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).

Human Genetic Disorders Caused by Mutations in Genes Encoding Biosynthetic Enzymes for Sulfated Glycosaminoglycans

“…Furthermore, the mutation results in a decrease in the biosynthesis of GAGs. Fibroblasts from patients produce not only a PG form of decorin, which is secreted by the fibroblasts and has a single DS chain, but also DS-free decorin presumably bearing the linkage region trisaccharide stub Gal␤1-3Gal␤1-4Xyl (65). Furthermore, the numbers of CS and HS chains on the core proteins at the surface of the fibroblasts are reduced to 65 and 53% of those in control subjects, respectively (65).…”

“…A mutation (R277Q) in the B3GAT3 gene coding for GlcAT-I was identified for this Larsen-like syndrome family (65). Larsen syndrome is characterized by dislocations of the hip, knee, and elbow joints; equinovarus foot deformity; and craniofacial dysmorphism that includes hypertelorism, prominence of the forehead, a depressed nasal bridge, and a flattened midface (66,67).…”

“…Larsen syndrome is characterized by dislocations of the hip, knee, and elbow joints; equinovarus foot deformity; and craniofacial dysmorphism that includes hypertelorism, prominence of the forehead, a depressed nasal bridge, and a flattened midface (66,67). The R277Q mutation causes a drastic reduction in GlcAT-I activity in the patients' fibroblasts (ϳ5% of control fibroblasts) (65). Although wild-type GlcAT-I is located in the cis and cis-medial Golgi in control fibroblasts, the amount of mutant protein is markedly reduced as demonstrated by immunofluorescent staining using anti-GlcAT-I antibody, indicating that the GlcAT-I mutant may be produced to a lesser extent, be degraded, or be susceptible to a protease compared with the wild type (65).…”

“…The R277Q mutation causes a drastic reduction in GlcAT-I activity in the patients' fibroblasts (ϳ5% of control fibroblasts) (65). Although wild-type GlcAT-I is located in the cis and cis-medial Golgi in control fibroblasts, the amount of mutant protein is markedly reduced as demonstrated by immunofluorescent staining using anti-GlcAT-I antibody, indicating that the GlcAT-I mutant may be produced to a lesser extent, be degraded, or be susceptible to a protease compared with the wild type (65). Furthermore, the mutation results in a decrease in the biosynthesis of GAGs.…”

Diseases of glycosylation beyond classical congenital disorders of glycosylation

“…A mutation in the 1-3 GlcAtransferase gene (B3GAT3, OMIM ID: 606374) (Fig. 5) was found in patients presenting with short stature, congenital heart defects and joint dislocations [73]. The mutant B3GAT3 enzyme showed decreased activity, which reduced the level of heparan, chondroitin and dermatan sulfate chains on proteoglycans.…”