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Variants in DTNA cause a mild, dominantly inherited muscular dystrophy

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Abstract

DTNA encodes α-dystrobrevin, a component of the macromolecular dystrophin–glycoprotein complex (DGC) that binds to dystrophin/utrophin and α-syntrophin. Mice lacking α-dystrobrevin have a muscular dystrophy phenotype, but variants in DTNA have not previously been associated with human skeletal muscle disease. We present 12 individuals from four unrelated families with two different monoallelic DTNA variants affecting the coiled-coil domain of α-dystrobrevin. The five affected individuals from family A harbor a c.1585G > A; p.Glu529Lys variant, while the recurrent c.1567_1587del; p.Gln523_Glu529del DTNA variant was identified in the other three families (family B: four affected individuals, family C: one affected individual, and family D: two affected individuals). Myalgia and exercise intolerance, with variable ages of onset, were reported in 10 of 12 affected individuals. Proximal lower limb weakness with onset in the first decade of life was noted in three individuals. Persistent elevations of serum creatine kinase (CK) levels were detected in 11 of 12 affected individuals, 1 of whom had an episode of rhabdomyolysis at 20 years of age. Autism spectrum disorder or learning disabilities were reported in four individuals with the c.1567_1587 deletion. Muscle biopsies in eight affected individuals showed mixed myopathic and dystrophic findings, characterized by fiber size variability, internalized nuclei, and slightly increased extracellular connective tissue and inflammation. Immunofluorescence analysis of biopsies from five affected individuals showed reduced α-dystrobrevin immunoreactivity and variably reduced immunoreactivity of other DGC proteins: dystrophin, α, β, δ and γ-sarcoglycans, and α and β-dystroglycans. The DTNA deletion disrupted an interaction between α-dystrobrevin and syntrophin. Specific variants in the coiled-coil domain of DTNA cause skeletal muscle disease with variable penetrance. Affected individuals show a spectrum of clinical manifestations, with severity ranging from hyperCKemia, myalgias, and exercise intolerance to childhood-onset proximal muscle weakness. Our findings expand the molecular etiologies of both muscular dystrophy and paucisymptomatic hyperCKemia, to now include monoallelic DTNA variants as a novel cause of skeletal muscle disease in humans.

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Acknowledgements

We are indebted to the “Biobanc de l’Hospital Infantil Sant Joan de Déu per a la Investigació”, part of the Spanish Biobank Network of ISCIII for the sample and data procurement.

Funding

Daniel Natera-de Benito is supported by the Miguel Servet program from Instituto de Salud Carlos III, Spain (CP22/00141). Jordi Pijuan is supported by a Carmen de Torres fellowship of the SJD Research Institute. Francesc Palau is supported by Fundacion Isabel Gemio and AGAUR (2017 SGR 324). Janet Hoenicka is supported by the Torro Solidari-RAC1 i Torrons Vicens. The work in Peter B. Kang's laboratory was supported in part by NIH R01 NS080929. The work in Louis M. Kunkel's laboratory was supported in part by NIH R01AR064300 and the Bernard F. and Alva B. Gimbel Foundation. Work in Carsten G. Bönneman’s laboratory is supported by intramural funds by the NIH National Institute of Neurological Disorders and Stroke. Sequencing and analysis of families C and D were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1HG008900 and in part by National Human Genome Research Institute grant R01HG009141.

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Author notes

  1. Andres Nascimento, Christine C. Bruels, Peter B. Kang, and Daniel Natera-de Benito have contributed equally to the manuscript.

Authors and Affiliations

  1. Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu 2, Esplugues de Llobregat, Barcelona, Spain

    Andres Nascimento, Laura Carrera-García, Jessica Expósito-Escudero, Carlos Ortez & Daniel Natera-de Benito

  2. Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain

    Andres Nascimento, Anna Codina, Laura Carrera-García, Jessica Expósito-Escudero, Carlos Ortez, Cristina Jou & Daniel Natera-de Benito

  3. Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Madrid, Spain

    Andres Nascimento, Jordi Pijuan, Delia Yubero, Loreto Martorell, Josep M. Grau-Junyent, Carlos Ortez, Francesc Palau, Cristina Jou & Janet Hoenicka

  4. Department of Neurology, Paul and Sheila Wellstone Muscular Dystrophy Center, University of Minnesota Medical School, 420 Delaware Street SE, MMC 295, Minneapolis, MN, 55455, USA

    Christine C. Bruels, Seth A. Stafki & Peter B. Kang

  5. Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

    Sandra Donkervoort, A. Reghan Foley, Ying Hu, Safoora B. Syeda & Carsten G. Bönnemann

  6. Department of Pathology, Hospital Sant Joan de Déu, Barcelona, Spain

    Anna Codina & Cristina Jou

  7. Department of Internal Medicine, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain

    Jose C. Milisenda & Josep M. Grau-Junyent

  8. Division of Genetics and Genomics, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Elicia A. Estrella, Lynn S. Pais, Vijay S. Ganesh, Anne O’Donnell-Luria & Louis M. Kunkel

  9. Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Elicia A. Estrella, Partha S. Ghosh & Basil T. Darras

  10. Division of Pediatric Neurology, University of Florida College of Medicine, Gainesville, FL, 32610, USA

    Chengcheng Li

  11. Laboratory of Neurogenetics and Molecular Medicine-IPER, Institut de Recerca Sant Joan de Déu, Barcelona, Spain

    Jordi Pijuan, Francesc Palau & Janet Hoenicka

  12. Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, 02111, USA

    Isabelle Draper

  13. Program in Medical and Population Genetics, Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Lynn S. Pais, Vijay S. Ganesh & Anne O’Donnell-Luria

  14. Analytic and Translational Genetics Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    Lynn S. Pais, Vijay S. Ganesh & Anne O’Donnell-Luria

  15. Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA

    Vijay S. Ganesh

  16. Department of Genetic and Molecular Medicine-IPER, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, Barcelona, Spain

    Delia Yubero, Loreto Martorell & Francesc Palau

  17. National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA

    Iago Pinal-Fernandez & Andrew L. Mammen

  18. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Iago Pinal-Fernandez & Andrew L. Mammen

  19. Department of Pathology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Hart G. W. Lidov

  20. Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA

    Peter B. Kang

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  1. Andres Nascimento
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Corresponding authors

Correspondence to Peter B. Kang or Daniel Natera-de Benito.

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None of the authors has any conflict of interest to disclose.

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This study was performed in accordance with the Declaration of Helsinki and was approved by the Hospital Sant Joan de Déu Clinical Research Ethics Committee (reference PIC-04-18). Data were collected in accordance with the ethical guidelines of each of the institutions involved. Written informed consent for study participation was obtained by qualified clinicians.

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Nascimento, A., Bruels, C.C., Donkervoort, S. et al. Variants in DTNA cause a mild, dominantly inherited muscular dystrophy. Acta Neuropathol 145, 479–496 (2023). https://doi.org/10.1007/s00401-023-02551-7

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  • DOI: https://doi.org/10.1007/s00401-023-02551-7

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