Carbohydrate (N-Acetylgalactosamine 4-O) Sulfotransferase 14 (CHST14)

Reference work entry


The CHST14 gene, localized at 15q14, is a single exon gene with an open reading frame of 1131 base pairs, encoding a 43 kDa protein dermatan-4-O-sulfotransferase-1 (D4ST1) that catalyzes the 4-O-sulfation of N-acetyl-D-galactosamine residues in dermatan sulfate (DS). Both nearly exhaustively desulfated DS and partially desulfated DS serve as excellent substrates for the enzyme. Chst14/D4st1-deficient mice showed growth retardation as well as multiple system abnormalities including neurology such as decreased neurogenesis and diminished proliferation of neural stem cells. Recently, recessive loss-of-function mutations in the CHST14 gene were found to cause a specific form of Ehlers-Danlos syndrome (EDS) designated as D4ST1-deficient EDS (DD-EDS). The disorder is characterized by progressive multisystem fragility-related manifestations (skin hyperextensibilty and fragility, progressive spinal and foot deformities, large subcutaneous hematoma) and various malformations (facial features, congenital eye/heart/gastrointestinal defects, congenital multiple contractures). Glycosaminoglycan (GAG) chains from the affected skin fibroblasts were composed of a negligible amount of DS and excess chondroitin sulfate (CS), which was suggested to result from an impaired lock by 4-O-sulfation due to D4ST1 deficiency followed by back epimerization from L-iduronic acid to D-glucuronic acid. GAG chains of decorin from the affected skin fibroblasts were composed exclusively of CS and no DS, the opposite features observed in normal controls. Thus, skin fragility in the disorder was supposed to be caused by impaired assembly of collagen fibrils mediated by decorin bearing a CS chain that replaced a DS chain. The disorder stresses the importance of the role of CHST14/D4ST1 and DS in human development and maintenance of extracellular matrices.


Chondroitin Sulfate Collagen Fibril Dermatan Sulfate Chondroitin Sulfate Chain GalNAc Residue 


