| *608183 | |||||||||||||||||||||
| CHONDROITIN SULFATE SYNTHASE 1; CHSY1 | |||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||
| CHONDROITIN SYNTHASE 1; CSS1 CARBOHYDRATE SYNTHASE 1 KIAA0990 | |||||||||||||||||||||
| HGNC Approved Gene Symbol: CHSY1 | |||||||||||||||||||||
| Cytogenetic location: 15q26.3 Genomic coordinates (GRCh37): 15:101,715,927 - 101,792,136 (from NCBI) | |||||||||||||||||||||
| Gene Phenotype Relationships | |||||||||||||||||||||
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| TEXT | |||||||||||||||||||||
| Description | |||||||||||||||||||||
| CHSY1 synthesizes chondroitin sulfate, a glycosaminoglycan expressed on the surface of most cells and in extracellular matrices. Glycosaminoglycan chains are covalently linked to a wide range of core protein families and regulate many biologic processes, including cell proliferation and recognition, extracellular matrix deposition, and morphogenesis (summary by Kitagawa et al., 2001). | |||||||||||||||||||||
| Cloning | |||||||||||||||||||||
| By sequencing clones obtained from a brain cDNA library, Nagase et al. (1999) cloned CHSY1, which they designated KIAA0990. The CHSY1 transcript contains an Alu repeat within the 3-prime untranslated region, and the deduced protein contains 802 amino acids. RT-PCR detected intermediate to high expression in all tissues and individual brain regions examined. Expression was highest in lung, ovary, spinal cord, fetal liver, amygdala, and cerebellum and lowest in pancreas and adult and fetal whole brain. Kitagawa et al. (2001) further characterized KIAA0990. They determined that the CHSY1 protein has a calculated molecular mass of about 92 kD. CHSY1 contains an N-terminal type II transmembrane segment and a D8D motif, which is found in most glycosyltransferases. It also has 3 sites for N-glycosylation. The N-terminal half of CHSY1 shares weak sequence similarity with core-1 beta-1,3-galactosyltransferase-1 (C1GALT1), and the C-terminal half shares similarity with beta-1,4-galactosyltransferase-2 (B4GALT2; 604013). Northern blot analysis detected a 5.0-kb transcript in all tissues examined, with highest expression in placenta, followed by spleen, lung, and peripheral blood leukocytes. Li et al. (2010) performed in situ hybridization analysis and found Chsy1 expression in mouse chondrocytes and the developing mouse inner ear at embryonic days 12.5 and 14.5. In wildtype zebrafish, whole-mount in situ hybridization revealed widespread expression of chsy1 in the head and prominent expression in the floor plate and the fin epithelium at 24 hours postfertilization. During the second day of development, prominent expression was also detected in the heart, chondrocytes of the developing head skeleton, pharyngeal endoderm of the branchial arches, distal regions of the pectoral fin buds, and epithelial protrusions of the inner ears. These protrusions later fused to form the semicircular canal ducts, and chsy1 transcript levels appeared to drop after fusion. | |||||||||||||||||||||
| Gene Structure | |||||||||||||||||||||
| Kitagawa et al. (2001) determined that the CHSY1 gene contains 3 exons and spans more than 40 kb. | |||||||||||||||||||||
| Mapping | |||||||||||||||||||||
| The International Radiation Hybrid Mapping Consortium mapped the CHSY1 gene to chromosome 15 (RH27419). Tian et al. (2010) noted that the CHSY1 gene maps to chromosome 15q26.3. | |||||||||||||||||||||
| Gene Function | |||||||||||||||||||||
| Using a variety of acceptor and donor substrates, Kitagawa et al. (2001) found that soluble CHSY1 expressed in COS-1 cells acted as a galactosyltransferase that could transfer glucuronic acid (GlcUA) from UDP-(14C)GlcUA and N-acetylgalactosamine (GalNAc) from UDP-(3H)GalNAc to the polymer chondroitin. Identification of the reaction products determined that CHSY1 showed both beta-1,3-GlcUA transferase and beta-1,4-GalNAc transferase activities. Li et al. (2010) observed that in the inner ears of zebrafish larvae, chsy1 was expressed similarly to the bone morphogenetic protein (see BMP2B, 112262) inhibitor dan (NBL1; 600613) and in a complementary fashion to bmp2b. Unrestricted Bmp2b signaling or loss of Dan activity led to reduced chsy1 expression and, during epithelial morphogenesis, defects similar to those that occur upon Chsy1 inactivation, indicating that Bmp signaling affects inner ear development by repressing chsy1. Tian et al. (2010) analzyed components of the NOTCH (see 164951) signaling pathway in fibroblasts from patients with a truncating CHSY1 mutation (608183.0006) and found massive production of JAG1 (601920) and subsequent NOTCH activation, which could only be reversed with a wildtype but not a Fringe catalytically dead CHSY1 construct. RNAi knockdown of CHSY1 resulted in enhanced osteogenesis in human fetal osteoblasts and remarkable upregulation of JAG2 in human neural glioblastoma cells. Antisense morpholino knockdown of chsy1 in zebrafish embryos partially phenocopied the human disorder (605282); it increased notch output and impaired skeletal, pectoral fin, and retinal development. Tian et al. (2010) concluded that CHSY1 is a secreted FRINGE enzyme required for adjustment of NOTCH signaling throughout human and fish embryogenesis and particularly during limb patterning. | |||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||
