Faulty Initiation of Proteoglycan Synthesis Causes Cardiac and Joint Defects

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• 作者：Sevjidmaa Baasanjav¹ ; ² ; ¹⁴ ; Lihadh Al-Gazali³ ; ¹⁴ ; Taishi Hashiguchi⁴ ; ¹⁴ ; Shuji Mizumoto⁴ ; Bjoern Fischer¹ ; Denise Horn¹ ; Dominik Seelow¹ ; Bassam  ; R. Ali⁵ ; Samir  ; A.A. Aziz⁶ ; Ruth Langer⁷ ; Ahmed  ; A.H. Saleh⁶ ; Christian Becker⁸ ; Gudrun Nü ; rnberg⁸ ; Vincent Cantagrel⁹ ; Joseph  ; G. Gleeson⁹ ; Delphine Gomez¹⁰ ; Jean-Baptiste Michel¹⁰ ; Sigmar Stricker¹¹ ; Tom  ; H. Lindner² ; Peter Nü ; rnberg⁸ ; Kazuyuki Sugahara⁴ ; Stefan Mundlos¹ ; ¹¹ ; ^{stefan.mundlos@charite.de"" rel=""nofollow} ; Katrin Hoffmann¹ ; ¹¹ ; ¹² ; ¹³ ; ^{katrin.hoffmann@medizin.uni-halle.de"" rel=""nofollow}
• 刊名：The American Journal of Human Genetics
• 出版年：2011
• 出版时间：15 July 2011
• 年：2011
• 卷：89
• 期：1
• 页码：15-27
• 全文大小：894 K

文摘

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).