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000153984 0247_ $$2doi$$a10.1126/scitranslmed.aaz3267
000153984 0247_ $$2ISSN$$a1946-6234
000153984 0247_ $$2ISSN$$a1946-6242
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000153984 1001_ $$0P:(DE-HGF)0$$aLutz, Anne-Kathrin$$b0
000153984 245__ $$aAutism-associated SHANK3 mutations impair maturation of neuromuscular junctions and striated muscles
000153984 260__ $$aWashington, DC$$bAAAS$$c2020
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000153984 520__ $$aHeterozygous 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.
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000153984 536__ $$0G:(DE-HGF)POF3$$aPOF III - Programmorientierte Förderung III (POF)$$cPOF$$x2
000153984 536__ $$0G:(EU-Grant)862085$$aDISPLAYGHT - DISPLAY backliGHT illumination by femtosecond laser micromachining (862085)$$c862085$$fERC-2019-PoC$$x3
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000153984 650_2 $$2MeSH$$aAnimals
000153984 650_2 $$2MeSH$$aAutistic Disorder
000153984 650_2 $$2MeSH$$aHumans
000153984 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells
000153984 650_2 $$2MeSH$$aMice
000153984 650_2 $$2MeSH$$aMicrofilament Proteins
000153984 650_2 $$2MeSH$$aMuscle, Skeletal
000153984 650_2 $$2MeSH$$aMutation: genetics
000153984 650_2 $$2MeSH$$aNerve Tissue Proteins: genetics
000153984 650_2 $$2MeSH$$aNeuromuscular Junction
000153984 7001_ $$0P:(DE-HGF)0$$aPfaender, Stefanie$$b1
000153984 7001_ $$0P:(DE-HGF)0$$aIncearap, Berra$$b2
000153984 7001_ $$0P:(DE-HGF)0$$aIoannidis, Valentin$$b3
000153984 7001_ $$0P:(DE-HGF)0$$aOttonelli, Ilaria$$b4
000153984 7001_ $$0P:(DE-HGF)0$$aFöhr, Karl J.$$b5
000153984 7001_ $$0P:(DE-HGF)0$$aCammerer, Judith$$b6
000153984 7001_ $$0P:(DE-HGF)0$$aZoller, Marvin$$b7
000153984 7001_ $$0P:(DE-HGF)0$$aHigelin, Julia$$b8
000153984 7001_ $$0P:(DE-HGF)0$$aGiona, Federica$$b9
000153984 7001_ $$0P:(DE-HGF)0$$aStetter, Maximilian$$b10
000153984 7001_ $$0P:(DE-HGF)0$$aStoecker, Nicole$$b11
000153984 7001_ $$0P:(DE-2719)9001442$$aAlami, Najwa Ouali$$b12$$udzne
000153984 7001_ $$0P:(DE-HGF)0$$aSchön, Michael$$b13
000153984 7001_ $$0P:(DE-2719)9001440$$aOrth, Michael$$b14$$udzne
000153984 7001_ $$0P:(DE-HGF)0$$aLiebau, Stefan$$b15
000153984 7001_ $$0P:(DE-HGF)0$$aBarbi, Gotthold$$b16
000153984 7001_ $$0P:(DE-HGF)0$$aGrabrucker, Andreas M.$$b17
000153984 7001_ $$0P:(DE-HGF)0$$aDelorme, Richard$$b18
000153984 7001_ $$0P:(DE-HGF)0$$aFauler, Michael$$b19
000153984 7001_ $$0P:(DE-HGF)0$$aMayer, Benjamin$$b20
000153984 7001_ $$0P:(DE-2719)9001441$$aJesse, Sarah$$b21$$udzne
000153984 7001_ $$0P:(DE-2719)2812851$$aRoselli, Francesco$$b22
000153984 7001_ $$0P:(DE-2719)2812633$$aLudolph, Albert C.$$b23
000153984 7001_ $$00000-0001-8164-9220$$aBourgeron, Thomas$$b24
000153984 7001_ $$0P:(DE-HGF)0$$aVerpelli, Chiara$$b25
000153984 7001_ $$00000-0002-3672-5703$$aDemestre, Maria$$b26
000153984 7001_ $$0P:(DE-2719)2812855$$aBöckers, Tobias$$b27$$eLast author
000153984 773__ $$0PERI:(DE-600)2518839-2$$a10.1126/scitranslmed.aaz3267$$gVol. 12, no. 547, p. eaaz3267 -$$n547$$peaaz3267 -$$tScience translational medicine$$v12$$x1946-6242$$y2020
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