TY - JOUR
T1 - Loss of Dermatan-4-Sulfotransferase 1 Function Results in Adducted Thumb-Clubfoot Syndrome
AU - Dündar, Munis
AU - Müller, Thomas
AU - Zhang, Qi
AU - Pan, Jing
AU - Steinmann, Beat
AU - Vodopiutz, Julia
AU - Gruber, Robert
AU - Sonoda, Tohru
AU - Krabichler, Birgit
AU - Utermann, Gerd
AU - Baenziger, Jacques U.
AU - Zhang, Lijuan
AU - Janecke, Andreas R.
N1 - Funding Information:
The technical support of Gabriele Rammesmayer is greatly acknowledged. This work was supported by grants from the Dr.-Legerlotz-Stiftung and the Jubiläumsfonds der Österreichischen Nationalbank (grant no. 12255 to ARJ), the National Institutes of Health Grants R01GM069968 (to L.Z.) and R01DK41738 (to J.U.B.), and the Swiss National Science Foundation 3200B0-109370/1 (to B.S.).
PY - 2009/12/11
Y1 - 2009/12/11
N2 - Adducted thumb-clubfoot syndrome is an autosomal-recessive disorder characterized by typical facial appearance, wasted build, thin and translucent skin, congenital contractures of thumbs and feet, joint instability, facial clefting, and coagulopathy, as well as heart, kidney, or intestinal defects. We elucidated the molecular basis of the disease by using a SNP array-based genome-wide linkage approach that identified distinct homozygous nonsense and missense mutations in CHST14 in each of four consanguineous families with this disease. The CHST14 gene encodes N-acetylgalactosamine 4-O-sulfotransferase 1 (D4ST1), which catalyzes 4-O sulfation of N-acetylgalactosamine in the repeating iduronic acid-α1,3-N-acetylgalactosamine disaccharide sequence to form dermatan sulfate. Mass spectrometry of glycosaminoglycans from a patient's fibroblasts revealed absence of dermatan sulfate and excess of chondroitin sulfate, showing that 4-O sulfation by CHST14 is essential for dermatan sulfate formation in vivo. Our results indicate that adducted thumb-clubfoot syndrome is a disorder resulting from a defect specific to dermatan sulfate biosynthesis and emphasize roles for dermatan sulfate in human development and extracellular-matrix maintenance.
AB - Adducted thumb-clubfoot syndrome is an autosomal-recessive disorder characterized by typical facial appearance, wasted build, thin and translucent skin, congenital contractures of thumbs and feet, joint instability, facial clefting, and coagulopathy, as well as heart, kidney, or intestinal defects. We elucidated the molecular basis of the disease by using a SNP array-based genome-wide linkage approach that identified distinct homozygous nonsense and missense mutations in CHST14 in each of four consanguineous families with this disease. The CHST14 gene encodes N-acetylgalactosamine 4-O-sulfotransferase 1 (D4ST1), which catalyzes 4-O sulfation of N-acetylgalactosamine in the repeating iduronic acid-α1,3-N-acetylgalactosamine disaccharide sequence to form dermatan sulfate. Mass spectrometry of glycosaminoglycans from a patient's fibroblasts revealed absence of dermatan sulfate and excess of chondroitin sulfate, showing that 4-O sulfation by CHST14 is essential for dermatan sulfate formation in vivo. Our results indicate that adducted thumb-clubfoot syndrome is a disorder resulting from a defect specific to dermatan sulfate biosynthesis and emphasize roles for dermatan sulfate in human development and extracellular-matrix maintenance.
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U2 - 10.1016/j.ajhg.2009.11.010
DO - 10.1016/j.ajhg.2009.11.010
M3 - Article
C2 - 20004762
AN - SCOPUS:71149085178
SN - 0002-9297
VL - 85
SP - 873
EP - 882
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -