Alternative titles; symbols
HGNC Approved Gene Symbol: CHST3
SNOMEDCT: 702400006, 725417001;
Cytogenetic location: 10q22.1 Genomic coordinates (GRCh38) : 10:71,964,395-72,013,558 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q22.1 | Spondyloepiphyseal dysplasia with congenital joint dislocations | 143095 | Autosomal recessive | 3 |
Chondroitin sulfate proteoglycans, which consist of a core protein with at least 1 covalently attached glycosaminoglycan (GAG) chain, are distributed on the surfaces of most cells and the extracellular matrix in virtually every tissue. See 118661. Chondroitin sulfate has a linear polymer structure that possesses repetitive, sulfated disaccharide units containing glucuronic acid (GlcA) and N-acetylgalactosamine (GalNAc). The major chondroitin sulfate found in mammalian tissues has sulfate groups at position 4 or 6 of GalNAc residues. Chondroitin 6-sulfotransferase (C6ST) catalyzes the transfer of sulfate from PAPS (3-prime-phosphoadenosine 5-prime-phosphosulfate) to position 6 of the GalNAc residues. By screening a placenta library with a chicken C6ST cDNA, Tsutsumi et al. (1998) isolated cDNAs encoding human C6ST. The predicted 479-amino acid protein shares 74% and 36% identity with chick C6ST and human keratan sulfate gal-6-sulfotransferase (CHST1; 603797), respectively. Recombinant human enzyme displayed C6ST activity with a marked specificity for a GlcA-GalNAc sequence. In addition, C6ST catalyzed the sulfation of keratan sulfate. They noted that a deficiency in C6ST has been associated with a heritable form of spondyloepiphyseal dysplasia (271630).
Independently, Fukuta et al. (1998) cloned human C6ST cDNAs. Using Northern blot analysis, they found that the 7.8-kb C6ST mRNA was ubiquitous. Smaller transcripts were also observed in skeletal muscle and heart.
Tsutsumi et al. (1998) reported that the C6ST gene contains 3 exons and spans more than 20 kb.
Gross (2014) mapped the CHST3 gene to chromosome 10q22.1 based on an alignment of the CHST3 sequence (GenBank AB012192) with the genomic sequence (GRCh37).
Iida et al. (2002) characterized single-nucleotide polymorphisms and insertion-deletion polymorphisms in both the CHST1 gene (603797) and the CHST3 gene.
In affected members of a large inbred Omani kindred with spondyloepiphyseal dysplasia and congenital joint dislocations (SEDCJD; 143095), Thiele et al. (2004) identified a homozygous arg304-to-gln mutation in the CHST3 gene (R304Q; 603799.0001).
In 6 unrelated patients born with joint dislocations, some of whom carried a diagnosis of recessive Larsen syndrome and others, humerospinal dysostosis, Hermanns et al. (2008) identified homozygosity or compound heterozygosity for 9 different mutations in the CHST3 gene (see, e.g., 603799.0002-603799.0006). Noting the relatively narrow phenotypic spectrum of these conditions, Hermanns et al. (2008) suggested that the disorders previously designated as Omani-type spondyloepiphyseal dysplasia and humerospinal dysostosis, as well as some patients given a diagnosis of recessive Larsen syndrome, might represent different age-related descriptions of the same condition.
In 2 Turkish sibs with spondyloepiphyseal dysplasia and congenital joint dislocations, born of consanguineous parents, van Roij et al. (2008) identified homozygosity for a missense mutation in the CHST3 gene (603799.0007).
In 2 sibs and their affected uncle from a consanguineous Turkish pedigree with spondyloepiphyseal dysplasia and subluxation of the radial head, Tuysuz et al. (2009) identified homozygosity for a missense mutation in the CHST3 gene (T141M; 603799.0009).
Unger et al. (2010) identified homozygous or compound heterozygous mutations in CHST3 in 18 patients with spondyloepiphyseal dysplasia and congenital joint dislocations from 17 families. The patients had presented with various diagnoses, including 15 who had been diagnosed with Larsen syndrome (see, e.g., 603799.0011 and 603799.0012), 2 with chondrodysplasia with multiple dislocations (see, e.g., 603799.0002), 1 with humerospinal dysostosis (see 603799.0010), 1 with Desbuquois syndrome (see 251450), and 1 with spondyloepiphyseal dysplasia.
In 2 Somali half sibs with chondrodysplasia, Tanteles et al. (2013) identified homozygosity for a missense mutation in the CHST3 gene (603799.0013).
In affected members of the large inbred kindred with spondyloepiphyseal dysplasia with congenital joint dislocations (SEDCJD; 143095), first described by Rajab et al. (2004) and designated 'Omani type,' Thiele et al. (2004) identified a homozygous 911G-A transition in exon 3 of the CHST3 gene, resulting in an arg304-to-gln (R304Q) substitution. The mutation occurs in the highly conserved 3-prime-phosphoadenosine 5-prime-phosphosulfate (PAPS) binding site.
In a 10.5-year-old Turkish-German girl with spondyloepiphyseal dysplasia and congenital joint dislocations (SEDCJD; 143095), born of consanguineous parents, Hermanns et al. (2008) identified homozygosity for a 776T-C transition in exon 3 of the CHST3 gene, resulting in a leu259-to-pro (L259P) substitution at a highly conserved residue. The parents were heterozygous for the mutation, and the patient had an unaffected brother. Functional analysis in cultured skin fibroblasts revealed that the L259P mutation severely impaired or abolished CHST3 function. Unger et al. (2010) restudied this patient and noted that although she had initially been diagnosed as having Larsen syndrome (see 245600), there was now clear evidence of SED with severe spinal degeneration.
In a Lebanese boy with SED and congenital joint dislocations, who was originally reported by Megarbane and Ghanem (2004) and given the diagnosis of 'chondrodysplasia with multiple dislocations,' Unger et al. (2010) identified homozygosity for the L259P mutation in the CHST3 gene.
In a 17-year-old Swiss patient with spondyloepiphyseal dysplasia with congenital joint dislocations (SEDCJD; 143095), born of parents from the same small village, Hermanns et al. (2008) identified homozygosity for a 664C-T transition in exon 3 of the CHST3 gene, resulting in an arg222-to-trp (R222W) substitution at a highly conserved residue. The parents were heterozygous for the mutation, and the patient had an unaffected brother. Functional analysis in cultured skin fibroblasts revealed that the R222W mutation severely impaired or abolished CHST3 function. Unger et al. (2010) restudied this patient and noted that although initially the diagnosis had been Larsen syndrome (see 245600), there was now clear evidence of SED with severe spinal degeneration.
In a Sardinian boy with spondyloepiphyseal dysplasia and congenital joint dislocations (SEDCJD; 143095), Hermanns et al. (2008) identified homozygosity for a 920T-C transition in exon 3 of the CHST3 gene, resulting in a leu307-to-pro (L307P) substitution at a highly conserved residue. The parents were heterozygous for the mutation. Although the patient previously carried a diagnosis of recessive Larsen syndrome (245600), the authors noted that his appearance was 'identical' to that of the patient originally reported with humerospinal dysostosis by Hall (1997) (see 603799.0010).
Unger et al. (2010) studied cultured fibroblasts from the Sardinian boy who was homozygous for L307P and observed almost no C6ST activity compared to controls.
In a 31-year-old Spanish man with spondyloepiphyseal dysplasia with congenital joint dislocations (SEDCJD; 143095), originally reported as having humerospinal dysostosis (HSD) at 2 years of age by Cortina et al. (1979), Hermanns et al. (2008) identified compound heterozygosity for 2 mutations in the CHST3 gene: a 1-bp deletion (1086delG) in exon 3, resulting in a frameshift and premature termination of the protein, and a 603C-A transversion in exon 3, resulting in a tyr201-to-ter (Y201X; 603799.0006) substitution at a highly conserved residue. The parents were each heterozygous for one of the mutations; a sister was unaffected. In another Spanish patient who had originally been diagnosed with HSD, Hermanns et al. (2008) identified compound heterozygosity for mutations in the CHST3 gene: 1086delG and a 1114G-A transition in exon 3, resulting in a glu372-to-lys (E372K; 603799.0008) substitution at a highly conserved residue. The E372K mutation was not found in more than 250 control chromosomes.
