Chondroitin Sulfate N-acetylgalactosaminyltransferase-1 (CSGalNAcT-1) Deficiency Results in a Mild Skeletal Dysplasia and Joint Laxity.
Mutations in genes encoding enzymes responsible for the biosynthesis and structural diversity of glycosaminoglycans (GAGs) cause a variety of disorders affecting bone and connective tissues, including Desbuquois dysplasia (DD). In an infant with prenatal-onset disproportionate short stature, joint laxity, and radiographic findings typical for DD compound-heterozygosity for a large intragenic deletion, and a p.Pro384Arg missense mutation in CSGALNACT1 was found. CSGALNACT1 encodes chondroitin sulfate N-acetylgalactosaminyltransferase-1 (CSGalNAcT-1, ChGn-1), which initiates chondroitin sulfate (CS) chain biosynthesis on the so-called GAG-protein linker region tetrasaccharide. Biochemical studies revealed a reduced GalNAc-transferase activity of the Arg-384 mutant protein, whereas no differences in proteoglycan synthesis in fibroblasts and the GAG content in the urine were found between patient and controls. This is the first description of bi-allelic loss-of-function mutations in CSGALNACT1 that produce a skeletal dysplasia reminiscent of the skeletal dysplasia of Csgalnact1-/-mice, and adds to the genetic heterogeneity of DD.
Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
Julia
J
Vodopiutz
Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, Tempaku ku, Nagoya, Aichi, Japan.
Shuji
S
Mizumoto
Department of Pediatrics, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Ekkehart
E
Lausch
Department of Molecular Medicine, Unit of Biochemistry, University of Pavia, Pavia, Italy.
Antonio
A
Rossi
Department of Medical Genetics, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
Sheila
S
Unger
Department of Pediatrics, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Nikolaus
N
Janocha
Department of Molecular Medicine, Unit of Biochemistry, University of Pavia, Pavia, Italy.
Rossella
R
Costantini
Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
Rainer
R
Seidl
Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
Susanne
S
Greber-Platzer
Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, Tempaku ku, Nagoya, Aichi, Japan.
Shuhei
S
Yamada
Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
Thomas
T
Müller
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Bernd
B
Jilma
Paediatric Department, Orthopaedic Hospital of Speising, Vienna, Austria.
Rudolf
R
Ganger
Department of Pediatrics, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
Andrea
A
Superti-Furga
Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan.
Shiro
S
Ikegawa
Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, Tempaku ku, Nagoya, Aichi, Japan.
Kazuyuki
K
Sugahara
Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.|Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
Andreas R
AR
Janecke
D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D005091:Exons; D005260:Female; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007593:Joint Instability / Q000175:diagnosis* / Q000235:genetics*; D009139:Musculoskeletal Abnormalities / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D017350:N-Acetylgalactosaminyltransferases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011859:Radiography; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D012720:Severity of Illness Index
D011993:Recombinant Fusion Proteins; D017350:N-Acetylgalactosaminyltransferases; C472559:chondroitin sulfate N-acetylgalactosaminyltransferase-1
CSGALNACT1; chondroitin sulfate N-acetylgalactosaminyltransferase-1; glycosaminoglycan; proteoglycan; skeletal dysplasia