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@ARTICLE{Lutz:153984,
      author       = {Lutz, Anne-Kathrin and Pfaender, Stefanie and Incearap,
                      Berra and Ioannidis, Valentin and Ottonelli, Ilaria and
                      Föhr, Karl J. and Cammerer, Judith and Zoller, Marvin and
                      Higelin, Julia and Giona, Federica and Stetter, Maximilian
                      and Stoecker, Nicole and Alami, Najwa Ouali and Schön,
                      Michael and Orth, Michael and Liebau, Stefan and Barbi,
                      Gotthold and Grabrucker, Andreas M. and Delorme, Richard and
                      Fauler, Michael and Mayer, Benjamin and Jesse, Sarah and
                      Roselli, Francesco and Ludolph, Albert C. and Bourgeron,
                      Thomas and Verpelli, Chiara and Demestre, Maria and
                      Böckers, Tobias},
      title        = {{A}utism-associated {SHANK}3 mutations impair maturation of
                      neuromuscular junctions and striated muscles},
      journal      = {Science translational medicine},
      volume       = {12},
      number       = {547},
      issn         = {1946-6242},
      address      = {Washington, DC},
      publisher    = {AAAS},
      reportid     = {DZNE-2021-00001},
      pages        = {eaaz3267 -},
      year         = {2020},
      abstract     = {Heterozygous mutations of the gene encoding the
                      postsynaptic protein SHANK3 are associated with syndromic
                      forms of autism spectrum disorders (ASDs). One of the
                      earliest clinical symptoms in SHANK3-associated ASD is
                      neonatal skeletal muscle hypotonia. This symptom can be
                      critical for the early diagnosis of affected children;
                      however, the mechanism mediating hypotonia in ASD is not
                      completely understood. Here, we used a combination of
                      patient-derived human induced pluripotent stem cells
                      (hiPSCs), Shank3Δ11(−/−) mice, and Phelan-McDermid
                      syndrome (PMDS) muscle biopsies from patients of different
                      ages to analyze the role of SHANK3 on motor unit
                      development. Our results suggest that the hypotonia in
                      SHANK3 deficiency might be caused by dysfunctions in all
                      elements of the voluntary motor system: motoneurons,
                      neuromuscular junctions (NMJs), and striated muscles. We
                      found that SHANK3 localizes in Z-discs in the skeletal
                      muscle sarcomere and co-immunoprecipitates with α-ACTININ.
                      SHANK3 deficiency lead to shortened Z-discs and severe
                      impairment of acetylcholine receptor clustering in
                      hiPSC-derived myotubes and in muscle from
                      Shank3Δ11(−/−) mice and patients with PMDS, indicating
                      a crucial role for SHANK3 in the maturation of NMJs and
                      striated muscle. Functional motor defects in
                      Shank3Δ11(−/−) mice could be rescued with the troponin
                      activator Tirasemtiv that sensitizes muscle fibers to
                      calcium. Our observations give insight into the function of
                      SHANK3 besides the central nervous system and imply
                      potential treatment strategies for SHANK3-associated ASD.},
      keywords     = {Animals / Autistic Disorder / Humans / Induced Pluripotent
                      Stem Cells / Mice / Microfilament Proteins / Muscle,
                      Skeletal / Mutation: genetics / Nerve Tissue Proteins:
                      genetics / Neuromuscular Junction},
      cin          = {AG Böckers / Clinical Study Center Ulm / AG Roselli},
      ddc          = {500},
      cid          = {I:(DE-2719)1910002 / I:(DE-2719)5000077 /
                      I:(DE-2719)1910001},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342) / 344
                      - Clinical and Health Care Research (POF3-344) / POF III -
                      Programmorientierte Förderung III (POF) / DISPLAYGHT -
                      DISPLAY backliGHT illumination by femtosecond laser
                      micromachining (862085)},
      pid          = {G:(DE-HGF)POF3-342 / G:(DE-HGF)POF3-344 / G:(DE-HGF)POF3 /
                      G:(EU-Grant)862085},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:32522805},
      doi          = {10.1126/scitranslmed.aaz3267},
      url          = {https://pub.dzne.de/record/153984},
}