification center and osteoporosis of long bones. Impaired sulfate uptake was demonstrated in chondrocytes, osteoblasts and fibroblasts. In spite of the generalized nature of the sulfate uptake defect, significant proteoglycan undersulfation was detected only in cartilage. Chondrocyte proliferation and apoptosis studies suggested that reduced proliferation and/or lack of terminal chondrocyte differentiation might contribute to reduced bone growth. The similarity with human DTD makes this mouse strain a useful model to explore pathogenetic and therapeutic aspects of DTDST-related disorders.
PID Serval
serval:BIB_686F0B905551
PMID
Open Access
Oui
Date de création
2008-01-21T11:50:45.588Z
Date de création dans IRIS
2025-05-20T17:07:18Z
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Nom
REF.pdf
Version du manuscrit
published
Taille
593.55 KB
Format
Adobe PDF
PID Serval
serval:BIB_686F0B905551.P001
URN
urn:nbn:ch:serval-BIB_686F0B9055511
Somme de contrôle
(MD5):0e47a79a1b5fe5e1a841527a6408fa50