Human Molecular Genetics Advance Access originally published online on February 9, 2005
Human Molecular Genetics 2005 14(6):859-871; doi:10.1093/hmg/ddi079
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A diastrophic dysplasia sulfate transporter (SLC26A2) mutant mouse: morphological and biochemical characterization of the resulting chondrodysplasia phenotype
1Dipartimento di Biochimica ‘Alessandro Castellani’, Università di Pavia, I-27100 Pavia, Italy, 2Centro Ricerca Sperimentale, Istituto Regina Elena, I-00100 Roma, Italy and 3Division of Molecular Pediatrics, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland
* To whom correspondence should be addressed at: Dipartimento di Biochimica ‘Alessandro Castellani’, Via Taramelli, 3/B, I-27100 Pavia, Italy. Tel: +39 382987229; Fax: +39 382423108; Email: antrossi{at}unipv.it
Received August 3, 2004; Revised January 18, 2005; Accepted February 1, 2005
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.
Present address: EMBL, Monterotondo, Rome, Italy.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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