TY - JOUR
T1 - The diastrophic dysplasia gene encodes a novel sulfate transporter
T2 - Positional cloning by fine-structure linkage disequilibrium mapping
AU - Hästbacka, Johanna
AU - de la Chapelle, Albert
AU - Mahtani, Melanie M.
AU - Clines, Greg
AU - Reeve-Daly, Mary Pat
AU - Daly, Mark
AU - Hamilton, Bruce A.
AU - Kusumi, Kenro
AU - Trivedi, Bijal
AU - Weaver, Alix
AU - Coloma, Antonio
AU - Lovett, Michael
AU - Buckler, Alan
AU - Kaitila, Ilkka
AU - Lander, Eric S.
N1 - Funding Information:
We thank Tau Mu Yi for help in analyzing the transmembrane structure of the DTDST protein; Julie Segre, Jennifer Nemhauser, and Armand MacMurray for assistance; Tomi MBkelB, Claude Sardet, and Arthur Lander for many helpful conversations and much advice; Teresa Costa, Clair Francomano, Pierre Maroteaux, Martine Le Merrer, Ben Hamel, Peter Beighton, Michael Patton, Charles Scott, J. van Tintelen, Bernhard Zabel, and Hester Kroesfor sharing patient samples; Claude Sardet for sharing his cDNA library; David Schlessinger, PatriciaTail-Ion-Miller, and Juha Kere for sharing YACs; Charles Sherr, Mark Roberts, and Thomas Look for sharing maps and cosmid clones from the CSVR-PDGFRB region; Annie Hampe for sharing tinpublished sequence from the region beyond the Blend of CSFlR; and Carl-Henrik Heldin and Lena Claesson-Welsh for studies on the function of PDGFRB in cells from DTD patients. We are also very grateful to the many DTD patients and families who participated in this study. This work was supported in part by grants from the National Institutes of Health (HG00098 to E. S. L., AR41970 to A. d. I. C. and HGO0882 to M. L.), the Markey Foundation (to E. S. L.) and the Academy of Finland and the Juselius Foundation (to A. d. I. C.). J. H. is the recipient of a Sigrid Juselius postdoctoral fellowship. M. M. M. is the recipient of a postdoctoral fellowship from the Canadian Medical Research Council. B. A. H. is the recipient of a postdoctoral fellowship from the Helen Hay Whitney Foundation. A. C. was supported by fellowship from the Direction General de la lnvestigacion Cientifica y Tecnica, Spain.
PY - 1994/9/23
Y1 - 1994/9/23
N2 - Diastrophic dysplasia (DTD) is a well-characterized autosomal recessive osteochondrodysplasia with clinical features including dwarfism, spinal deformation, and specific joint abnormalities. The disease occurs in most populations, but is particularly prevalent in Finland owing to an apparent founder effect. DTD maps to distal chromosome 5q and, based on linkage disequilibrium studies in the Finnish population, we had previously predicted that the DTD gene should lie about 64 kb away from the CSF1R locus. Here, we report the positional cloning of the DTD gene by fine-structure linkage disequilibrium mapping. The gene lies in the predicted location, approximately 70 kb proximal to CSF1R, and encodes a novel sulfate transporter. Impaired function of its product is likely to lead to undersulfation of proteoglycans in cartilage matrix and thereby to cause the clinical phenotype of the disease. These results demonstrate the power of linkage disequilibrium mapping in isolated populations for positional cloning.
AB - Diastrophic dysplasia (DTD) is a well-characterized autosomal recessive osteochondrodysplasia with clinical features including dwarfism, spinal deformation, and specific joint abnormalities. The disease occurs in most populations, but is particularly prevalent in Finland owing to an apparent founder effect. DTD maps to distal chromosome 5q and, based on linkage disequilibrium studies in the Finnish population, we had previously predicted that the DTD gene should lie about 64 kb away from the CSF1R locus. Here, we report the positional cloning of the DTD gene by fine-structure linkage disequilibrium mapping. The gene lies in the predicted location, approximately 70 kb proximal to CSF1R, and encodes a novel sulfate transporter. Impaired function of its product is likely to lead to undersulfation of proteoglycans in cartilage matrix and thereby to cause the clinical phenotype of the disease. These results demonstrate the power of linkage disequilibrium mapping in isolated populations for positional cloning.
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U2 - 10.1016/0092-8674(94)90281-X
DO - 10.1016/0092-8674(94)90281-X
M3 - Article
C2 - 7923357
AN - SCOPUS:0027978110
SN - 0092-8674
VL - 78
SP - 1073
EP - 1087
JO - Cell
JF - Cell
IS - 6
ER -