Dystrophin (<i>DMD</i>) Missense Variant in Cats with Becker-Type Muscular Dystrophy
Muscular dystrophy due to dystrophin deficiency in humans is phenotypically divided into a severe Duchenne and milder Becker type. Dystrophin deficiency has also been described in a few animal species, and few <i>DMD</i> gene variants have been identified in animals. Here, we characteriz...
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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| author | Stephanie Hilton Matthias Christen Thomas Bilzer Vidhya Jagannathan Tosso Leeb Urs Giger |
| author_facet | Stephanie Hilton Matthias Christen Thomas Bilzer Vidhya Jagannathan Tosso Leeb Urs Giger |
| author_sort | Stephanie Hilton |
| collection | DOAJ |
| description | Muscular dystrophy due to dystrophin deficiency in humans is phenotypically divided into a severe Duchenne and milder Becker type. Dystrophin deficiency has also been described in a few animal species, and few <i>DMD</i> gene variants have been identified in animals. Here, we characterize the clinical, histopathological, and molecular genetic aspects of a family of Maine Coon crossbred cats with clinically mild and slowly progressive muscular dystrophy. Two young adult male littermate cats exhibited abnormal gait and muscular hypertrophy with macroglossia. Serum creatine kinase activities were highly increased. Histopathologically, dystrophic skeletal muscle exhibited marked structural changes including atrophic, hypertrophic, and necrotic muscle fibers. Immunohistochemistry showed irregularly reduced expression of dystrophin but the staining of other muscle proteins such as β- and γ-sarcoglycans as well as desmin was also diminished. Whole genome sequencing of one affected cat and genotyping of the littermate found both to be hemizygous mutant at a single <i>DMD</i> missense variant (c.4186C>T). No other protein-changing variants in candidate genes for muscular dystrophy were detected. In addition, one clinically healthy male littermate was hemizygous wildtype, while the queen and one female littermate were clinically healthy, but heterozygous. The predicted amino acid exchange (p.His1396Tyr) resides in a conserved central rod spectrin domain of dystrophin. Various protein modeling programs did not predict major disruption of the dystrophin protein by this substitution, but the altered charge of the region may still affect protein function. This study represents the first genotype-to-phenotype correlation of Becker-type dystrophin deficiency in companion animals. |
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| last_indexed | 2024-03-11T08:43:42Z |
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| spelling | doaj.art-24b299c0c3494a2a86621c279805f7bd2023-11-16T20:56:32ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01244319210.3390/ijms24043192Dystrophin (<i>DMD</i>) Missense Variant in Cats with Becker-Type Muscular DystrophyStephanie Hilton0Matthias Christen1Thomas Bilzer2Vidhya Jagannathan3Tosso Leeb4Urs Giger5Tierärztliche Klinik für Kleintiere, Robert-Bosch-Str. 8a, 61267 Neu-Anspach, GermanyInstitute of Genetics, Vetsuisse Faculty, University of Bern, Bremgartenstrasse 109a, 3001 Bern, SwitzerlandInstitut für Pathologie Leverkusen (E. Kilic), Paracelsusstrasse 17, 51375 Leverkusen, GermanyInstitute of Genetics, Vetsuisse Faculty, University of Bern, Bremgartenstrasse 109a, 3001 Bern, SwitzerlandInstitute of Genetics, Vetsuisse Faculty, University of Bern, Bremgartenstrasse 109a, 3001 Bern, SwitzerlandVetsuisse Faculty, University of Zürich, Winterthurerstrasse 260, 8057 Zürich, SwitzerlandMuscular dystrophy due to dystrophin deficiency in humans is phenotypically divided into a severe Duchenne and milder Becker type. Dystrophin deficiency has also been described in a few animal species, and few <i>DMD</i> gene variants have been identified in animals. Here, we characterize the clinical, histopathological, and molecular genetic aspects of a family of Maine Coon crossbred cats with clinically mild and slowly progressive muscular dystrophy. Two young adult male littermate cats exhibited abnormal gait and muscular hypertrophy with macroglossia. Serum creatine kinase activities were highly increased. Histopathologically, dystrophic skeletal muscle exhibited marked structural changes including atrophic, hypertrophic, and necrotic muscle fibers. Immunohistochemistry showed irregularly reduced expression of dystrophin but the staining of other muscle proteins such as β- and γ-sarcoglycans as well as desmin was also diminished. Whole genome sequencing of one affected cat and genotyping of the littermate found both to be hemizygous mutant at a single <i>DMD</i> missense variant (c.4186C>T). No other protein-changing variants in candidate genes for muscular dystrophy were detected. In addition, one clinically healthy male littermate was hemizygous wildtype, while the queen and one female littermate were clinically healthy, but heterozygous. The predicted amino acid exchange (p.His1396Tyr) resides in a conserved central rod spectrin domain of dystrophin. Various protein modeling programs did not predict major disruption of the dystrophin protein by this substitution, but the altered charge of the region may still affect protein function. This study represents the first genotype-to-phenotype correlation of Becker-type dystrophin deficiency in companion animals.https://www.mdpi.com/1422-0067/24/4/3192<i>Felis catus</i>felinemyopathycreatine kinaseDuchennemutation |
| spellingShingle | Stephanie Hilton Matthias Christen Thomas Bilzer Vidhya Jagannathan Tosso Leeb Urs Giger Dystrophin (<i>DMD</i>) Missense Variant in Cats with Becker-Type Muscular Dystrophy International Journal of Molecular Sciences <i>Felis catus</i> feline myopathy creatine kinase Duchenne mutation |
| title | Dystrophin (<i>DMD</i>) Missense Variant in Cats with Becker-Type Muscular Dystrophy |
| title_full | Dystrophin (<i>DMD</i>) Missense Variant in Cats with Becker-Type Muscular Dystrophy |
| title_fullStr | Dystrophin (<i>DMD</i>) Missense Variant in Cats with Becker-Type Muscular Dystrophy |
| title_full_unstemmed | Dystrophin (<i>DMD</i>) Missense Variant in Cats with Becker-Type Muscular Dystrophy |
| title_short | Dystrophin (<i>DMD</i>) Missense Variant in Cats with Becker-Type Muscular Dystrophy |
| title_sort | dystrophin i dmd i missense variant in cats with becker type muscular dystrophy |
| topic | <i>Felis catus</i> feline myopathy creatine kinase Duchenne mutation |
| url | https://www.mdpi.com/1422-0067/24/4/3192 |
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