Welander Distal Myopathy Caused by an Ancient Founder Mutation in TIA1 Associated with Perturbed Splicing

Authors

  • Joakim Klar,

    1. Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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    • Communicated by Michel Goossens

  • Maria Sobol,

    1. Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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    • Communicated by Michel Goossens

  • Atle Melberg,

    1. Department of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden
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  • Katrin Mäbert,

    1. Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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  • Adam Ameur,

    1. Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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  • Anna C.V. Johansson,

    1. Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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  • Lars Feuk,

    1. Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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  • Miriam Entesarian,

    1. Department of Women's and Children's Health,, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
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  • Hanna Örlén,

    1. Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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  • Olivera Casar-Borota,

    1. Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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  • Niklas Dahl

    Corresponding author
    • Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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  • These authors contributed equally to this work.

  • Contract grant sponsors: Swedish Research Council; Selander Foundation; Uppsala University; SciLifeLab; Uppsala University Hospital; RFI/VR “SNISS” Swedish National Infrastructure for large Scale Sequencing and the Science for Life Laboratory; Swedish Society for Medical Research.

Correspondence to: Niklas Dahl, Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, Uppsala 751 85, Sweden. E-mail: niklas.dahl@igp.uu.se

ABSTRACT

Welander distal myopathy (WDM) is an adult onset autosomal dominant disorder characterized by distal limb weakness, which progresses slowly from the fifth decade. All WDM patients are of Swedish or Finnish descent and share a rare chromosome 2p13 haplotype. We restricted the WDM-associated haplotype followed by whole exome sequencing. Within the conserved haplotype, we identified a single heterozygous mutation c.1150G>A (p.E384K) in T-cell intracellular antigen-1 (TIA1) in all WDM patients investigated (n = 43). The TIA1 protein regulates splicing, and translation through direct interaction with mRNA and the p.E384K mutation is located in the C-terminal Q-rich domain that interacts with the U1-C splicing factor. TIA1 has been shown to prevent skipping of SMN2 exon 7, and we show that WDM patients have increased levels of spliced SMN2 in skeletal muscle cells when compared with controls. Immunostaining of WDM muscle biopsies showed accumulation of TIA1 and stress granulae proteins adjacent to intracellular inclusions, a typical finding in WDM. The combined findings strongly suggest that the TIA1 mutation causes perturbed RNA splicing and cellular stress resulting in WDM. The selection against the mutation is likely to be negligible and the age of the TIA1 founder mutation was calculated to approximately 1,050 years, which coincides with the epoch of early seafaring across the Baltic Sea.

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