Mammalian Genome

, Volume 27, Issue 9–10, pp 495–502 | Cite as

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

  • Jacquelyn M. Evans
  • Melissa L. Cox
  • Jonathan Huska
  • Frank Li
  • Luis Gaitero
  • Ling T. Guo
  • Margaret L. Casal
  • Henk L. Granzier
  • G. Diane SheltonEmail author
  • Leigh Anne ClarkEmail author


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.


Pathogenic Variant Whole Exome Sequencing Nebulin Nemaline Myopathy Thoracic Limb 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



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.

Supplementary material

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


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Jacquelyn M. Evans
    • 1
  • Melissa L. Cox
    • 2
  • Jonathan Huska
    • 3
  • Frank Li
    • 4
  • Luis Gaitero
    • 3
  • Ling T. Guo
    • 5
  • Margaret L. Casal
    • 6
  • Henk L. Granzier
    • 4
  • G. Diane Shelton
    • 5
    Email author
  • Leigh Anne Clark
    • 1
    Email author
  1. 1.Department of Genetics and BiochemistryClemson UniversityClemsonUSA
  2. 2.CAG GmbH - Center for Animal GeneticsTübingenGermany
  3. 3.Ontario Veterinary CollegeUniversity of GuelphGuelphCanada
  4. 4.Department of Cellular and Molecular MedicineUniversity of ArizonaTucsonUSA
  5. 5.Department of PathologyUniversity of California San DiegoLa JollaUSA
  6. 6.School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaUSA

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