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Background  Deletions and mutations in the  SHANK3  gene are strongly associated with autism spectrum disorder and underlie the autism-associated disorder Phelan–McDermid syndrome. SHANK3 is a scaffolding protein found at the post-synaptic membrane of excitatory neurons.    Methods  Single-molecule fluorescence in-situ hybridization (smFISH) allows the visualization of single mRNA transcripts in vitro .  Here we perform and quantify smFISH in human inducible pluripotent stem cell (hiPSC)-derived cortical neurons, targeting the  SHANK3  transcript.    Results  Both smFISH and conventional immunofluorescence staining demonstrated a developmental increase in SHANK3 mRNA and protein, respectively, in control human cortical neurons. Analysis of single  SHANK3  mRNA molecules in neurons derived from an autistic individual heterozygous for  SHANK3  indicated that while the number of  SHANK3  mRNA transcripts remained comparable with control levels in the cell soma, there was a 50% reduction within neuronal processes, suggesting that local, dendritic targeting of  SHANK3  mRNA may be specifically affected in  SHANK3  haploinsufficiency.    Conclusion  Human  SHANK3  mRNA shows developmentally regulated dendritic localization in hiPSC-derived neurons, which is reduced in neurons generated from a haploinsufficient individual with autism. Although further replication is needed, given the importance of local mRNA translation in synaptic function, this could represent an important early abnormality.

stem cell research and therapy

Single-molecule fluorescence in-situ hybridization reveals that human SHANK3 mRNA expression varies during development and in autism-associated SHANK3 heterozygosity