Faulty initiation of proteoglycan synthesis causes cardiac and joint defects

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 NürnbergKazuyuki Sugahara, Stefan Mundlos, Katrin Hoffmann

Research output: Contribution to journalArticlepeer-review

97 Citations (Scopus)


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 (Larsenlike syndrome, B3GAT3 type).

Original languageEnglish
Pages (from-to)15-27
Number of pages13
JournalAmerican Journal of Human Genetics
Issue number1
Publication statusPublished - Jul 15 2011

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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