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  Faulty initiation of proteoglycan synthesis causes cardiac and joint defects

Baasanjav, S., Al-Gazali, L., Hashiguchi, T., Mizumoto, S., Fischer, B., Horn, D., et al. (2011). Faulty initiation of proteoglycan synthesis causes cardiac and joint defects. Am J Hum Genet, 89(1), 15-27. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21763480 http://pdn.sciencedirect.com/science?_ob=MiamiImageURL&_cid=276895&_user=28761&_pii=S000292971100214X&_check=y&_origin=article&_zone=toolbar&_coverDate=15-Jul-2011&view=c&originContentFamily=serial&wchp=dGLzVlB-zSkzS&md5=649207de536a6fe4c92490e7b79131b7/1-s2.0-S000292971100214X-main.pdf.

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Baasanjav, S., Author
Al-Gazali, L., Author
Hashiguchi, T., Author
Mizumoto, S., Author
Fischer, B., Author
Horn, D., Author
Seelow, D.1, Author           
Ali, B. R., Author
Aziz, S. A., Author
Langer, R., Author
Saleh, A. A., Author
Becker, C., Author
Nurnberg, G., Author
Cantagrel, V., Author
Gleeson, J. G., Author
Gomez, D., Author
Michel, J. B., Author
Stricker, S.1, Author           
Lindner, T. H., Author
Nurnberg, P., Author
Sugahara, K., AuthorMundlos, S.1, Author           Hoffmann, K.1, Author            more..
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              


Free keywords: Adolescent; Amino Acid Sequence; Aortic Valve/pathology; Case-Control Studies; Child; Chondroitin Sulfates/analysis; Chromosomes, Human, Pair 11/genetics; Consanguinity; Dermatan Sulfate/analysis; Electrophoresis, Polyacrylamide Gel; Fibroblasts/metabolism; Fluorescent Antibody Technique; Glucuronosyltransferase/*genetics; Heart Defects, Congenital/*pathology; Heparan Sulfate Proteoglycans/analysis; Humans; Immunoblotting; Male; Mitral Valve/pathology; Models, Molecular; Molecular Sequence Data; Pedigree; Proteoglycans/*biosynthesis
 Abstract: Proteoglycans are a major component of extracellular matrix and contribute to normal embryonic and postnatal development by ensuring tissue stability and signaling functions. We studied five patients with recessive joint dislocations and congenital heart defects, including bicuspid aortic valve (BAV) and aortic root dilatation. We identified linkage to chromosome 11 and detected a mutation (c.830G>A, p.Arg277Gln) in B3GAT3, the gene coding for glucuronosyltransferase-I (GlcAT-I). The enzyme catalyzes an initial step in the synthesis of glycosaminoglycan side chains of proteoglycans. Patients' cells as well as recombinant mutant protein showed reduced glucuronyltransferase activity. Patient fibroblasts demonstrated decreased levels of dermatan sulfate, chondroitin sulfate, and heparan sulfate proteoglycans, indicating that the defect in linker synthesis affected all three lines of O-glycanated proteoglycans. Further studies demonstrated that GlcAT-I resides in the cis and cis-medial Golgi apparatus and is expressed in the affected tissues, i.e., heart, aorta, and bone. The study shows that reduced GlcAT-I activity impairs skeletal as well as heart development and results in variable combinations of heart malformations, including mitral valve prolapse, ventricular septal defect, and bicuspid aortic valve. The described family constitutes a syndrome characterized by heart defects and joint dislocations resulting from altered initiation of proteoglycan synthesis (Larsen-like syndrome, B3GAT3 type).



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Title: Am J Hum Genet
Source Genre: Journal
Publ. Info: -
Pages: - Volume / Issue: 89 (1) Sequence Number: - Start / End Page: 15 - 27 Identifier: ISSN: 1537-6605 (Electronic) 0002-9297 (Linking)