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

AI Summary

De novo SRSF3 variants cause variable developmental phenotypes, most consistently developmental delay and mild to moderate intellectual disability.
Identified variants include conserved RRM missense changes and recurrent frameshifts or nonsense truncations, with predicted NMD yet overall normal SRSF3 mRNA and protein levels.
Functional assays show reduced RNA binding, decreased C-terminal phosphorylation and protein instability, altered YTHDC1/NXF1 interactions, and impaired nucleocytoplasmic shuttling for truncations.

TL;DR (AI Generated)

SRSF3 (SRp20), a member of the serine/arginine-rich protein family of splicing factors, plays a central role in constitutive and alternative splicing.

The C-terminal arginine/serine-rich domain of SRSF3 undergoes dynamic phosphorylation cycles that regulate its subcellular localization, protein-protein interactions, and nuclear mRNA export while also indirectly modulating the RNA-binding capability.

We report nine individuals with variable developmental phenotypes, including developmental delay and/or mild to moderate intellectual disability as the most consistent feature, and de novo SRSF3 variants.

Basic summary

Am J Hum Genet. 2026 Oct 20:S0002-9297(26)00383-6. doi: 10.1016/j.ajhg.2026.09.018. Online ahead of print.

ABSTRACT

SRSF3 (SRp20), a member of the serine/arginine-rich protein family of splicing factors, plays a central role in constitutive and alternative splicing. The C-terminal arginine/serine-rich domain of SRSF3 undergoes dynamic phosphorylation cycles that regulate its subcellular localization, protein-protein interactions, and nuclear mRNA export while also indirectly modulating the RNA-binding capability. We report nine individuals with variable developmental phenotypes, including developmental delay and/or mild to moderate intellectual disability as the most consistent feature, and de novo SRSF3 variants. These variants comprise c.181G>C (p.Asp61His) and c.242C>G (p.Ser81Trp), affecting highly conserved residues within the RNA recognition motif, c.330_331del (p.Pro111Serfs∗20), c.402_403del (p.Arg137Ilefs∗16), c.477dup (p.Ser160Valfs∗3), and a recurrent nonsense variant c.445C>T (p.Arg149∗). For c.330_331del, nonsense-mediated mRNA decay (NMD) was predicted. Qualitative RT-PCR followed by Sanger sequencing and RNA sequencing (RNA-seq) of fibroblasts from this individual demonstrated NMD of SRSF3 transcripts containing the variant. However, overall SRSF3 mRNA and protein levels were comparable to control cells, suggestive of a compensatory mechanism acting in these cells. Comprehensive functional studies of ectopically expressed SRSF3^Asp61His, SRSF3^Ser81Trp, SRSF3^Arg137Ilefs^∗¹⁶, SRSF3^Arg149^∗, and SRSF3^Ser160Valfs^∗³ in HEK293T cells revealed reduced complex formation with polyadenylated RNA as well as intrinsic instability of C-terminally truncated variant proteins, correlating with decreased C-terminal phosphorylation. Complex formation with the nuclear export proteins YTHDC1 and NXF1 was reduced for SRSF3^Arg137Ilefs^∗¹⁶ and SRSF3^Arg149^∗ and increased for SRSF3^Ser81Trp. Additionally, nucleocytoplasmic shuttling, assessed in HeLa cells, was reduced for the C-terminally truncated SRSF3 variant proteins. Together, our data demonstrate distinct functional defects for the disease-associated SRSF3 variants, which may underlie phenotypic variability in affected individuals.