1. Academic Validation
  2. Chondroitin Sulfate N-acetylgalactosaminyltransferase-1 (CSGalNAcT-1) Deficiency Results in a Mild Skeletal Dysplasia and Joint Laxity

Chondroitin Sulfate N-acetylgalactosaminyltransferase-1 (CSGalNAcT-1) Deficiency Results in a Mild Skeletal Dysplasia and Joint Laxity

  • Hum Mutat. 2017 Jan;38(1):34-38. doi: 10.1002/humu.23070.
Julia Vodopiutz 1 Shuji Mizumoto 2 Ekkehart Lausch 3 Antonio Rossi 4 Sheila Unger 5 Nikolaus Janocha 3 Rossella Costantini 4 Rainer Seidl 1 Susanne Greber-Platzer 1 Shuhei Yamada 2 Thomas Müller 6 Bernd Jilma 7 Rudolf Ganger 8 Andrea Superti-Furga 9 Shiro Ikegawa 10 Kazuyuki Sugahara 2 Andreas R Janecke 6 11
Affiliations

Affiliations

  • 1 Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
  • 2 Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, Tempaku ku, Nagoya, Aichi, Japan.
  • 3 Department of Pediatrics, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 4 Department of Molecular Medicine, Unit of Biochemistry, University of Pavia, Pavia, Italy.
  • 5 Department of Medical Genetics, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
  • 6 Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
  • 7 Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
  • 8 Paediatric Department, Orthopaedic Hospital of Speising, Vienna, Austria.
  • 9 Department of Pediatrics, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
  • 10 Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan.
  • 11 Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
Abstract

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.

Keywords

CSGALNACT1; chondroitin sulfate N-acetylgalactosaminyltransferase-1; glycosaminoglycan; proteoglycan; skeletal dysplasia.

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