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A novel species- and skeletal muscle specific microexon regulated by alternative splicing diversifies the menu of clathrin heavy chains in mice and rats

ABSTRACT: Tiny exons, known as microexons, are often alternatively spliced in a tissue-specific manner. The existence of alternatively spliced microexons and their regulation have been greatly investigated in brain development and autism spectrum disorders, but very little is known about microexons in other tissues. We previously reported that a microexon (exon 31, 21 nt) in the essential clathrin heavy chain (CLTC) gene is developmentally regulated by alternative splicing specifically in striated muscles and this regulation is conserved between mice and humans. CLTC protein is one of the two clathrin heavy chains that exist in humans, drives clathrin-mediated endocytosis and is required for the formation of the skeletal muscle contractile apparatus. Here, we report the discovery of another microexon in Cltc pre-mRNA (exon 33, 38 nt, herein referred to as microexon 33). Microexon 33 is the penultimate exon in Cltc gene and is exclusively included in mouse and rat adult skeletal muscles, encoding a premature stop codon that escapes nonsense-mediated decay. Microexon 33 inclusion is generates a CLTC isoform with a short C-terminus in which the last 41 residues are replaced by a distinct 10 amino acid sequence. This divergence, specific to rodent adult skeletal muscle, occurs at the same residue position at which in humans the highly homologous CLTCL1 gene (which encodes the other clathrin heavy chain in humans) undergoes constitutive inclusion of its penultimate exon (another microexon, 40 nt). While CLTCL1 is a pseudogene in mice and rats, CLTCL1 is expressed at the highest level in human skeletal muscle, where it regulates glucose homeostasis but not clathrin-mediated endocytosis. Therefore, humans have diversified the menu of clathrin heavy chain proteins by gene duplication (CLTC, CLTCL1) and tissue-specific gene expression, whereas mice and rats have achieved similar diversification by tissue-specific regulation of Cltc alternative splicing.

ORGANISM(S): Mus musculus

PROVIDER: GSE333636 | GEO | 2026/09/10

REPOSITORIES: GEO

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Project description:A major challenge in understanding autism spectrum disorder (ASD) is to establish the underlying convergent genetic and molecular mechanisms. Neuronal microexons represent a highly conserved class of alternative splicing event and are enriched in genes with diverse and critical functions in nervous system biology. Previous studies have provided evidence that microexon splicing is disrupted in the brains of approximately one-third of ASD individuals, in part as a consequence of altered neuronal activity. Moreover, mice with microexon splicing deficiencies display multiple ASD-like phenotypes. However, the full landscape of microexons is not known, and whether these exons are directly impacted human genetic variation has not been previously investigated. Through extensive profiling of brain RNA-Seq data, we have discovered several hundred new neuronal microexons, including many that have highly specific neuronal subtype-specific splicing patterns, and others with the potential to control gene expression by activating nonsense-mediated mRNA decay. By developing a machine learning model that predicts neuronally-spliced microexons from genome sequence, we have defined critical regulatory elements surrounding the expanded repertoire of microexons. Using this model, we identify rare and common variants that are predicted to alter microexon splicing patterns in approximately 30% of ASD-affected individuals, relative to their unaffected siblings, with rare variants having the strongest impact. These variants are mostly detected in idiopathic individuals and converge on a subset of microexons concentrated in synaptic and additional ASD-linked genes, but also in genes not previously linked to autism. Our results collectively define an expanded repertoire of neuronal microexons, delineate their regulatory code, and pinpoint genetic variants that impact their splicing, with implications for the disruption of functions central to neuronal biology and brain disorders.

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A novel species- and skeletal muscle specific microexon regulated by alternative splicing diversifies the menu of clathrin heavy chains in mice and rats

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