Institute of Medical Genetics, Charité University Medicine, Berlin, Germany.
Am J Hum Genet. 2011 Jul 15;89(1):15-27. doi: 10.1016/j.ajhg.2011.05.021.
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).
蛋白聚糖是细胞外基质的主要成分，通过确保组织稳定性和信号功能，为正常的胚胎和产后发育做出贡献。我们研究了五名患有隐性关节脱位和先天性心脏缺陷的患者，包括二叶式主动脉瓣（BAV）和主动脉根部扩张。我们发现与 11 号染色体连锁，并在编码糖基转移酶-I（GlcAT-I）的 B3GAT3 基因中检测到突变（c.830G>A，p.Arg277Gln）。该酶催化蛋白聚糖糖胺聚糖侧链合成的初始步骤。患者的细胞和重组突变蛋白显示出降低的糖基转移酶活性。患者成纤维细胞表现出硫酸皮肤素、硫酸软骨素和硫酸乙酰肝素蛋白聚糖水平降低，表明连接物合成的缺陷影响了所有三种 O-糖基化蛋白聚糖。进一步的研究表明，GlcAT-I 位于顺式和顺式中等高尔基体中，并在受影响的组织中表达，即心脏、主动脉和骨骼。该研究表明，GlcAT-I 活性降低会损害骨骼和心脏发育，并导致心脏畸形的各种组合，包括二尖瓣脱垂、室间隔缺损和二叶式主动脉瓣。所描述的家族构成了一种综合征，其特征是心脏缺陷和关节脱位，这是由于蛋白聚糖合成起始改变所致（Larsen 样综合征，B3GAT3 型）。
