Variants in DTNA cause a mild, dominantly inherited muscular dystrophy

Andres Nascimento, Christine C. Bruels, Sandra Donkervoort, A. Reghan Foley, Anna Codina, Jose C. Milisenda, Elicia A. Estrella, Chengcheng Li, Jordi Pijuan, Isabelle Draper, Ying Hu, Seth A. Stafki, Lynn S. Pais, Vijay S. Ganesh, Anne O’Donnell-Luria, Safoora B. Syeda, Laura Carrera-García, Jessica Expósito-Escudero, Delia Yubero, Loreto MartorellIago Pinal-Fernandez, Hart G.W. Lidov, Andrew L. Mammen, Josep M. Grau-Junyent, Carlos Ortez, Francesc Palau, Partha S. Ghosh, Basil T. Darras, Cristina Jou, Louis M. Kunkel, Janet Hoenicka, Carsten G. Bönnemann, Peter B. Kang, Daniel Natera-de Benito

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)479-496
Number of pages18
JournalActa Neuropathologica
Issue number4
StatePublished - Apr 2023

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.


  • Dystrophin
  • Muscle sarcolemmal proteins
  • Myalgia
  • Rhabdomyolysis
  • hyperCKemia
  • α-Dystrobrevin


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