Reciprocal control of translation and transcription in autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and the presence of restricted patterns of interest and repetitive behaviors. ASD is genetically heterogeneous and is believed to be caused by both inheritable and de novo gene variations. Studies have revealed an extremely complex genetic landscape of ASD, favoring the idea that mutations in different clusters of genes interfere with interconnected downstream signaling pathways and circuitry, resulting in aberrant behavior. In this review, we describe a select group of candidate genes that represent both syndromic and nonsyndromic forms of ASD and encode proteins that are important in transcriptional and translational regulation. We focus on the interplay between dysregulated translation and transcription in ASD with the hypothesis that dysregulation of each synthetic process triggers a feedback loop to act on the other, which ultimately exacerbates ASD pathophysiology. Finally, we summarize findings from interdisciplinary studies that pave the way for the investigation of the cooperative impact of different genes and pathways underlying the development of ASD.

Interactome analysis illustrates diverse gene regulatory processes associated with LIN28A in human iPS cell-derived neural progenitor cells

“…Translational regulation is crucial for normal brain development, and its dysregulation is known to cause neurodevelopmental disorders such as Rett syndrome and autism-spectrum disorders ( Longo and Klann, 2021 ). EIF3D is known as a peripheral subunit of eIF3 and binds to 5′ cap of mRNA independent of canonical eIF4E-dependent mechanism, especially for expression of specific proteins involved in cell cycle and differentiation ( Lee et al., 2015 ).…”

Interactome Analysis Illustrates Diverse Gene Regulatory Processes Associated with LIN28A in Human iPS Cell-Derived Neural Progenitor Cells

“…Translational regulation is crucial for normal brain development, and its dysregulation is known to cause neurodevelopmental disorders such as Rett syndrome and autism-spectrum disorders (Longo and Klann, 2021). EIF3D is known as a peripheral subunit of eIF3 and binds to 5 0 cap of mRNA independent of canonical eIF4E-dependent mechanism, especially for expression of specific proteins involved in cell cycle and differentiation (Lee et al, 2015).…”

Signalling pathways in autism spectrum disorder: mechanisms and therapeutic implications

“… 78 , 83 , 84 Mutations located in intronic and intergenic regions are the third variation type of ASD. 85 …”

“…Syndromic generally refers to mutations in a specific gene or genome, manidesting as neurological syndromes (such as fragile X syndrome, tuberous sclerosis, Rett syndrome, Phelan–McDermid syndrome and Angelman syndrome). 79 , 85 Non-syndromic, also regarded as idiopathic, which accounts for the vast majority, is not associated with other neurological disorders (or syndromes) but is related to some genes associated with autism. 85 In heterogeneous genetic structures, syndromic ASD caused by high-penetrance single-gene mutations represent only a minority of ASD cases, the majority of cases are idiopathic.…”

“… 79 , 85 Non-syndromic, also regarded as idiopathic, which accounts for the vast majority, is not associated with other neurological disorders (or syndromes) but is related to some genes associated with autism. 85 In heterogeneous genetic structures, syndromic ASD caused by high-penetrance single-gene mutations represent only a minority of ASD cases, the majority of cases are idiopathic. 86 In fact, due to the overlap of phenotypes and growing understanding of intersecting biology, it remains controversial that the definition and boundary between syndromic and idiopathic ASD.…”