  1. Bian S, Akyüz N, Bernreuther C, Loers G, Laczynska E, Jakovcevski I, Schachner M (2011) Dermatan sulfotransferase Chst14/D4st1, but not chondroitin sulfotransferase Chst11/C4st1, regulates proliferation and neurogenesis of neural progenitor cells. J Cell Sci 124:4051–4063PubMedCrossRefGoogle Scholar
  2. Dündar M, Demiryilmaz F, Demiryilmaz I, Kumandas S, Erkilic K, Kendirch M, Tuncel M, Ozyazgan I, Tolmie JL (1997) An autosomal recessive adducted thumb-club foot syndrome observed in Turkish cousins. Clin Genet 51:61–64PubMedCrossRefGoogle Scholar
  3. Dündar M, Kurtoglu S, Elmas B, Demiryilmaz F, Candemir Z, Ozkul Y, Durak AC (2001) A case with adducted thumb and club foot syndrome. Clin Dysmorphol 10:291–293PubMedCrossRefGoogle Scholar
  4. Dündar M, Müller T, Zhang Q, Pan J, Steinmann B, Vodopiutz J, Gruber R, Sonoda T, Krabichler B, Utermann G, Baenziger JU, Zhang L, Janecke AR (2009) Loss of dermatan-4-sulfotransferase 1 function results in adducted thumb-clubfoot syndrome. Am J Hum Genet 85:873–882PubMedCentralPubMedCrossRefGoogle Scholar
  5. Evers MR, Xia G, Kang HG, Schachner M, Baeziger JU (2001) Molecular cloning and characterization of a dermatan-specific N-acetylgalactosamine 4-O-sulfotransferase. J Biol Chem 276:36344–36353PubMedCrossRefGoogle Scholar
  6. Janecke AR, Unsinn K, Kreczy A, Baldissera I, Gassner I, Neu N, Utermann G, Müller T (2001) Adducted thumb-club foot syndrome in sibs of a consanguineous Austrian family. J Med Genet 38:265–269PubMedCrossRefGoogle Scholar
  7. Kosho T (2011) Discovery and delineation of dermatan 4-O-sulfotransferase-1 (D4ST1)-deficient Ehlers-Danlos syndrome. Shinshu Med J 59:305–319Google Scholar
  8. Kosho T (2013) Discovery and delineation of dermatan 4-O-sulfotransferase-1 (D4ST1)-deficient Ehlers-Danlos syndrome. In: Oiso N (ed) Current Genetics in Dermatology, Intech, 73–86Google Scholar
  9. Kosho T, Takahashi J, Ohashi H, Nishimura G, Kato H, Fukushima Y (2005) Ehlers–Danlos syndrome type VIB with characteristic facies, decreased curvatures of the spinal column, and joint contractures in two unrelated girls. Am J Med Genet A 138A:282–287PubMedCrossRefGoogle Scholar
  10. Kosho T, Miyake N, Hatamochi A, Takahashi J, Kato H, Miyahara T, Igawa Y, Yasui H, Ishida T, Ono K, Kosuda T, Inoue A, Kohyama M, Hattori T, Ohashi H, Nishimura G, Kawamura R, Wakui K, Fukushima Y, Matsumoto N (2010) A new Ehlers–Danlos syndrome with craniofacial characteristics, multiple congenital contractures, progressive joint and skin laxity, and multisystem fragility-related manifestations. Am J Med Genet A 152A:1333–1346PubMedGoogle Scholar
  11. Kosho T, Miyake N, Mizumoto S, Hatamochi A, Fukushima Y, Yamada S, Sugahara K, Matsumoto N (2011) A response to: loss of dermatan-4-sulfotransferase 1 (D4ST1/CHST14) function represents the first dermatan sulfate biosynthesis defect, “dermatan sulfate-deficient Adducted Thumb-Clubfoot Syndrome”. Which name is appropriate, “Adducted Thumb-Clubfoot Syndrome” or “Ehlers-Danlos syndrome”? Hum Mutat 32:1507–1509PubMedCrossRefGoogle Scholar
  12. Malfait F, Syx D, Vlummens P, Symoens S, Nampoothiri S, Hermanns-Lê L, Van Lear, De Paepe A (2010) Musculocontractural Ehlers–Danlos syndrome (former EDS type VIB) and adducted thumb clubfoot syndrome (ATCS) represent a single clinical entity caused by mutations in the dermatan-4-sulfotransferase 1 encoding CHST14 gene. Hum Mutat 31:1233–1239PubMedCrossRefGoogle Scholar
  13. Mendoza-Londono R, Chitayat D, Kahr WH, Hinek A, Blaser S, Dupuis L, Goh E, Badilla-Porras R, Howard A, Mittaz L, Superti-Furga A, Unger S, Nishimura G, Bonafe L (2012) Extracellular matrix and platelet function in patients with musculocontractural Ehlers-Danlos syndrome caused by mutations in the CHST14 gene. Am J Med Genet A 158A:1344–1354PubMedCrossRefGoogle Scholar
