468: When a splicing factor breaks in different ways

Lisfeld J et al., The American Journal of Human Genetics - SRSF3 is an essential splicing factor, one of the serine/arginine-rich proteins that help cells cut and paste their RNA messages and send them out of the nucleus. Losing it completely is lethal in mouse embryos. This study describes nine individuals with new, non-inherited SRSF3 variants and variable developmental phenotypes, with developmental delay and/or mild to moderate intellectual disability as the most consistent feature. Functional experiments in patient fibroblasts and human cell lines showed that each variant damaged the protein in a different combination of ways, which may help explain why affected individuals differ so much. Key terms: SRSF3, splicing, de novo variants, neurodevelopmental disorder, spliceosomopathy.

Study Highlights:
Through GeneMatcher, the team recruited nine subjects with six heterozygous de novo SRSF3 variants: two missense variants in the RNA recognition motif, three frameshifts and a recurrent nonsense variant, p.Arg149*, found in four unrelated subjects. In fibroblasts from subject 3, transcripts carrying the c.330_331del frameshift were largely degraded by nonsense-mediated decay, with only about 12.5% of SRSF3 reads carrying the deletion, yet overall SRSF3 mRNA and protein levels were normal, suggesting compensation from the other allele. In HEK293T cells, all five variant proteins tested formed less complex with polyadenylated RNA than wild type, while the three C-terminally truncated proteins were poorly phosphorylated, less stable, at about 46% to 59% of wild-type levels, and showed reduced nucleocytoplasmic shuttling in HeLa cells. Complex formation with the export factors YTHDC1 and NXF1 was reduced for p.Arg137Ilefs*16 and p.Arg149* and increased for p.Ser81Trp.

Conclusion:
De novo SRSF3 variants define a new spliceosomopathy with a broad developmental spectrum, and the variants appear to act through distinct mechanisms rather than simple loss of half the protein. The cohort is small, most functional work used overexpressed proteins in cell lines rather than affected tissues, the evidence against haploinsufficiency comes from one subject and one cell type, and the c.330_331del variant remains of uncertain significance.

Article title:
De novo variants in the essential splicing factor gene SRSF3 cause variable developmental phenotypes

First author:
Lisfeld J

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2026.09.018

Reference:
Lisfeld J., Chinn I.K., Yuan B., Casar C., Müller C., Elron E., et al. De novo variants in the essential splicing factor gene SRSF3 cause variable developmental phenotypes. The American Journal of Human Genetics. (2026). https://doi.org/10.1016/j.ajhg.2026.09.018

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Episode link: https://basebybase.com/episodes/srsf3-de-novo-variants-splicing-factor-development

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-10-25.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, in...

Chapters

• (00:00:03) - Introduction: Nine Children, One Gene
• (00:01:03) - The Film Editor Analogy
• (00:01:42) - Study Credits and Paper Overview
• (00:02:23) - Understanding Splicing and the Spliceosome
• (00:02:57) - SR Proteins and SRSF3 Basics
• (00:03:29) - SRSF3 Structure and Phosphorylation Cycle
• (00:04:41) - SRSF3's Self-Regulating Poison Exon
• (00:05:18) - Finding the Children via GeneMatcher
• (00:05:55) - Types of Variants Found
• (00:06:30) - Lab Methods: Testing the Variants
• (00:07:05) - Control Variants for Validation
• (00:07:33) - Clinical Features of the Children
• (00:08:02) - Variability Within the Same Variant
• (00:08:44) - Subject 3: A Surprising Compensation
• (00:09:16) - Confirming Normal Protein Levels in Subject 3
• (00:09:48) - Interpreting Subject 3's Uncertain Variant
• (00:10:20) - Tail Tagging Experiments
• (00:11:19) - Protein Stability and Tag Protection
• (00:11:28) - RNA Gripping Deficits Across Variants
• (00:11:50) - Nuclear Shuttling Defects
• (00:12:36) - Export Partner Binding Differences
• (00:13:06) - Each Variant's Unique Defect Combination
• (00:13:44) - SRSF3 as a New Spliceosomopathy
• (00:14:18) - Comparison to SRSF1 and Clinical Implications
• (00:14:52) - Challenging Assumptions About Truncating Variants
• (00:15:24) - Study Limitations
• (00:16:02) - Summary: One Gene, Many Breaks
• (00:16:35) - Closing and Credits