title: A diastrophic dysplasia sulfate transporter (SLC26A2) mutant mouse: morphological and biochemical characterization of the resulting chondrodysplasia phenotype.
abstract: 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.
authors.affiliation: Dipartimento di Biochimica Alessandro Castellani, Università di Pavia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Forlino
authors.forename: Rocco
authors.initials: R
authors.lastname: Piazza
authors.forename: Cecilia
authors.initials: C
authors.lastname: Tiveron
authors.forename: Sara
authors.initials: S
authors.lastname: Della Torre
authors.forename: Laura
authors.initials: L
authors.lastname: Tatangelo
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonafè
authors.forename: Benedetta
authors.initials: B
authors.lastname: Gualeni
authors.forename: Assunta
authors.initials: A
authors.lastname: Romano
authors.forename: Fabio
authors.initials: F
authors.lastname: Pecora
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cetta
authors.forename: Antonio
authors.initials: A
authors.lastname: Rossi
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D026901:Membrane Transport Proteins; D051379:Mice; D008822:Mice, Transgenic; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D000076988:Sulfate Transporters
chemical_list: D027321:Anion Transport Proteins; D002352:Carrier Proteins; D026901:Membrane Transport Proteins; C089651:SLC26A2 protein, human; C513264:Slc26a2 protein, mouse; D000076988:Sulfate Transporters