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Fabry disease: correlation between structural changes in α-galactosidase, and clinical and biochemical phenotypes

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Abstract

Fabry disease comprises classic and variant phenotypes. The former needs early enzyme replacement therapy, and galactose infusion is effective for some variant cases. Attempts of early diagnosis before manifestations appear will begin in the near future. However, it is difficult to predict the phenotype, to determine the therapeutic approach, only from genetic information. Thus we attempted structural analysis from a novel viewpoint. We built structural models of mutant α-galactosidases resulting from 161 missense mutations (147 classic and 14 variant), and evaluated the influence of each replacement on the structure by calculating the numbers of atoms affected. Among them, 11 mutants, biochemically characterized, were further investigated by color imaging of the influenced atoms. In the variant group, the number of atoms influenced by amino-acid replacement was small, especially in the main chain. In 85% of the cases, less than three atoms in the main chain are influenced. In this group, small structural changes, located apart from the active site, result in destabilization of the mutant enzymes, but galactose can stabilize them. Structural changes caused by classic Fabry mutations are generally large or are located in functionally important regions. In 82% of the cases, three atoms or more in the main chain are affected. The classic group comprises dysfunctional and unstable types, and galactose is not expected to stabilize the mutant enzymes. This study demonstrated the correlation of structural changes, and clinical and biochemical phenotypes. Structural investigation is useful for elucidating the bases of Fabry disease and clinical treatment.

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Acknowledgements

We wish to thank Prof. K. Itoh (Department of Medical Biotechnology, Graduate School of Pharmaceutical Sciences, The University of Tokushima), and Drs. M. Kotani and Y. Tajima (Department of Clinical Genetics, The Tokyo Metropolitan Institute of Medical Science) for their valuable comments. This work was partly supported by grants from the Tokyo Metropolitan Government, the Japan Society for the Promotion of Science, CREST, the Japan Science and Technology Agency, the Ministry of Education, Science, Sports and Culture of Japan, and the Ministry of Health, Labor and Welfare of Japan.

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Authors and Affiliations

  1. Celestar Lexico-Sciences Inc., MTG-17, 1-3 Nakase, Mihama-ku, Chiba, 261-8501, Japan

    Fumiko Matsuzawa, Sei-ichi Aikawa & Hirofumi Doi

  2. Department of Analytical Biochemistry, School of Health Sciences, Kumamoto University, 4-24-1 Kuhonji, Kumamoto, 862-0976, Japan

    Toshika Okumiya

  3. Department of Clinical Genetics, Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8613, Japan

    Hitoshi Sakuraba

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  1. Fumiko Matsuzawa
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  2. Sei-ichi Aikawa
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  3. Hirofumi Doi
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  4. Toshika Okumiya
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  5. Hitoshi Sakuraba
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Correspondence to Hitoshi Sakuraba.

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Matsuzawa, F., Aikawa, Si., Doi, H. et al. Fabry disease: correlation between structural changes in α-galactosidase, and clinical and biochemical phenotypes. Hum Genet 117, 317–328 (2005). https://doi.org/10.1007/s00439-005-1300-5

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  • DOI: https://doi.org/10.1007/s00439-005-1300-5

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