The first three authors contributed equally to this article.
Loss-of-function mutations of CHST14 in a new type of Ehlers-Danlos syndrome†
Article first published online: 8 JUN 2010
© 2010 Wiley-Liss, Inc.
Volume 31, Issue 8, pages 966–974, August 2010
How to Cite
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. and Matsumoto, N. (2010), Loss-of-function mutations of CHST14 in a new type of Ehlers-Danlos syndrome. Hum. Mutat., 31: 966–974. doi: 10.1002/humu.21300
Communicated by Jürgen Horst
- Issue published online: 15 JUL 2010
- Article first published online: 8 JUN 2010
- Accepted manuscript online: 8 JUN 2010 12:00AM EST
- Manuscript Accepted: 24 MAY 2010
- Manuscript Received: 17 MAR 2010
- Ehlers-Danlos syndrome;
- dermatan sulfate;
- dermatan 4-O-sulfotransferase 1;
- collagen bundle formation;
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-D-galactosamine (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. Hum Mutat 31:1–9, 2010. © 2010 Wiley-Liss, Inc.