title: Exome sequencing reveals a nebulin nonsense mutation in a dog model of nemaline myopathy.
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.
authors.affiliation: Department of Genetics and Biochemistry, Clemson University, Clemson, SC, 29634, USA.
authors.forename: Jacquelyn M
authors.initials: JM
authors.lastname: Evans
authors.affiliation: CAG GmbH - Center for Animal Genetics, Tübingen, Germany.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Cox
authors.affiliation: Ontario Veterinary College, University of Guelph, Guelph, ON, Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Huska
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, 85724, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Li
authors.affiliation: Ontario Veterinary College, University of Guelph, Guelph, ON, Canada.
authors.forename: Luis
authors.initials: L
authors.lastname: Gaitero
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA, 92093, USA.
authors.forename: Ling T
authors.initials: LT
authors.lastname: Guo
authors.affiliation: School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Casal
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, 85724, USA.
authors.forename: Henk L
authors.initials: HL
authors.lastname: Granzier
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA, 92093, USA. gshelton@ucsd.edu.
authors.forename: G Diane
authors.initials: GD
authors.lastname: Shelton
authors.affiliation: Department of Genetics and Biochemistry, Clemson University, Clemson, SC, 29634, USA. lclark4@clemson.edu.
authors.forename: Leigh Anne
authors.initials: LA
authors.lastname: Clark
mesh_terms: D000818:Animals; D001483:Base Sequence; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D005260:Female; D056726:Genetic Association Studies; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology; D017696:Myopathies, Nemaline / Q000235:genetics / Q000662:veterinary*; D000073359:Exome Sequencing
chemical_list: D018389:Codon, Nonsense; D009124:Muscle Proteins; C035620:nebulin