Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 89, Issue 1, Pages 15-27Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2011.05.021
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Funding
- Mongolian government
- Charite Medical faculty
- Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) [20390019]
- Northern Advancement Center for Science & Technology of Hokkaido
- Japan Society for the Promotion of Science, Japan [23790066]
- Deutsche Forschungsgemeinschaft (DFG) [SFB 577, A4]
- Grants-in-Aid for Scientific Research [23390016, 20390019, 23790066] Funding Source: KAKEN
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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 (GIcAT-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 GIcAT-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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