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Faulty initiation of proteoglycan synthesis causes cardiac and joint defects.

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).

SUBMITTER: Baasanjav S

PROVIDER: S-EPMC3135799 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Faulty initiation of proteoglycan synthesis causes cardiac and joint defects.

Baasanjav Sevjidmaa S Al-Gazali Lihadh L Hashiguchi Taishi T Mizumoto Shuji S Fischer Bjoern B Horn Denise D Seelow Dominik D Ali Bassam R BR Aziz Samir A A SA Langer Ruth R Saleh Ahmed A H AA Becker Christian C Nürnberg Gudrun G Cantagrel Vincent V Gleeson Joseph G JG Gomez Delphine D Michel Jean-Baptiste JB Stricker Sigmar S Lindner Tom H TH Nürnberg Peter P Sugahara Kazuyuki K Mundlos Stefan S Hoffmann Katrin K

American journal of human genetics 20110701 1

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 cata ...[more]

PMID: 21763480

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Faulty initiation of proteoglycan synthesis causes cardiac and joint defects.

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Faulty initiation of proteoglycan synthesis causes cardiac and joint defects.

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