Berra Incearap

Ulm University, Germany

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

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Biography

Berra Incearap is a PhD student at the Institute for Anatomy and Cell Biology at the University of Ulm lead by Prof. Dr. Tobias Böckers. As a student from the International Graduate School in Molecular Medicine Ulm, she is interested in investigating the effect of an autism-associated SHANK3 mutation on myelin sheath.

From 2014 to 2017 Mrs. Incearap studied Biology at the University of Ulm, Germany. She completed this study course with a Bachelor of Science and continued her scientific education with the master's course Molecular and Translational Neuroscience at the same institution. In 2019 she was able to finish this course with a master’s degree. In her master´s thesis, she was focusing on understanding the concept of an autism-associated SHANK3 mutation on neonatal skeletal muscle hypotonia utilizing human induced pluripotent stem cell techniques, a transgenic mouse model, and skeletal muscle biopsies from Phelan-McDermid Syndrome patients with SHANK3 deletions.

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), 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 ?-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.