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Heparan sulfate (HS) is a linear polysaccharide that consists of alternating disaccharide units comprising N-acetylglucosamine (GlcNAc) and glucuronic acid residues with 100-200 repeats. HS is covalently attached to core proteins to form proteoglycans that are ubiquitously expressed in the extracellular matrix and on cell surfaces, regulating signal transductions via interactions with various morphogens as well as growth factors (1). Details of biosynthetic enzymes of HS are referred to within the section in this series entitled: “Biosynthesis of Heparan sulfate/Heparin”. Pathogenic variants of their genes cause congenital disorders, including neuronal, immune, and skeletal anomalies (Table 1) (2).
Heterozygous pathogenic variants in EXT1 or EXT2, which encode HS-polymerase involved in the biosynthesis of repeating disaccharides in the HS chain, cause multiple osteochondromas (formerly called multiple exostoses) (3-5). Multiple osteochondromas are autosomal dominant disorders, which are characterized by cartilage-capped bony outgrowths located at growth plates of long bones including the femora, a short stature, camptomelic dysplasia including the forearm and crus, and early-onset osteoarthritis. More than 100 cases have been reported among Japanese patients with pathogenic variants in EXT1 and EXT2 (6).
Complex homozygous pathogenic variants, p.Met87Arg and p.Arg95Cys, in EXT2 cause seizures-scoliosis-macrocephaly syndrome, but not multiple osteochondromas (7). Clinical features of patients are characterized by seizures, intellectual disability, hypotonia, scoliosis, macrocephaly, hypertelorism, and renal dysfunction.
Homozygous pathogenic variants in EXTL3 cause immunoskeletal dysplasia with neurodevelopmental abnormalities (8-10). Clinical symptoms of patients include severe combined immunodeficiency with a complete absence of T cells, severe platyspondyly, kyphoscoliosis, brachydactyly, generalized platyspondyly, short and plump limb bones, metacarpals, and phalanges, premature craniosynostosis, neurological abnormalities including intellectual disability, generalized seizures, opisthotonus, and hyperreflexia, developmental delay, nystagmus, and muscular hypotonia. Levels of HS from patients’ fibroblasts as well as in serum and urine of affected individuals are decreased compared with control subjects. Furthermore, induced pluripotent stem (iPS) cells from patients show defects in differentiation into thymic epithelial progenitor cells. The recombinant mutant EXTL3-P381L shows a reduction in GlcNAc transferase activity compared with the wild-type enzyme.
Homozygous pathogenic variants in the N-sulfotransferase domain of N-deacetylase/N-sulfotransferase-1 (NDST1) cause autosomal recessive intellectual disability (11). In addition, a patient with the compound heterozygous variant, p.Ala372Ser/p.Ala736Val, in NDST1 showed seizures, cranial nerve palsies, ataxia, developmental delay, a short stature, severe respiratory difficulties in infancy, and distinctive facial features, including bifid uvula and a long nose (12).
Compound heterozygous variants in HS 2-O-sulfotransferase-1 (HS2ST1) cause neurofacioskeletal syndrome with or without renal agenesis (13). Clinical symptoms of patients include brachydactyly of the hands and feet, flexion contractures, corpus callosum agenesis or hypoplasia, intellectual disability, uni- or bilateral renal agenesis, developmental delay, and facial dysmorphism such as a coarse face, upslanted palpebral fissures, a broad nasal tip, and wide mouth.
Homozygous or heterozygous pathogenic variants in HS 6-O-sulfotransferase-1 (HS6ST1) cause idiopathic hypogonadotropic hypogonadism with or without anosmia, which is characterized by male infertility due to impaired secretion and action of gonadotropin-releasing hormone (14).
Table 1. Congenital disorders of HS deficiency
| Coding genes | Enzymes | Chromosomal location | MIM* number | Human genetic disorders |
| EXT1 | GlcNAcT/
GlcAT
| 8q24.11 | 133700
215300
608177
| Exostoses multiple type 1; Multiple osteochondroma; Chondrosarcoma |
| EXT2 | GlcNAcT/
GlcAT | 11p11.2 | 133701
616682
608210
| Exostoses multiple type 2; Multiple osteochondroma; Seizures-scoliosis-macrocephaly syndrome |
| EXTL3 | GlcNAcT | 8p21.1 | 617425
605744
| Immunoskeletal dysplasia with neurodevelopmental abnormalities;
Neuro-immuno-skeletal dysplasia syndrome;
Spondyloepimetaphyseal dysplasia with immunodeficiency
|
| NDST1 | NDST1 | 5q33.1 | 616116
600853
| Mental retardation autosomal recessive 46 |
| HS2ST1 | HS2ST1 | 1p22.3 | 604844
619194
| Neurofacioskeletal syndrome with or without renal agenesis |
| HS6ST1 | HS6ST1 | 2q14.3 | 614880
604846
| Hypogonadotropic hypogonadism 15 with or without anosmia |
* MIM, Mendelian inheritance in man
Shuji Mizumoto
(Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University)
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