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Exome sequencing reveals a nebulin nonsense mutation in a dog model of nemaline myopathy

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Abstract

Nemaline myopathy (NM) is a congenital muscle disorder associated with muscle weakness, hypotonia, and rod bodies in the skeletal muscle fibers. Mutations in 10 genes have been implicated in human NM, but spontaneous cases in dogs have not been genetically characterized. We identified a novel recessive myopathy in a family of line-bred American bulldogs (ABDs); rod bodies in muscle biopsies established this as NM. Using SNP profiles from the nuclear family, we evaluated inheritance patterns at candidate loci and prioritized TNNT1 and NEB for further investigation. Whole exome sequencing of the dam, two affected littermates, and an unaffected littermate revealed a nonsense mutation in NEB (g.52734272 C>A, S8042X). Whole tissue gel electrophoresis and western blots confirmed a lack of full-length NEB in affected tissues, suggesting nonsense-mediated decay. The pathogenic variant was absent from 120 dogs of 24 other breeds and 100 unrelated ABDs, suggesting that it occurred recently and may be private to the family. This study presents the first molecularly characterized large animal model of NM, which could provide new opportunities for therapeutic approaches.

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Acknowledgments

Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Numbers R15AR062868 and R01AR053897. The authors wish to thank the dog owners for contributing samples to this study, and James R. Clark for helping prepare Fig. 2.

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Authors and Affiliations

  1. Department of Genetics and Biochemistry, Clemson University, Clemson, SC, 29634, USA

    Jacquelyn M. Evans & Leigh Anne Clark

  2. CAG GmbH - Center for Animal Genetics, Tübingen, Germany

    Melissa L. Cox

  3. Ontario Veterinary College, University of Guelph, Guelph, ON, Canada

    Jonathan Huska & Luis Gaitero

  4. Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, 85724, USA

    Frank Li & Henk L. Granzier

  5. Department of Pathology, University of California San Diego, La Jolla, CA, 92093, USA

    Ling T. Guo & G. Diane Shelton

  6. School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Margaret L. Casal

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  1. Jacquelyn M. Evans
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  2. Melissa L. Cox
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  9. G. Diane Shelton
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Corresponding authors

Correspondence to G. Diane Shelton or Leigh Anne Clark.

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Supplemental Video. Affected American bulldog.(MOV 6839 kb)

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Evans, J.M., Cox, M.L., Huska, J. et al. Exome sequencing reveals a nebulin nonsense mutation in a dog model of nemaline myopathy. Mamm Genome 27, 495–502 (2016). https://doi.org/10.1007/s00335-016-9644-9

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  • DOI: https://doi.org/10.1007/s00335-016-9644-9

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