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Chondroitin sulfate (CS) is a linear polysaccharide that consists of alternating disaccharide units comprising N-acetyl-galactosamine (GalNAc) and glucuronic acid (GlcA) residues with 100-200 repeats. CS is covalently attached to core proteins to form proteoglycans, which are ubiquitously expressed in the extracellular matrix and on cell surfaces. Details of biosynthetic enzymes of CS are referred to within the section in this series entitled: “Chondroitin sulfate/dermatan sulfate glycosaminoglycans: Their biosynthetic machineries”. Pathogenic variants of their genes cause congenital disorders, including skeletal anomalies and heart defects (Table 1) (1).
Pathogenic variants of chondroitin synthase-1 (CHSY1) cause Temtamy preaxial brachydactyly syndrome, characterized by bilateral, symmetric preaxial brachydactyly, hyperphalangism of digits, facial dysmorphism, dental anomalies, sensorineural hearing loss, delayed motor and mental development, and growth retardation (2-4). CS levels in skin sections from a patient were lower than those in control skin based on immunohistochemistry using an anti-CS antibody (4). A decrease in CS may cause disturbances of NOTCH and bone morphogenetic protein signaling, resulting in abnormal skeletal formation.
Defects and pathogenic variants in CS-GalNAc transferase-1 (CSGALNACT1/ChGn1) causes mild skeletal dysplasia with joint laxity and advanced bone age (5, 6). Recombinant mutant enzymes, P384R, D432Y, and N264S, exhibit weaker GalNAc transferase activity than that of the wild-type enzyme, and the level of CS is decreased in patients' fibroblasts compared to controls (6).
Defects and pathogenic variants in CHST11 encoding chondroitin 4-O-sulfotransferase-1 (C4ST1) causes osteochondrodysplasia, brachydactyly, and overlapping malformed digits (7, 8). Clinical features of patients are characterized by skeletal defects including mild short stature, brachydactyly, adducted thumbs, overriding digits (most often third over fourth), clino-symphalangism, syndactyly, hexadactyly, scoliosis, dislocation, osteoarthritis, and pectus excavatum, and being deaf-mute (8).
Defects and pathogenic variants in CHST3 encoding chondroitin 6-O-sulfotransferase-1 (C6ST1) cause spondyloepiphyseal dysplasia with congenital joint dislocations (9-12). Clinical features of patients are characterized by a short stature, severe kyphoscoliosis, mild brachydactyly, fusion of the carpal bones, metacarpal shortening, osteoarthritis in the elbow, wrist, and knee joints, deafness, and ventricular septal, mitral, and/or tricuspid defects. Furthermore, C6ST activity is decreased in skin fibroblasts from patients, resulting in a defect in 6-O-sulfated modification of CS chains. Some patients have been diagnosed with: Larsen syndrome, characterized by congenital joint dislocations; humero-spinal dysostosis, characterized by dislocation of the knees, bilateral clubfeet, and elbow joint and spinal dysplasia; chondrodysplasia with multiple dislocations (Megarbane type); Desbuquois syndrome (13, 14). The different pathological diagnoses based on pathogenic variants in CHST3 may be due to differences of amino acid substitutions in C6ST1 and/or age-related descriptions of the same conditions. In addition, SNP of CHST3 has been reported as a susceptibility gene for lumbar disc degeneration (15). Such degeneration is a collective term for intervertebral disk degeneration, and causes lumbar disc herniation and sciatica.
Table 1. Congenital disorders of CS deficiency
| Coding genes | Enzymes | Chromosomal location | MIM* number | Human genetic disorders |
| CHSY1 | CHSY1 | 15q26.3 | 605282
608183
| Temtamy pre-axial brachydactyly syndrome; Syndromic recessive pre-axial brachydactyly. |
| CSGALNACT1 | CSGalNAcT1 | 8p21.3 | 616615
618870
| Mild skeletal dysplasia with joint laxity;
Desbuquois dysplasia
|
| CHST3 | C6ST1 | 10q22.1 | 143095
603799
| Spondyloepiphyseal dysplasia with congenital joint dislocations; Spondyloepiphyseal dysplasia Omani type; Chondrodysplasia with multiple dislocations Megarbane type; Humerospinal dysostosis; Larsen syndrome autosomal recessive type; Desbuquois syndrome |
| CHST11 | C4ST1 | 12q23.3 | 610128
618167
| Osteochondrodysplasia, brachydactyly, and overlapping malformed digits |
* MIM, Mendelian inheritance in man
Shuji Mizumoto
(Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University)
| References |
| (1) |
Mizumoto S, and Yamada S: Congenital disorders of deficiency in glycosaminoglycan biosynthesis. Front. Genet. 12, 717535, 2021 |
| (2) |
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Tian J, Ling L, Shboul M, Lee H, O'Connor B, Merriman B, Nelson SF, Cool S, Ababneh OH, Al-Hadidy A, Masri A, Hamamy H, Reversade, B: Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling. Am. J. Hum. Genet. 87, 768-778, 2010 |
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Vodopiutz J, Mizumoto S, Lausch E, Rossi A, Unger S, Janocha N, Costantini R, Seidl R, Greber-Platzer S, Yamada S, Müller T, Jilma B, Ganger R, Superti-Furga A, Ikegawa S, Sugahara K, Janecke AR: Chondroitin sulfate N-acetylgalactosaminyltransferase-1 (CSGalNAcT-1) deficiency results in a mild skeletal dysplasia and joint laxity. Hum. Mutat. 38, 34-38, 2017 |
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