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Dysferlin deletion in SJL mice (SJL-Dysf) defines a natural model for limb girdle muscular dystrophy 2B

Nature Genetics volume 23, pages 141–142 (1999)Cite this article

The SJL mouse strain1 is susceptible to many induced autoimmune diseases such as experimental autoimmune encephalitis (EAE) and inflammatory muscle disease2,3. Additionally, the skeletal muscle of SJL mice was shown to have an increased regenerative capacity4, and demonstrates the spontaneous occurrence of what has been designated an 'inflammatory myopathy', accompanied by loss of strength5,6.

Using primers designed for the human DYSF sequence, we amplified and sequenced cDNA from normal control mice (BALB/C, C57BL/10, C57BL/6, C3H and B6C3FE) and SJL mice. RT-PCR analysis using primers encoding the last C2 domain consistently failed in the SJL mouse, suggesting the presence of a deletion. We designed additional primers mapping outside the putative deletion, subcloned and sequenced the products of these primers, and identified a 171-bp deletion in SJL-Dysf (Fig. 2b). By extrapolation from the human sequence, this deletion is expected to map to nt 5,260–5,430. Assuming that the structure of the gene is conserved between mouse and human, this in-frame deletion predicts the removal of 57 amino acids, including most of the fourth C2 domain. This C2 domain extends from amino acid 1,582 to 1,660, whereas the deletion spans amino acids 1,628 to 1,685. The mutant molecule would be approximately 6.5 kD smaller than the native protein, too small a difference to be readily detected, as the normal protein is approximately 230 kD. The last C2 domain is conserved in other members of the fer-like gene family, including Caenorhabditis elegans fer-1 ( ref. 10) and human OTOF (ref. 13), suggesting that it is functionally significant. It is possible that the deletion in this region, although in-frame, results in a highly unstable molecule, hence the low abundance of the mutant protein. The exact molecular basis of this cDNA deletion is probably due to a splice-site mutation, as this fragment is present in genomic DNA of SJL mice (data not shown). Formal proof will require determination of the genomic structure of mouse Dysf.

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Figure 1: Progressive muscular dystrophy causes age-dependent histomorphological changes and muscle weakness in SJL mice.
Figure 2: Dysferlin expression in normal and SJL mouse muscle and identification of the deleted Dysfsjl allele.

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Acknowledgements

We thank G. Schaden for technical assistance and J.A. Encinas for providing information on polymorphic DNA markers. This work was supported by the Verein zur Erforschung der Muskelerkrankungen bei Kindern and grant SFB Nr. 006-F613 from the Austrian Science Research Fund (R.E.B.), by the Muscular Dystrophy Campaign, the Association Francaise contre les Myopathies, the Medical Research Council of Great Britain, Action Research and a grant-in-aid of the BMBF through the German Human Genome Projekt (A.R.).

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Authors and Affiliations

  1. Neuromuscular Research Department, Institute of Anatomy, University of Vienna, Waehringerstrasse 13, Vienna, A-1090 , Austria

    Reginald E. Bittner, Silva Ivanova, Thomas Raffelsberger & Isabel Maerk

  2. Neurobiology Department, University Medical School, Newcastle Upon Tyne, UK

    Louise V.B. Anderson, Jennifer A. Moss & Keith Davison

  3. Mikrosatellitenzentrum, Max-Delbrueck-Centre, Berlin, D-13092, Germany

    Elke Burkhardt, Martin Jung & André Reis

  4. School of Biochemistry and Genetics, University of Newcastle upon Tyne,, UK

    Rumaisa Bashir, Elizabeth Vafiadaki, Ruth Harrison & Kate M.D. Bushby

  5. Research Institute of Laboratory Animal Breeding,, Himberg, A-2325, Austria

    Harald Höger

  6. Institute of Brain Research, University of Vienna, , Vienna, A-1090, Austria

    Maria Storch & Hans Lassmann

  7. Institute of Human Genetics, Charité, Humboldt University,, Berlin, D-13353, Germany

    Mohsen Karbasiyan & André Reis

  8. Department of Neurology, University of Graz, Austria

    Maria Storch

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Correspondence to Reginald E. Bittner.

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Bittner, R., Anderson, L., Burkhardt, E. et al. Dysferlin deletion in SJL mice (SJL-Dysf) defines a natural model for limb girdle muscular dystrophy 2B. Nat Genet 23, 141–142 (1999). https://doi.org/10.1038/13770

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