For discussion of the tyr201-to-ter (Y201X) mutation in the CHST3 gene that was found in compound heterozygous state in a patient with spondyloepiphyseal dysplasia with congenital joint dislocations (SEDCJD;143095) by Hermanns et al. (2008), see 603799.0005.
In 2 Turkish sibs with spondyloepiphyseal dysplasia and congenital joint dislocations (SEDCJD; 143095), born of second-cousin parents, van Roij et al. (2008) identified homozygosity for an 857T-C transition in the CHST3 gene, predicted to result in a leu286-to-pro (L286P) substitution at a highly conserved residue adjacent to the binding site for PAPS. Functional studies in patient fibroblasts showed dramatically reduced C6ST1 activity compared to wildtype.
For discussion of the glu372-to-lys (E372K) mutation in the CHST3 gene that was found in compound heterozygous state in a patient with spondyloepiphyseal dysplasia with congenital joint dislocations (SEDCJD;143095) by Hermanns et al. (2008), see 603799.0005.
In 2 affected sibs and their affected paternal uncle in a consanguineous Turkish pedigree with spondyloepiphyseal dysplasia and congenital joint dislocations (SEDCJD; 143095), Tuysuz et al. (2009) identified homozygosity for a 422C-T transition in exon 3 of the CHST3 gene, resulting in a thr141-to-met (T141M) substitution at a conserved residue. Western blot analysis showed comparable expression levels of the mutant and wildtype proteins, but sulfotransferase activity of the mutant was reduced to less than 30% of wildtype.
In a 15-year-old patient with spondyloepiphyseal dysplasia and congenital joint dislocations (SEDCJD; 143095), originally reported by Hall (1997) with a diagnosis of humerospinal dysostosis, Unger et al. (2010) identified homozygosity for a 475T-A transversion in the CHST3 gene, resulting in a phe159-to-ile (F159I) substitution. The mutation was not found in more than 250 control chromosomes. Follow-up evaluation of the patient by Unger et al. (2010) showed a dysplastic mitral valve with stenosis and moderate insufficiency, as well as a mildly thickened aortic valve.
In a patient with spondyloepiphyseal dysplasia and congenital joint dislocations (SEDCJD; 143095), who was referred for evaluation of presumed Larsen syndrome (see 245600), Unger et al. (2010) identified homozygosity for a 481C-T transition in the CHST3 gene, resulting in a leu161-to-phe (L161F) substitution. The mutation was not found in more than 250 control chromosomes.
In a patient with spondyloepiphyseal dysplasia and congenital joint dislocations (SEDCJD; 143095), who had initially been diagnosed with Larsen syndrome (see 150250) but who was negative for mutation in the FLNB gene (603381), Unger et al. (2010) identified homozygosity for a 988C-T transition in the CHST3 gene, resulting in a gln330-to-ter (Q330X) substitution.
In a 14-year-old Somali girl and her 3-year-old maternal half brother with chondrodysplasia (SEDCJD; 143095), Tanteles et al. (2013) identified homozygosity for a c.1063G-A transition in exon 3 of the CHST3 gene, resulting in a gly355-to-arg (G355R) substitution at a highly conserved residue. The boy was born with dislocated knees and clubfeet, whereas the girl presented at 5 years of age with short stature and genua valga. Their unaffected parents were heterozygous for the mutation; the sibs had different fathers, who both originated from the same village.
Cortina, H., Vidal, J., Vallcanera, A., Alberto, C., Muro, D., Dominguez, F. Humero-spinal dysostosis. Pediat. Radiol. 8: 188-190, 1979. [PubMed: 112567] [Full Text: https://doi.org/10.1007/BF00973833]
Fukuta, M., Kobayashi, Y., Uchimura, K., Kimata, K., Habuchi, O. Molecular cloning and expression of human chondroitin 6-sulfotransferase. Biochim. Biophys. Acta 1399: 57-61, 1998. [PubMed: 9714738] [Full Text: https://doi.org/10.1016/s0167-4781(98)00089-x]
Gross, M. B. Personal Communication. Baltimore, Md. 5/21/2014.
