TY - JOUR
T1 - Autism-associated SHANK3 mutations impair maturation of neuromuscular junctions and striated muscles
AU - Lutz, Anne Kathrin
AU - Pfaender, Stefanie
AU - Incearap, Berra
AU - Ioannidis, Valentin
AU - Ottonelli, Ilaria
AU - Föhr, Karl J.
AU - Cammerer, Judith
AU - Zoller, Marvin
AU - Higelin, Julia
AU - Giona, Federica
AU - Stetter, Maximilian
AU - Stoecker, Nicole
AU - Alami, Najwa Ouali
AU - Schön, Michael
AU - Orth, Michael
AU - Liebau, Stefan
AU - Barbi, Gotthold
AU - Grabrucker, Andreas M.
AU - Delorme, Richard
AU - Fauler, Michael
AU - Mayer, Benjamin
AU - Jesse, Sarah
AU - Roselli, Francesco
AU - Ludolph, Albert C.
AU - Bourgeron, Thomas
AU - Verpelli, Chiara
AU - Demestre, Maria
AU - Boeckers, Tobias M.
N1 - Publisher Copyright:
© 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
PY - 2020/6/10
Y1 - 2020/6/10
N2 - 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), Shank3∆11(−/−) 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 Shank3∆11(−/−) mice and patients with PMDS, indicating a crucial role for SHANK3 in the maturation of NMJs and striated muscle. Functional motor defects in Shank3∆11(−/−) 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.
AB - 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), Shank3∆11(−/−) 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 Shank3∆11(−/−) mice and patients with PMDS, indicating a crucial role for SHANK3 in the maturation of NMJs and striated muscle. Functional motor defects in Shank3∆11(−/−) 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.
UR - http://www.scopus.com/inward/record.url?scp=85086356081&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aaz3267
DO - 10.1126/scitranslmed.aaz3267
M3 - Article
C2 - 32522805
AN - SCOPUS:85086356081
SN - 1946-6234
VL - 12
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 547
M1 - eaaz3267
ER -