title: 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).
authors.affiliation: Institute of Medical Genetics, Charité University Medicine, Berlin, Germany.
authors.forename: Sevjidmaa
authors.initials: S
authors.lastname: Baasanjav
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
authors.forename: Taishi
authors.initials: T
authors.lastname: Hashiguchi
authors.forename: Shuji
authors.initials: S
authors.lastname: Mizumoto
authors.forename: Bjoern
authors.initials: B
authors.lastname: Fischer
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
authors.forename: Dominik
authors.initials: D
authors.lastname: Seelow
authors.forename: Bassam R
authors.initials: BR
authors.lastname: Ali
authors.forename: Samir A A
authors.initials: SA
authors.lastname: Aziz
authors.forename: Ruth
authors.initials: R
authors.lastname: Langer
authors.forename: Ahmed A H
authors.initials: AA
authors.lastname: Saleh
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Vincent
authors.initials: V
authors.lastname: Cantagrel
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
authors.forename: Delphine
authors.initials: D
authors.lastname: Gomez
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Michel
authors.forename: Sigmar
authors.initials: S
authors.lastname: Stricker
authors.forename: Tom H
authors.initials: TH
authors.lastname: Lindner
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugahara
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.forename: Katrin
authors.initials: K
authors.lastname: Hoffmann
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001021:Aortic Valve / Q000473:pathology; D016022:Case-Control Studies; D002648:Child; D002809:Chondroitin Sulfates / Q000032:analysis; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D003241:Consanguinity; D003871:Dermatan Sulfate / Q000032:analysis; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D014453:Glucuronosyltransferase / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000473:pathology*; D019812:Heparan Sulfate Proteoglycans / Q000032:analysis; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008943:Mitral Valve / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010375:Pedigree; D011509:Proteoglycans / Q000096:biosynthesis*
chemical_list: D019812:Heparan Sulfate Proteoglycans; D011509:Proteoglycans; D003871:Dermatan Sulfate; D002809:Chondroitin Sulfates; D014453:Glucuronosyltransferase