Skeletal Dysplasias Caused by Sulfation Defects
Abstract
:1. Introduction
2. The Cellular Metabolism of Sulfate
2.1. The Origin of Intracellular Sulfate
2.2. The Sulfate Activation Pathway
2.3. The Sulfation Pathway
3. Sulfate Metabolism and Genetic Diseases
3.1. Skeletal Dysplasias Linked to Proteins Involved in Sulfate Metabolism
3.2. Skeletal Dysplasias Linked to Proteins Involved in GAG Sulfation
4. Alterations of Extracellular Matrix and Cell Homeostasis Due to Defects in PG Sulfation
5. Conclusions and Perspectives
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ACG1B | achondrogenesis type 1B |
AO2 | atelosteogenesis type 2 |
APS | adenosine 5′-phosphosulfate |
BCYM1A | brachyolmia type 1 Hobaek form |
BCYM1B | brachyolmia type 1 Toledo form |
BCYM4 | brachyolmia type 4 |
BPNT2 | 3′(2′) 5′-bisphosphate nucleotidase 2 |
C4ST | chondroitin-4-O-sulfotransferase |
C6ST | chondroitin-6-O-sulfotransferase |
CS | chondroitin sulfate |
D4ST | dermatan-4-O-sulfotransferase |
DHEA | dehydroepiandrosterone |
DHEAS | dehydroepiandrosterone sulfate ester |
DS | dermatan sulfate |
DTD | diastrophic dysplasia |
DTDST | diastrophic dysplasia sulfate transporter |
ECM | extracellular matrix |
EDM4 | recessive multiple epiphyseal dysplasia |
EDSMC1 | Ehlers-Danlos syndrome musculocontractural type 1 |
GAG | glycosaminoglycan |
GalNAc | N-acetylgalactosamine |
gPAPP | Golgi resident phosphoadenosine phosphate phosphatase |
HS | heparan sulfate |
IMPAD1 | inositol monophosphatase domain-containing protein 1 |
OCBMD | osteochondrodysplasia brachydactyly and overlapping malformed digits |
PAP | phosphoadenosine phosphate |
PAPS | 3′-phosphoadenosine 5′-phosphosulfate |
PAPSS | PAPS synthetase |
PAPST | PAPS transporter |
PG | proteoglycan |
SEDCJD | spondyloepiphyseal dysplasia with congenital joint dislocations |
ST | carbohydrate sulfotransferase |
SULT | cytosolic sulfotransferase |
TPST | tyrosylprotein sulfotransferase |
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Pathology | MIM/Inheritance | Causative Gene | Protein Product and Function | Biochemical Phenotype | References |
---|---|---|---|---|---|
Achondrogenesis type 1B (ACG1B) | 600972/AR | SLC26A2 | Sulfate/chloride antiporter present on cell membrane. | Severe cartilage PG undersulfation; reduced sulfate uptake in fibroblasts. | [60,65,66,71,93] |
Atelosteogenesis type 2 (AO2) | 256050/AR | SLC26A2 | Sulfate/chloride antiporter present on cell membrane. | Severe cartilage PG undersulfation; reduced sulfate uptake in fibroblasts. | [60,65,66,94] |
Diastrophic dysplasia (DTD) | 222600/AR | SLC26A2 | Sulfate/chloride antiporter present on cell membrane. | Cartilage PG undersulfation; reduced sulfate uptake in fibroblasts; in mice altered sulfate uptake in chondrocytes, and osteoblasts; altered Ihh signaling; reduced chondrocytes proliferation. | [34,60,65,66,67,68,69,70] |
Recessive multiple epiphyseal dysplasia (EDM4) | 226900/AR | SLC26A2 | Sulfate/chloride antiporter present on cell membrane. | Reduced sulfate uptake. | [60,65,95] |
Spondyloepimetaphyseal dysplasia, SEMD, Pakistani type or Brachyolmia type 4 (BCYM4) | 612847/AR | PAPSS2 | PAPS synthetase 2, enzyme that synthesizes the universal sulfate donor (PAPS). | Macromolecular undersulfation; signs of androgen excess (in a minority of patients); very low DHEAS levels and increased androgen levels (in one patient). | [40,42,72,73,76] |
Brachyolmia type 1 (includes Hobaek form and Toledo form, BCYM1A and 1B respectively) | 271530/AR 271630/AR | PAPSS2 | PAPS synthetase 2, enzyme that synthesizes the universal sulfate donor (PAPS). | Undersulfation of CS; low activity of PAPS-CS sulfotransferase; signs of androgen excess (in a minority of patients). | [73,74,75,76] |
Chondrodysplasia with joint dislocations, gPAPP type | 614078/AR | BPNT2 | Golgi resident PAP phosphatase, enzyme that hydrolyzes PAP to AMP and phosphate. | In mice impaired CS and HS sulfation. | [56,57,58,77] |
Spondyloepiphyseal dysplasia with congenital joint dislocations (SEDCJD or SED Omani type) | 143095/AR | CHST3 | Carbohydrate sulfotransferase-3, enzyme that transfers sulfate to GalNAc residues of CS. | Depletion of 6-O-sulfated GalNAc residues in CS chains in fibroblasts and urine. | [78,79,80,81,82,83,84] |
Ehlers-Danlos syndrome musculocontractural type 1 (EDSMC1) | 601776/AR | CHST14 | Carbohydrate sulfotransferase-14, enzyme that transfers sulfate to GalNAc residues of DS. | Reduction of 4-O-sulfation in GalNAc residues in DS chains; decrease of DS and increase of CS chain synthesis. | [85,86,87,88,89] |
Osteochondrodysplasia, brachydactyly and overlapping malformed digits (OCBMD) | 618167/AR | CHST11 | Carbohydrate sulfotransferase-11, enzyme that transfers sulfate to GalNAc residues of CS. | In mice abnormal CS localization; strong up-regulation of TGF-β signaling and down-regulation of BMP signaling; altered morphology of the growth plate. | [90,91,92] |
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Paganini, C.; Gramegna Tota, C.; Superti-Furga, A.; Rossi, A. Skeletal Dysplasias Caused by Sulfation Defects. Int. J. Mol. Sci. 2020, 21, 2710. https://doi.org/10.3390/ijms21082710
Paganini C, Gramegna Tota C, Superti-Furga A, Rossi A. Skeletal Dysplasias Caused by Sulfation Defects. International Journal of Molecular Sciences. 2020; 21(8):2710. https://doi.org/10.3390/ijms21082710
Chicago/Turabian StylePaganini, Chiara, Chiara Gramegna Tota, Andrea Superti-Furga, and Antonio Rossi. 2020. "Skeletal Dysplasias Caused by Sulfation Defects" International Journal of Molecular Sciences 21, no. 8: 2710. https://doi.org/10.3390/ijms21082710