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Mucopolysaccharidosis IVA: characterization of a common mutation found in Finnish patients with attenuated phenotype

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Abstract

Mucopolysaccharidosis IVA (MPS IVA) is caused by the deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase encoded by the GALNS gene on chromosome 16. We describe, in detail, the clinical phenotype of five patients from three unrelated Finnish families and have characterized the disease-causing mutations in GALNS. Genotypes of the patients are D60N/A291T, D60N/W230X, and D60N/1374delT. Mutation 1374delT introduces premature termination of GALNS. Cells over-expressing the novel mutation W230X and A291T had no residual GALNS activity, whereas D60N gave 12.2% residual activity compared with the wild type. Co-transfection of D60N/A291T and D60N/W230X showed 5.5% and 6.7% of wild type activity, respectively. The precursor proteins of D60N and A291T were observed at 55 kDa and 57 kDa, respectively, whereas there was no detectable band in cells over-expressing W230X. At 55°C, the mutant protein showed lower thermostability than the wild type protein at pH 3.8 and 7.0. The tertiary structural model of the GALNS protein revealed that aspartic acid at position 60 is located on the surface of the molecule, away from the active site. This makes it unlikely that the enzymatic function of the protein with D60N is severely impaired. On the other hand, A291 and W230 are localized near the active site. The molecular characteristics of the D60N mutation explain the attenuated clinical phenotype of the patients.

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Acknowledgements

We thank Dr. Paolo Tortora and Dr. Gabriele Toieta for providing the anti-GALNS anti serum. This study was supported in part by a Grant-in Aid for Scientific Research 12670740, 12670789, from the Ministry of Education, Science, Sports and Culture of Japan, and by a grant from the Ministry of Health and Welfare of Japan. A.M.M is grateful to the Japan Society for the Promotion of Science (JSPS) for support.

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  1. Adriana Maria Montaño

    Present address: Biosystems Science, The Graduate University for Advanced Studies, Shonan Village, Hayama, 240-0193, Kanagawa, Japan

Authors and Affiliations

  1. Department of Pediatrics, Gifu University School of Medicine, Tsukasa-machi 40, 500-8705, Gifu City , Japan

    Adriana Maria Montaño, Kazuko Sukegawa, Shunji Tomatsu, Zenichiro Kato, Seiji Fukuda, Tadao Orii & Naomi Kondo

  2. Clinical Genetics Unit, Helsinki University Hospital, Helsinki, Finland

    Ilkka Kaitila

  3. Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St Louis, Missouri, USA

    Shunji Tomatsu

  4. Research Center for Structural Biology, Institute for Protein Research, Osaka University, Osaka, Japan

    Haruki Nakamura

  5. Department of Human Welfare, Faculty of Human Welfare, Chubu Gakuin University, Seki, Japan

    Tadao Orii

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  1. Adriana Maria Montaño
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Corresponding author

Correspondence to Adriana Maria Montaño.

Additional information

Electronic database information: accession numbers for the data in this article are as follows:

OMIM#253000

GDB: 129085

GenBank: NM_000512, SEG_HUMNA6SS

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Montaño, A.M., Kaitila, I., Sukegawa, K. et al. Mucopolysaccharidosis IVA: characterization of a common mutation found in Finnish patients with attenuated phenotype. Hum Genet 113, 162–169 (2003). https://doi.org/10.1007/s00439-003-0959-8

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