Widespread intron retention and exon skipping characterise alternative splicing changes in a C. elegans model of spinal muscular atrophy

Rashid, Saman, Shen, Aykut, Yong, Amy, Akay, Alper and Dimitriadi, Maria (2026) Widespread intron retention and exon skipping characterise alternative splicing changes in a C. elegans model of spinal muscular atrophy. Human Molecular Genetics, 35 (2). ISSN 0964-6906

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Abstract

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by reduced levels of the survival motor neuron (SMN) protein, an essential component of the RNA splicing machinery. Although disruption of alternative splicing is a well-established hallmark of SMA, the specific splicing events that contribute to disease pathogenesis remain poorly understood. We utilised an established Caenorhabditis elegans SMA model to investigate global splicing changes using poly(A)+RNA-seq and custom transcriptome assembly. Zygotic loss of smn-1 led to extensive transcriptomic changes, including over 1000 alternative splicing events, many of which were functionally tied to larval development. Exon skipping and intron retention were the most prevalent splicing alterations, and sequence motif analysis indicated a general shift from strong to weak splice site usage; however, no single motif accounted for the majority of observed splicing changes. Notably, we identified an overlap between smn-1 dependent splicing and those regulated by U6 snRNA m6A methylation. Our findings reinforce the conserved, broad role of SMN in maintaining splicing fidelity and reveal specific sequence biases associated with splicing errors in SMA.

Item Type:	Article
Additional Information:	Data availability: All raw and experimental data have been deposited in ArrayExpress (https://www.ebi.ac.uk/biostudies/arrayexpress) under accession E-MTAB-16084.
Uncontrolled Keywords:	alternative splicing,c. elegans,exon skipping,intron retention,sma,molecular biology,genetics,genetics(clinical) ,/dk/atira/pure/subjectarea/asjc/1300/1312
Faculty \ School:	Faculty of Science > School of Biological Sciences
UEA Research Groups:	Faculty of Science > Research Groups > Cells and Tissues
Related URLs:	http://www.scopus.com/inward/record.url?...
Depositing User:	LivePure Connector
Date Deposited:	31 Mar 2026 10:30
Last Modified:	05 Apr 2026 06:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/102660
DOI:	10.1093/hmg/ddaf176

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