Exome sequencing reveals a nebulin nonsense mutation in a dog model of nemaline myopathy
| Autor: | G. Diane Shelton, Luis Gaitero, Jonathan Huska, Melissa L. Cox, Henk Granzier, Ling T. Guo, Jacquelyn M. Evans, Frank Li, Margaret L. Casal, Leigh Anne Clark |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Nemaline Nonsense mutation DNA Mutational Analysis Muscle Proteins Myopathies Nemaline Article Whole Exome Sequencing 03 medical and health sciences Nebulin Nemaline myopathy Dogs Exome Sequencing medicine Genetics Animals 2.1 Biological and endogenous factors Dog Diseases Aetiology Muscle Skeletal Myopathy Codon Exome sequencing Genetic Association Studies Pediatric Genetics & Heredity biology Base Sequence Muscle weakness Skeletal medicine.disease Molecular biology Hypotonia 030104 developmental biology Nonsense Codon Nonsense Congenital muscle disorder Musculoskeletal biology.protein Muscle Congenital Structural Anomalies Myopathies Female medicine.symptom |
| Zdroj: | Mammalian genome : official journal of the International Mammalian Genome Society, vol 27, iss 9-10 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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