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Macular corneal dystrophy type I and type II are caused by distinct mutations in a new sulphotransferase gene

Nature Genetics volume 26, pages 237–241 (2000)Cite this article

A Correction to this article was published on 01 January 2001

Abstract

Macular corneal dystrophy (MCD; MIM 217800) is an autosomal recessive hereditary disease in which progressive punctate opacities in the cornea result in bilateral loss of vision, eventually necessitating corneal transplantation. MCD is classified into two subtypes, type I and type II, defined by the respective absence and presence of sulphated keratan sulphate in the patient serum, although both types have clinically indistinguishable phenotypes1,2. The gene responsible for MCD type I has been mapped to chromosome 16q22, and that responsible for MCD type II may involve the same locus3,4,5. Here we identify a new carbohydrate sulphotransferase gene (CHST6), encoding an enzyme designated corneal N-acetylglucosamine-6-sulphotransferase (C-GlcNAc6ST), within the critical region of MCD type I. In MCD type I, we identified several mutations that may lead to inactivation of C-GlcNAc6ST within the coding region of CHST6. In MCD type II, we found large deletions and/or replacements caused by homologous recombination in the upstream region of CHST6. In situ hybridization analysis did not detect CHST6 transcripts in corneal epithelium in an MCD type II patient, suggesting that the mutations found in type II lead to loss of cornea-specific expression of CHST6.

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Figure 1: Genomic organization and peptide sequence of CHST6.
Figure 2: Distribution of sulphated keratan sulphate and CHST6 transcripts in human normal and MCD type II corneas.
Figure 3: MCD type I mutations in family E.
Figure 4: DNA rearrangements found in the upstream region of CHST6 in MCD type II patients.

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Acknowledgements

We thank N. Hiraoka, R. Aoki, H. Nakagawa, S. Saburi and A. Suzuki for discussions; C. Sotozono for patient DNA samples; M. Onda for normal Japanese samples; and S. Kubota and A. Pai for technical assistance. This work was supported by NIH grant CA71932 (M.N.F.), AG04736 and AR39239 (E.J.-M.A.T.). This work was also supported by Grant-in-Aid for Scientific Research (09671800, 10178104, 10470365) from the Ministry of Education, Science, Sports and Culture of Japan (H.W., J.N. and S.K.)

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Authors and Affiliations

  1. Glycobiology Program, The Burnham Institute, La Jolla, California, USA

    Tomoya O. Akama & Michiko N. Fukuda

  2. Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Kohji Nishida, Takahiro Nakamura, Atsuyoshi Dota, Satoshi Kawasaki & Shigeru Kinoshita

  3. Institute of Organ Transplants, Reconstructive Medicine and Tissue Engineering, Shinshu University Graduate School of Medicine, Shinshu University Hospital, Matsumoto, Japan

    Jun Nakayama

  4. Central Clinical Laboratories, Osaka University Medical School, Osaka, Japan

    Jun Nakayama

  5. Department of Ophthalmology, Osaka University Medical School, Osaka, Japan

    Kohji Nishida, Hitoshi Watanabe, Yoshitsugu Inoue, Naoyuki Maeda, Shuji Yamamoto & Yoshikazu Shimomura

  6. Otsuka GEN Research Institute, Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan

    Kouichi Ozaki, Tsutomu Fujiwara & Akira Tanigami

  7. Department of Biochemistry and Internal Medicine, Rush Medical College, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois, USA

    Eugene J.-M.A. Thonar

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  1. Tomoya O. Akama
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Correspondence to Akira Tanigami or Michiko N. Fukuda.

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Akama, T., Nishida, K., Nakayama, J. et al. Macular corneal dystrophy type I and type II are caused by distinct mutations in a new sulphotransferase gene. Nat Genet 26, 237–241 (2000). https://doi.org/10.1038/79987

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