Loss-of-function mutations of CHST14 in a new type of Ehlers-Danlos syndrome

Noriko Miyake, Tomoki Kosho, Shuji Mizumoto, Tatsuya Furuichi, Atsushi Hatamochi, Yoji Nagashima, Eiichi Arai, Kazuo Takahashi, Rie Kawamura, Keiko Wakui, Jun Takahashi, Hiroyuki Kato, Hiroshi Yasui, Tadao Ishida, Hirofumi Ohashi, Gen Nishimura, Masaaki Shiina, Hirotomo Saitsu, Yoshinori Tsurusaki, Hiroshi DoiYoshimitsu Fukushima, Shiro Ikegawa, Shuhei Yamada, Kazuyuki Sugahara, Naomichi Matsumoto

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129 Citations (Scopus)


Ehlers-Danlos syndrome (EDS) is a heterogeneous connective tissue disorder involving skin and joint laxity and tissue fragility. A new type of EDS, similar to kyphoscoliosis type but without lysyl hydroxylase deficiency, has been investigated. We have identified a homozygous CHST14 (carbohydrate sulfotransferase 14) mutation in the two familial cases and compound heterozygous mutations in four sporadic cases. CHST14 encodes dermatan 4-O-sulfotransferase 1 (D4ST1), which transfers active sulfate from 3′-phosphoadenosine 5′-phosphosulfate to position 4 of the N-acetyl-Dgalactosamine (GalNAc) residues of dermatan sulfate (DS). Transfection experiments of mutants and enzyme assays using fibroblast lysates of patients showed the loss of D4ST1 activity. CHST14 mutations altered the glycosaminoglycan (GAG) components in patients' fibroblasts. Interestingly, DS of decorin proteoglycan, a key regulator of collagen fibril assembly, was completely lost and replaced by chondroitin sulfate (CS) in the patients' fibroblasts, leading to decreased flexibility of GAG chains. The loss of the decorin DS proteoglycan due to CHST14 mutations may preclude proper collagen bundle formation or maintenance of collagen bundles while the sizes and shapes of collagen fibrils are unchanged as observed in the patients' dermal tissues. These findings indicate the important role of decorin DS in the extracellular matrix and a novel pathomechanism in EDS.

Original languageEnglish
Pages (from-to)966-974
Number of pages9
JournalHuman Mutation
Issue number8
Publication statusPublished - 08-2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)


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