Document Detail

Faulty initiation of proteoglycan synthesis causes cardiac and joint defects.
MedLine Citation:
PMID:  21763480     Owner:  NLM     Status:  MEDLINE    
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).
Sevjidmaa Baasanjav; Lihadh Al-Gazali; Taishi Hashiguchi; Shuji Mizumoto; Bjoern Fischer; Denise Horn; Dominik Seelow; Bassam R Ali; Samir A A Aziz; Ruth Langer; Ahmed A H Saleh; Christian Becker; Gudrun Nürnberg; Vincent Cantagrel; Joseph G Gleeson; Delphine Gomez; Jean-Baptiste Michel; Sigmar Stricker; Tom H Lindner; Peter Nürnberg; Kazuyuki Sugahara; Stefan Mundlos; Katrin Hoffmann
Publication Detail:
Type:  Case Reports; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  American journal of human genetics     Volume:  89     ISSN:  1537-6605     ISO Abbreviation:  Am. J. Hum. Genet.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-07-18     Completed Date:  2011-09-19     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  0370475     Medline TA:  Am J Hum Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  15-27     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Institute of Medical Genetics, Charité University Medicine, Berlin, Germany.
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MeSH Terms
Amino Acid Sequence
Aortic Valve / pathology
Case-Control Studies
Chondroitin Sulfates / analysis
Chromosomes, Human, Pair 11 / genetics
Dermatan Sulfate / analysis
Electrophoresis, Polyacrylamide Gel
Fibroblasts / metabolism
Fluorescent Antibody Technique
Glucuronosyltransferase / genetics*
Heart Defects, Congenital / pathology*
Heparan Sulfate Proteoglycans / analysis
Mitral Valve / pathology
Models, Molecular
Molecular Sequence Data
Proteoglycans / biosynthesis*
Reg. No./Substance:
0/Heparan Sulfate Proteoglycans; 0/Proteoglycans; 24967-94-0/Dermatan Sulfate; 9007-28-7/Chondroitin Sulfates; EC

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