| In 5 consanguineous families with Temtamy preaxial brachydactyly syndrome (TPBS; 605282), including the Egyptian family originally described by Temtamy et al. (1998), Li et al. (2010) analyzed the candidate gene CHSY1 and identified 5 different homozygous mutations (608183.0001-608183.0005, respectively), that cosegregated with disease in each family and were not found in more than 150 controls. In a brother and sister with TPBS from a consanguineous Jordanian family, Tian et al. (2010) identified homozygosity for a 1-bp deletion in the CHSY1 gene (608183.0006). | |||||||||||||||||||||
| Animal Model | |||||||||||||||||||||
| By RNA-mediated interference and deletion mutagenesis, Mizuguchi et al. (2003) depleted chondroitin synthase from C. elegans. Blocking chondroitin synthesis resulted in cytokinesis defects in early embryogenesis. Reversion of cytokinesis was often observed in chondroitin-depleted embryos, and cell division eventually stopped, resulting in early embryonic death. Li et al. (2010) demonstrated that in developing zebrafish, both loss and gain of chsy1 function lead to defects similar to those in human patients with Temtamy preaxial brachydactyly syndrome (TPBS; 605282). The defects observed included reduced body length, compromised formation of the pectoral fin, severe midline deficiencies in the cartilage of the neurocranium, and compromised formation of the epithelial protrusions and semicircular canals in the inner ear. Li et al. (2010) noted that the strikingly similar zebrafish phenotypes obtained after chsy1 inactivation or overexpression might explain why, in humans, brachydactyly can be caused by mutations leading either to loss or gain of BMP (see BMP1, 112264) signaling. | |||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | |||||||||||||||||||||
| Table View | |||||||||||||||||||||
| .0001 TEMTAMY PREAXIAL BRACHYDACTYLY SYNDROME | |||||||||||||||||||||
| CHSY1, 30-BP DEL, NT55 | |||||||||||||||||||||
| In a male proband from a consanguineous Egyptian family with Temtamy preaxial brachydactyly syndrome (TPBS; 605282), originally reported by Temtamy et al. (1998), Li et al. (2010) identified homozygosity for a 30-bp deletion (55-84del) in exon 1 of the CHSY1 gene, removing 10 residues (G19_L28del). The mutation was not found in more than 150 controls. | |||||||||||||||||||||
| .0002 TEMTAMY PREAXIAL BRACHYDACTYLY SYNDROME | |||||||||||||||||||||
| CHSY1, 1-BP DEL, 14G | |||||||||||||||||||||
| In a male proband from a consanguineous Egyptian family with Temtamy preaxial brachydactyly syndrome (TPBS; 605282), Li et al. (2010) identified homozygosity for a 1-bp deletion (14delG) in exon 1 of the CHSY1 gene, predicted to cause a frameshift and a premature termination codon. The mutation was not found in more than 150 controls. | |||||||||||||||||||||
| .0003 TEMTAMY PREAXIAL BRACHYDACTYLY SYNDROME | |||||||||||||||||||||
| CHSY1, GLN69TER | |||||||||||||||||||||
| In a sister and 2 brothers with Temtamy preaxial brachydactyly syndrome (TPBS; 605282) from a consanguineous Turkish family, Li et al. (2010) identified homozygosity for a 205C-T transition in exon 1 of the CHSY1 gene, resulting in a gln69-to-ter (Q69X) substitution. The mutation was not found in more than 150 controls. | |||||||||||||||||||||
| .0004 TEMTAMY PREAXIAL BRACHYDACTYLY SYNDROME | |||||||||||||||||||||
| CHSY1, IVS1AS, C-G, -3 | |||||||||||||||||||||
| In a 4-year-old girl with Temtamy preaxial brachydactyly syndrome (TPBS; 605282) from a consanguineous Sri Lankan family, originally reported by Race et al. (2010), Li et al. (2010) identified homozygosity for an acceptor splice site transversion (321-3C-G) in intron 1 of the CHSY1 gene, predicted to cause skipping of exon 2 and result in a frameshift and premature protein truncation. Electropherograms of CHSY1 transcripts from the patient confirmed skipping of exon 2. The mutation was not found in more than 150 controls. | |||||||||||||||||||||
| .0005 TEMTAMY PREAXIAL BRACHYDACTYLY SYNDROME | |||||||||||||||||||||
| CHSY1, PRO539ARG | |||||||||||||||||||||
| In 2 sisters and a brother with Temtamy preaxial brachydactyly syndrome (TPBS; 605282) from a consanguineous Pakistani family originally reported by Race et al. (2010), Li et al. (2010) identified homozygosity for a 1616C-G transversion in exon 3 of the CHSY1 gene, resulting in a pro539-to-arg (P539R) substitution at a highly conserved residue within the chrondroitin N-acetylgalactosaminyltransferase (CHGN) domain of CHSY1. The unaffected parents were heterozygous for the mutation, which was not found in more than 150 controls. | |||||||||||||||||||||
| .0006 TEMTAMY PREAXIAL BRACHYDACTYLY SYNDROME | |||||||||||||||||||||
| CHSY1, 1-BP DEL, 96C | |||||||||||||||||||||
| In a brother and sister with Temtamy preaxial brachydactyly syndrome (TPBS; 605282) from a consanguineous Jordanian family, Tian et al. (2010) identified homozygosity for a 1-bp deletion (96delC) in the CHSY1 gene, introducing a frameshift leading to a premature stop codon at position 34, predicted to yield a severely truncated CHSY1 protein missing both its catalytic domains. CHSY1 was undetectable in patient fibroblasts but was detected at the expected molecular mass in a noncarrier unaffected sib. Immunohistochemistry on patient skin sections using a monoclonal antibody directed at chondroitin sulfate (CS) groups showed lower levels of CS in the stratum corneum, stratum germinativum, and dermal layers of the patient compared to control. | |||||||||||||||||||||
| REFERENCES | |||||||||||||||||||||
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