Human Molecular Genetics Advance Access published online on February 9, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi079
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1 Dipartimento di Biochimica "Alessandro Castellani", Università di Pavia, I-27100 Pavia, Italy
* To whom correspondence should be addressed. Mutations in the diastrophic dysplasia sulfate transporter (DTDST or SLC26A2) cause a family of recessively inherited chondrodysplasias that includes in order of decreasing severity achondrogenesis 1B, atelosteogenesis 2, diastrophic dysplasia 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 that 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 diastrophic dysplasia, 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 diastrophic dysplasia 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 diastrophic dysplasia makes this mouse strain a useful model to explore pathogenetic and therapeutic aspects of DTDST-related disorders.
Article
A diastrophic dysplasia sulfate transporter (SLC26A2) mutant mouse: morphological and biochemical characterization of the resulting chondrodysplasia phenotype
2 Centro Ricerca Sperimentale, Istituto Regina Elena, I-00100 Roma, Italy
3 Centro Ricerca Sperimentale, Istituto Regina Elena, I-00100 Roma, Italy.; EMBL, Monterotondo, Rome, Italy
4 Division of Molecular Pediatrics, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland
5 Dipartimento di Biochimica "Alessandro Castellani", Università di Pavia, Via Taramelli, 3/B, I-27100 Pavia, Italy
Antonio Rossi Dr., E-mail: antrossi{at}unipv.it
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