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The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone

Nature Genetics volume 37, pages 1309–1311 (2005)Cite this article

Abstract

We identified the gene underlying Marinesco-Sjögren syndrome, which is characterized by cerebellar ataxia, progressive myopathy and cataracts. We identified four disease-associated, predicted loss-of-function mutations in SIL1, which encodes a nucleotide exchange factor for the heat-shock protein 70 (HSP70) chaperone HSPA5. These data, together with the similar spatial and temporal patterns of tissue expression of Sil1 and Hspa5, suggest that disturbed SIL1-HSPA5 interaction and protein folding is the primary pathology in Marinesco-Sjögren syndrome.

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Figure 1: SIL1 structure, MSS-associated mutations and variants with their expression in individuals with MSS.

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Acknowledgements

We thank the affected individuals and their families for collaboration; S. Lindh for collecting the samples; H. Olanne, T. Jokinen, T. Järvinen, T.-T. Toivonen and P. Hakala for technical assistance; and M. Heikinheimo, T. Kivelä, A. Hirvasniemi, R. Herva, A. Vihola, J. Kallijärvi and E. Anttonen for help and advice. This study was supported by the Folkhälsan Research Foundation and the Academy of Finland (Finnish Centre of Excellence Programme 2000–2005). A.-K.A. and R.H.H. are fellows of the Helsinki Biomedical Graduate School.

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Authors and Affiliations

  1. Folkhälsan Institute of Genetics and Neuroscience Center, University of Helsinki, PO Box 63, Helsinki, FI-00014, Finland

    Anna-Kaisa Anttonen, Riikka H Hämäläinen, Laura Waris, Tarja Joensuu & Anna-Elina Lehesjoki

  2. Department of Medical Genetics, University of Helsinki, PO Box 63, Helsinki, FI-00014, Finland

    Anna-Kaisa Anttonen & Riikka H Hämäläinen

  3. Department of Neurology, and Department of Neurology, Pietarsaari Hospital, Pietarsaari, University of Oulu, PO Box 3, FI-68601, Oulu, Finland

    Ibrahim Mahjneh

  4. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis-Pasteur, 1 rue Laurent Fries, BP10142, Illkirch, FR-67404, France

    Clotilde Lagier-Tourenne & Michel Koenig

  5. Neuroscience Center, University of Helsinki, PO Box 63, FI-00014, Helsinki

    Outi Kopra

  6. Department of Molecular Medicine, National Public Health Institute, PO Box 63, Helsinki, Finland

    Outi Kopra

  7. Children's Hospital and Program for Developmental and Reproductive Biology, Biomedicum Helsinki, University of Helsinki, PO Box 63, Helsinki, FI-00014, Finland

    Mikko Anttonen

  8. Department of Pathology, University of Helsinki and Helsinki University Central Hospital, PO Box 21, Helsinki, FI-00014, Finland

    Hannu Kalimo & Anders Paetau

  9. Department of Medical Genetics, University Hospital of Tromsoe, Tromsoe, Norway

    Lisbeth Tranebjaerg

  10. Wilhelm Johannsen Centre of Functional Genomics, Institute of Medical Biochemistry and Genetics IMBG, University of Copenhagen, The Panum Institute, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark

    Lisbeth Tranebjaerg

  11. Department of Audiology, H:S Bispebjerg Hospital,

    Lisbeth Tranebjaerg

  12. Department of Audiology, H:S Bispebjerg Hospital, Copenhagen N, DK-2200, Denmark

    Lisbeth Tranebjaerg

  13. Neuropediatrie, Clinique Sainte Odile, 6 rue Simonis, Strasbourg, FR-67100, France

    Denys Chaigne

  14. Department of Women's and Children's Health / Pediatrics, Uppsala University, Uppsala, SE-751 85, Sweden

    Orvar Eeg-Olofsson

  15. Folkhälsan Institute of Genetics, University of Helsinki, PO Box 63, FI-00014, Helsinki

    Bjarne Udd

  16. Department of Neurology, Vaasa Central Hospital, Vaasa

    Bjarne Udd

  17. Department of Neurology, Vaasa Central Hospital, Tampere, Finland

    Bjarne Udd

  18. The Family Federation of Finland, PO Box 849, Helsinki, FI-00101, Finland

    Mirja Somer

  19. Department of Neurology, University of Helsinki, PO Box 63, Helsinki, FI-00014, Finland

    Hannu Somer

Authors
  1. Anna-Kaisa Anttonen
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  2. Ibrahim Mahjneh
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  3. Riikka H Hämäläinen
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  4. Clotilde Lagier-Tourenne
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  7. Mikko Anttonen
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  8. Tarja Joensuu
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  9. Hannu Kalimo
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  10. Anders Paetau
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  11. Lisbeth Tranebjaerg
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  12. Denys Chaigne
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  13. Michel Koenig
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  14. Orvar Eeg-Olofsson
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  15. Bjarne Udd
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  16. Mirja Somer
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  17. Hannu Somer
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  18. Anna-Elina Lehesjoki
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Corresponding author

Correspondence to Anna-Elina Lehesjoki.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

The main clinical findings in MSS. (PDF 755 kb)

Supplementary Fig. 2

Pedigrees of the eight families studied showing microsatellite marker genotypes in the linked region on chromosome 5q31. (PDF 45 kb)

Supplementary Fig. 3

Chromatograms showing SIL1 mutations in MSS patients with respective controls. (PDF 126 kb)

Supplementary Fig. 4

Analysis of SIL1 tissue expression. (PDF 217 kb)

Supplementary Fig. 5

Tissue expression of Sil1 and Hspa5 in mouse (PDF 1066 kb)

Supplementary Table 1

Clinical features of the patients. (PDF 52 kb)

Supplementary Methods (PDF 102 kb)

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Anttonen, AK., Mahjneh, I., Hämäläinen, R. et al. The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone. Nat Genet 37, 1309–1311 (2005). https://doi.org/10.1038/ng1677

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