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Chondroitin Sulfate N ‐acetylgalactosaminyltransferase‐1 (CSGalNAcT‐1) Deficiency Results in a Mild Skeletal Dysplasia and Joint Laxity
Author(s) -
Vodopiutz Julia,
Mizumoto Shuji,
Lausch Ekkehart,
Rossi Antonio,
Unger Sheila,
Janocha Nikolaus,
Costantini Rossella,
Seidl Rainer,
GreberPlatzer Susanne,
Yamada Shuhei,
Müller Thomas,
Jilma Bernd,
Ganger Rudolf,
SupertiFurga Andrea,
Ikegawa Shiro,
Sugahara Kazuyuki,
Janecke Andreas R.
Publication year - 2017
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23070
Subject(s) - biology , missense mutation , compound heterozygosity , exon , genetics , mutation , dysplasia , chondroitin , proteoglycan , biochemistry , glycosaminoglycan , gene , extracellular matrix
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.