Autism-associated SHANK3 mutations impair maturation of neuromuscular junctions and striated muscles

See allHide authors and affiliations

Science Translational Medicine  10 Jun 2020:
Vol. 12, Issue 547, eaaz3267
DOI: 10.1126/scitranslmed.aaz3267

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Autism and muscles

Mutations in SHANK3 are associated with autism spectrum disorders (ASDs) and Phelan-McDermid syndrome (PMDS). Children with ASD or PMDS present neurodevelopmental abnormalities and skeletal muscle hypotonia; the mechanisms mediating the decreased muscle tone are unclear. Now, Lutz et al. used patient-derived material and a mouse model to show that SHANK3 is expressed in muscle sarcomeres and plays a role in the maturation of the neuromuscular junctions (NMJs). Muscle biopsies from patients with PMDS showed alterations in NMJs and sarcomeres. Similarly, Shank3 deficiency in mice resulted in smaller NMJs, sarcomere abnormalities, and hypotonia. Muscular deficits in mice were rescued with the troponin activator Tirasemtiv, suggesting that the treatment might be effective for treating hypotonia in patients with SHANK3 mutations.


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.

View Full Text

Stay Connected to Science Translational Medicine