Hall, B. D. Humero-spinal dysostosis: report of the fourth case with emphasis on generalized skeletal involvement, abnormal craniofacial features, and mitral valve thickening. J. Pediat. Orthop. B 6: 11-14, 1997. [PubMed: 9039660]
Hermanns, P., Unger, S., Rossi, A., Perez-Aytes, A., Cortina, H., Bonafe, L., Boccone, L., Setzu, V., Dutoit, M., Sangiorgi, L., Pecora, F., Reicherter, K., Nishimura, G., Spranger, J., Zabel, B., Superti-Furga, A. Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive Larsen syndrome and humero-spinal dysostosis. Am. J. Hum. Genet. 82: 1368-1374, 2008. Note: Erratum: Am. J. Hum. Genet. 83: 293 only, 2008. [PubMed: 18513679] [Full Text: https://doi.org/10.1016/j.ajhg.2008.05.006]
Iida, A., Saito, S., Sekine, A., Mishima, C., Kitamura, Y., Kondo, K., Harigae, S., Osawa, S., Nakamura, Y. Catalog of 77 single-nucleotide polymorphisms (SNPs) in the carbohydrate sulfotransferase 1 (CHST1) and carbohydrate sulfotransferase 3 (CHST3) genes. J. Hum. Genet. 47: 14-19, 2002. [PubMed: 11829137] [Full Text: https://doi.org/10.1007/s10038-002-8650-9]
Megarbane, A., Ghanem, I. A newly recognized chondrodysplasia with multiple dislocations. (Letter) Am. J. Med. Genet. 130A: 107-109, 2004. [PubMed: 15368507] [Full Text: https://doi.org/10.1002/ajmg.a.30179]
Rajab, A., Kunze, J., Mundlos, S. Spondyloepiphyseal dysplasia Omani type: a new recessive type of SED with progressive spinal involvement. Am. J. Med. Genet. 126A: 413-419, 2004. [PubMed: 15098240] [Full Text: https://doi.org/10.1002/ajmg.a.20606]
Tanteles, G. A., Dixit, A., Dhar, S., Suri, M. Two Somali half-siblings with CHST3-related chondrodysplasia illustrating the phenotypic spectrum and intrafamilial variability. Am. J. Med. Genet. 161A: 2588-2593, 2013. [PubMed: 23918704] [Full Text: https://doi.org/10.1002/ajmg.a.36094]
Thiele, H., Sakano, M., Kitagawa, H., Sugahara, K., Rajab, A., Hohne, W., Ritter, H., Leschik, G., Nurnberg, P., Mundlos, S. Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement. Proc. Nat. Acad. Sci. 101: 10155-10160, 2004. [PubMed: 15215498] [Full Text: https://doi.org/10.1073/pnas.0400334101]
Tsutsumi, K., Shimakawa, H., Kitagawa, H., Sugahara, K. Functional expression and genomic structure of human chondroitin 6-sulfotransferase. FEBS Lett. 441: 235-241, 1998. [PubMed: 9883891] [Full Text: https://doi.org/10.1016/s0014-5793(98)01532-4]
Tuysuz, B., Mizumoto, S., Sugahara, K., Celebi, A., Mundlos, S., Turkmen, S. Omani-type spondyloepiphyseal dysplasia with cardiac involvement caused by a missense mutation in CHST3. Clin. Genet. 75: 375-383, 2009. [PubMed: 19320654] [Full Text: https://doi.org/10.1111/j.1399-0004.2009.01167.x]
Unger, S., Lausch, E., Rossi, A., Megarbane, A., Sillence, D., Alcausin, M., Aytes, A., Mendoza-Londono, R., Nampoothiri, S., Afroze, B., Hall, B., Lo, I. F. M., and 17 others. Phenotypic features of carbohydrate sulfotransferase 3 (CHST3) deficiency in 24 patients: congenital dislocations and vertebral changes as principal diagnostic features. Am. J. Med. Genet. 152A: 2543-2549, 2010. [PubMed: 20830804] [Full Text: https://doi.org/10.1002/ajmg.a.33641]
van Roij, M. H. H., Mizumoto, S., Yamada, S., Morgan, T., Tan-Sindhunata, M. B., Meijers-Heijboer, H., Verbeke, J. I. L. M., Markie, D., Sugahara, K., Robertson, S. P. Spondyloepiphyseal dysplasia, Omani type: further definition of the phenotype. Am. J. Med. Genet. 146A: 2376-2384, 2008. [PubMed: 18698629] [Full Text: https://doi.org/10.1002/ajmg.a.32482]