Abstract
Multiple Sulfatase Deficiency (MSD) is caused by mutations in the sulfatase-modifying factor 1 gene encoding the formylglycine-generating enzyme (FGE). FGE post translationally activates all newly synthesized sulfatases by generating the catalytic residue formylglycine. Impaired FGE function leads to reduced sulfatase activities. Patients display combined clinical symptoms of single sulfatase deficiencies. For ten MSD patients, we determined the clinical phenotype, FGE expression, localization and stability, as well as residual FGE and sulfatase activities. A neonatal, very severe clinical phenotype resulted from a combination of two nonsense mutations leading to almost fully abrogated FGE activity, highly unstable FGE protein and nearly undetectable sulfatase activities. A late infantile mild phenotype resulted from FGE G263V leading to unstable protein but high residual FGE activity. Other missense mutations resulted in a late infantile severe phenotype because of unstable protein with low residual FGE activity. Patients with identical mutations displayed comparable clinical phenotypes. These data confirm the hypothesis that the phenotypic outcome in MSD depends on both residual FGE activity as well as protein stability. Predicting the clinical course in case of molecularly characterized mutations seems feasible, which will be helpful for genetic counseling and developing therapeutic strategies aiming at enhancement of FGE.
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Acknowledgements
We would like to thank N Hollstein, N Eiselt, A Winter, M Balleininger, J Kaiser, T Wilke, M-A Frese and E Wiegmann for excellent technical assistance. We are grateful to M Henneke, H Rosewich, P Huppke, A Ohlenbusch, M Mariappan and B Mueksch for helpful discussions and K von Figura for his support to implement the project. This work was supported by the Research program of the Faculty of Medicine, Georg August University Göttingen (LS), by the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie and Shire Human Genetic Therapies, Inc. (Cambridge, MA, USA).
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Schlotawa, L., Ennemann, E., Radhakrishnan, K. et al. SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency. Eur J Hum Genet 19, 253–261 (2011). https://doi.org/10.1038/ejhg.2010.219
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DOI: https://doi.org/10.1038/ejhg.2010.219
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