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Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human

Nature Medicine volume 13, pages 1363–1367 (2007)Cite this article

Abstract

Proteoglycans are a family of extracellular macromolecules comprised of glycosaminoglycan chains of a repeated disaccharide linked to a central core protein1,2. Proteoglycans have critical roles in chondrogenesis and skeletal development. The glycosaminoglycan chains found in cartilage proteoglycans are primarily composed of chondroitin sulfate3. The integrity of chondroitin sulfate chains is important to cartilage proteoglycan function; however, chondroitin sulfate metabolism in mammals remains poorly understood. The solute carrier-35 D1 (SLC35D1) gene (SLC35D1) encodes an endoplasmic reticulum nucleotide-sugar transporter (NST) that might transport substrates needed for chondroitin sulfate biosynthesis4,5. Here we created Slc35d1-deficient mice that develop a lethal form of skeletal dysplasia with severe shortening of limbs and facial structures. Epiphyseal cartilage in homozygous mutant mice showed a decreased proliferating zone with round chondrocytes, scarce matrices and reduced proteoglycan aggregates. These mice had short, sparse chondroitin sulfate chains caused by a defect in chondroitin sulfate biosynthesis. We also identified that loss-of-function mutations in human SLC35D1 cause Schneckenbecken dysplasia, a severe skeletal dysplasia. Our findings highlight the crucial role of NSTs in proteoglycan function and cartilage metabolism, thus revealing a new paradigm for skeletal disease and glycobiology.

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Figure 1: Phenotype of the Slc35d1-deficient mice.
Figure 2: Effects of impaired chondroitin sulfate synthesis on cartilage proteoglycan in Slc35d1-deficient mice.
Figure 3: Loss-of-function mutations of SLC35D1 in Schneckenbecken dysplasia.

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Acknowledgements

We thank M. Nakayama (Kazusa DNA Research Institute) for donating the ES cell–BAC library. We are grateful to M. Muraoka for measurement of NST activity, to I. Kataoka and Y. Mizutani-Koseki for their assistance in histochemical analysis and in situ hybridization and to S. Tominaga for her help in genetic analysis of the human SLC35D1. This project was supported by Special Coordination Funds for the Promotion of Science and Technology from the Japanese Ministry of Education, Culture, Sports, Science and Technology (Contract Grant No. 13043003 to H.K.) and by grants-in-aid from the Ministry of Education, Culture, Sports and Science of Japan (Contract Grant No. 19209049), Research on Child Health and Development (Contract Grant Nos. 17C-1 and H18-005 to S.I.), the Ministry of Education, Culture, Sports and Science of Japan (Contract Grant No. 19510205 to S.H.) and the US National Institutes of Health (HD22657 and MO1-RR00425 to D.H.C. and D.L.R.). D.H.C. is the recipient of a Winnick Family Clinical Scholar Award.

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Author notes

  1. Shuichi Hiraoka and Tatsuya Furuichi: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory for Developmental Genetics, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehirocho, Tsurumi-ku, Yokohama, 230-0045, Kanagawa, Japan

    Shuichi Hiraoka, Minako Ogawa, Kayoko Katsuyama, Kyoichi Isono & Haruhiko Koseki

  2. Laboratory of Bone and Joint Diseases, Single Nucleotide Polymorphism Research Center, RIKEN, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

    Tatsuya Furuichi & Shiro Ikegawa

  3. Department of Radiology, Tokyo Metropolitan Kiyose Children's Hospital, 1-3-1 Umezono, Kiyose, 204-8567, Japan

    Gen Nishimura

  4. Department of Maxillofacial Biology, Maxillofacial Anatomy, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan

    Shunichi Shibata

  5. Department of Hard Tissue Engineering, Division of Biomatrix, Biochemistry, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan

    Masaki Yanagishita

  6. Medical Genetics Institute, Cedars-Sinai Medical Center, SSB-3, 8700 Beverly Blvd.

    David L Rimoin & Daniel H Cohn

  7. Departments of Human Genetics and Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, 90048, California, USA

    David L Rimoin & Daniel H Cohn

  8. Centre for Paediatrics and Adolescent Medicine, Freiburg University Hospital, Mathildenstrasse 1, Freiburg, D-79106, Germany

    Andrea Superti-Furga

  9. Department of Pathology, H04.312 University Medical Center Utrecht Postbox 85500, Utrecht, 3508 GA, The Netherlands

    Peter G Nikkels

  10. Faculty of Pharmaceutical Sciences, Chiba University, 1-33, Yayoi, Inage, 263-8522, Chiba, Japan

    Hidenao Toyoda & Akiko Kinoshita-Toyoda

  11. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, 332-0012, Saitama, Japan

    Hidenao Toyoda & Akiko Kinoshita-Toyoda

  12. Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, 332-0012, Saitama, Japan

    Hidenao Toyoda

  13. Department of Biochemical Cell Research, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8613, Japan

    Nobuhiro Ishida & Yutaka Sanai

Authors
  1. Shuichi Hiraoka
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  2. Tatsuya Furuichi
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Contributions

S.H. and T.F. performed the main experiments, analyzed data and prepared the manuscript. G.N., D.L.R., A.S.-F., P.G.N. and D.H.C. recruited human subjects and analyzed the human phenotypic data. S.S. and M.Y. performed proteoglycan analysis in knockout mice. M.O. and K.K. generated knockout mice and carried out histological analysis. H.T. and A.K.-T. determined glycosaminoglycan content. N.I., K.I. and Y.S. assayed mouse Slc35d1 protein. H.K. and S.I. planned and supervised the mouse and human parts of the project, respectively.

Corresponding authors

Correspondence to Haruhiko Koseki or Shiro Ikegawa.

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Supplementary Figs. 1–3, Supplementary Tables 1 and 2, Supplementary Case Report (PDF 1436 kb)

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Hiraoka, S., Furuichi, T., Nishimura, G. et al. Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human. Nat Med 13, 1363–1367 (2007). https://doi.org/10.1038/nm1655

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