  14. Mikami T, Mizumoto S, Kago N, Kitagawa H, Sugahara K (2003) Specificities of three distinct human chondroitin/dermatan N-acetylgalactosamine 4-O-sulfotransferases demonstrated using partially desulfated dermatan sulfate as an acceptor: implication of differential roles in dermatan sulfate biosynthesis. J Biol Chem 278:36115–36127PubMedCrossRefGoogle Scholar
  15. Miyake N, Kosho T, Mizumoto S, Furuichi T, Hatamochi A, Nagashima Y, Arai E, Takahashi K, Kawamura R, Wakui K, Takahashi J, Kato H, Yasui H, Ishida T, Ohashi H, Nishimura G, Shiina M, Saitsu H, Tsurusaki Y, Doi H, Fukushima Y, Ikegawa S, Yamada S, Sugahara K, Matsumoto N (2010) Loss-of-function mutations of CHST14 in a new type of Ehles–Danlos syndrome. Hum Mutat 31:966–974PubMedCrossRefGoogle Scholar
  16. Nomura Y (2006) Structural changes in decorin with skin aging. Connect Tissue Res 47:249–255PubMedCrossRefGoogle Scholar
  17. Shimizu K, Okamoto N, Miyake N, Taira K, Sato Y, Matsuda K, Akimaru N, Ohashi H, Wakui K, Fukushima Y, Matsumoto N, Kosho T (2011) Delineation of dermatan 4-O-sulfotransferase 1 deficient Ehlers-Danlos syndrome: observation of two additional patients and comprehensive review of 20 reported patients. Am J Med Genet A 155:1949–1958CrossRefGoogle Scholar
  18. Sonoda T, Kouno K (2000) Two brothers with distal arthrogryposis, peculiar facial appearance, cleft palate, short stature, hydronephrosis, retentio testis, and normal intelligence: a new type of distal arthrogryposis? Am J Med Genet 91:280–285PubMedCrossRefGoogle Scholar
  19. Tang T, Li L, Tang J, Li Y, Lin WY, Martin F, Grant D, Solloway M, Parker L, Ye W, Forrest W, Ghilardi N, Oravecz T, Platt KA, Rice DS, Hansen GM, Abuin A, Eberhart DE, Godowski P, Holt KH, Peterson A, Zambrowicz BP, de Sauvage FJ (2010) A mouse knockout library for secreted and transmembrane proteins. Nat Biotechnol 28:749–755PubMedCrossRefGoogle Scholar
  20. van Roij MH, Mizumoto S, Yamada S, Morgan T, Tan-Sindhunata MB, Meijers-Heijboer H, Verbeke JI, Markie D, Sugahara K, Robertson SP (2008) Spondyloepiphyseal dysplasia, Omani type: further definition of the phenotype. Am J Med Genet A 146:2376–2384CrossRefGoogle Scholar
  21. Voermans NC, Kempers M, Lammens M, van Alfen N, Janssen MC, Bönnemann C, van Engelen BG, Hamel BC (2012) Myopathy in a 20-year-old female patient with D4ST-1 deficient Ehlers-Danlos syndrome due to a homozygous CHST14 mutation. Am J Med Genet A 158A:850–855PubMedCrossRefGoogle Scholar
  22. Winters KA, Jiang Z, Xu W, Li S, Ammous Z, Jayakar P, Wierenga KJ (2012) Re-assigned diagnosis of D4ST1-deficient Ehlers-Danlos syndrome (adducted thumb-clubfoot syndrome) after initial diagnosis of Marden-Walker syndrome. Am J Med Genet A 158A:2935–2940PubMedCrossRefGoogle Scholar
  23. Yasui H, Adachi Y, Minami T, Ishida T, Kato Y, Imai K (2003) Combination therapy of DDAVP and conjugated estrogens for a recurrent large subcutaneous hematoma in Ehlers–Danlos syndrome. Am J Hematol 72:71–72PubMedCrossRefGoogle Scholar
  24. Zhang L, Müller T, Baenziger JU, Janecke AR (2010) Congenital disorders of glycosylation with emphasis on loss of dermatan-4-sulfotransferase. Prog Mol Biol Transl Sci 93:289–307PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2014

Authors and Affiliations

  • Tomoki Kosho
    • 1
  • Shuji Mizumoto
    • 2
  • Kazuyuki Sugahara
    • 2
  1. 1.School of MedicineDepartment of Medical Genetics, Shinshu UniversityMatsumotoJapan
  2. 2.Laboratory of Proteoglycan Signaling and TherapeuticsHokkaido University Graduate School of Life ScienceKita-kuJapan

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