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

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.

Coupling of autism genes to tissue-wide expression and dysfunction of synapse, calcium signalling and transcriptional regulation

“…The strong enrichment for neuronal processes and functions in tissues beyond the brain is of curious interest, but researchers are starting to explore other aspects of ASD that could have an impact on other organs such as the heart via the sympathetic and parasympathetic nervous systems [86], and the gastrointestinal tract via the enteric nervous system [87]. In fact there is growing evidence that heart rate is affected among Autistics [88][89][90][91], along with evidence that ASD genes could be involved in aspects of gastrointestinal development and function [74,[92][93][94][95][96][97]. There is a potential for more work on how the parts of the brain control heart rate and gastrointestinal, how they are altered in autism, or even if reported autonomic issues in co-morbidities such gastroesophageal reflux [98,99] hold true in the autistic population as well.…”

Genomics as a Clinical Decision Support Tool: Successful Proof of Concept for Improved ASD Outcomes

“…CJM was found to be homozygous for a relatively rare variant (c.1304 + 48C > T) in the SHANK3 gene, which is found in less than 4% of the population and is highly associated with increased ASD risk. Deletions and variations within the SHANK3 pathway have been associated with ASD [ 6 ], and this particular SNP has been associated with an odds ratio (OR) of 5.5 for ASD and an OR of 12.6 for pervasive developmental disorder [ 7 ]. This SNP appears to lead to decreased protein activity.…”

Restoring Shank3 in a rostral sensorimotor brainstem nucleus rescues reduced light-evoked behaviors in shank3ab-/- zebrafish.

“…Several animal models of PMS recapitulate muted responses to diverse sensory stimuli: pain in Shank3 mutant mice 5 , sound in Shank3 mutant rats 6 , and both touch and light in shank3ab mutant zebra sh 7,8 ; nonetheless, a brain-wide understanding of these muted responses is lacking. Hyporeactivity in PMS could re ect functional changes that either span the entire brain or are localized to speci c brain regions and/or muscle 9 . Zebra sh allow unique experimental approaches to identifying underlying mechanisms because, within the rst week of life, larvae have fully functional sensory-motor circuits and produce robust, stereotyped responses to calibrated sensory stimuli 10 These larval zebra sh have transparent vertebrate brains composed of only ~100,000 neurons, allowing unbiased functional approaches to map brain-wide neuronal activity.…”