The spliceosome catalyzes precursor messenger RNA (pre-mRNA) splicing, a function carried out by a ribonucleoprotein (RNP) complex composed of small nuclear RNAs (snRNAs), their associated small nuclear ribonucleoproteins (snRNPs), and additional trans-acting proteins. The conformation and composition of the spliceosome are ever-changing, which enables flexibility, yet makes it challenging to study 1, 2, 3, 4.

In eukaryotic splicing, genes are transcribed as pre-mRNAs, which become mature mRNAs once the introns are removed and the exons are joined. Some exons are present in every mRNA from a given gene, known as constitutive splicing, while others are only in some, known as alternative splicing [1]. Splicing assembly for RNA recognition and catalysis is an ordered and coordinated process: spliceosomal snRNPs and additional splicing factors interact in a specific sequence. In eukaryotes, there are two types of spliceosomes: major, U2-dependent spliceosome and minor, U12-dependent spliceosome, with the major conducting most splicing. In the major spliceosome, U1 is recruited to the 5’ splice site (complex E). U2 associates with the branch site to form the prespliceosome (complex A). The pre-assembled tri-sRNP (U4/U6.U5 in the major spliceosome) is recruited to form the precatalytic spliceosome (complex B). Subsequent rearrangements and destabilization of U1 and U4 lead to the formation of the activated spliceosome (Bact), and catalytic activation forms the catalytically activated spliceosome (B*). Splicing occurs in two steps: first, the catalytic step 1 spliceosome (complex C) is formed; second, the catalytic step 2 spliceosome (complex C*) is generated. Finally, the post-spliceosomal complex forms, after which the spliceosome dissociates (Figure 1) 1, 5, 6. Alternative splicing enables multiple mature mRNAs to be produced from the same pre-mRNA, particularly in the brain [7], but disruptions in this process can alter the ratio of mature mRNA isoforms, potentially leading to disease.

Neurodevelopment is a tightly controlled process of spatiotemporal patterning where gene expression occurs within specific tissues at specific times throughout development [8]. This process is in part regulated via alternative splicing [9], which ensures the building of a properly connected and functional neural network: even small changes in gene expression can lead to alterations in the network’s construction [10]. In the context of alternative splicing, a specific combination of splicing factors is required for each neurodevelopmental stage, resulting in a unique pattern of alternative splicing [11]. Disruptions in this process can cause neurodevelopmental disorders (NDDs), a group of heterogeneous conditions with both genetic and environmental contributions.

Spliceosomopathies are diseases caused by pathogenic variants in genes encoding spliceosome RNAs and proteins, leading to splicing defects. Phenotypically, spliceosomopathies have a greater impact on certain systems, including the craniofacial skeleton, retina, limbs, bone marrow, and spinal cord, resulting in conditions such as retinitis pigmentosa, myelodysplastic syndrome, craniofacial disorders, spinal muscular atrophy, amyotrophic lateral sclerosis, and genodermatosis poikiloderma with neutropenia, Clericuzio-type [12]. Although changes in alternative splicing are a known feature of spliceosomopathies, not all conditions induced by splicing changes are spliceosomopathies. To be defined as a spliceosomopathy, there must be a pathogenic variant in a spliceosome component. Yet, there are various NDDs caused by splice-altering variants in genes resulting in mis-splicing events like exon skipping (a type of alternative splicing) without the required pathogenic variant in a spliceosome component [13]. Changes in alternative splicing patterns have been detected in Autism Spectrum Disorder (ASD) patients’ brains 14, 15; therefore, alternative splicing has been a key focus in ASD research (reviewed in Ref. [11]). Previous reviews have examined splicing changes in NDDs through variants in splicing factors [11] (including WBP4, SRRM2, PRPF8, and DDX23), the chromatin basis of abnormal splicing [10], or splice site variants [13]. However, apart from the three spliceosome proteins (WBP4, PRPF8, and DDX23), these conditions are not classified as spliceosomopathies. This review focuses on spliceosomopathies in NDDs.