Spliceosomopathies and neurocristopathies: Two sides of the same coin?

Abstract

Mutations in core components of the spliceosome are responsible for a group of syndromes collectively known as spliceosomopathies. Patients exhibit microcephaly, micrognathia, malar hypoplasia, external ear anomalies, eye anomalies, psychomotor delay, intellectual disability, limb, and heart defects. Craniofacial malformations in these patients are predominantly found in neural crest cells‐derived structures of the face and head. Mutations in eight genes SNRPB, RNU4ATAC, SF3B4, PUF60, EFTUD2, TXNL4, EIF4A3, and CWC27 are associated with craniofacial spliceosomopathies. In this review, we provide a brief description of the normal development of the head and the face and an overview of mutations identified in genes associated with craniofacial spliceosomopathies. We also describe a model to explain how and when these mutations are most likely to impact neural crest cells. We speculate that mutations in a subset of core splicing factors lead to disrupted splicing in neural crest cells because these cells have increased sensitivity to inefficient splicing. Hence, disruption in splicing likely activates a cellular stress response that includes increased skipping of regulatory exons in genes such as MDM2 and MDM4, key regulators of P53. This would result in P53‐associated death of neural crest cells and consequently craniofacial malformations associated with spliceosomopathies.

An Alternative Splicing Program for Mouse Craniofacial Development

“…It has become clear that alternative splicing in different tissues is regulated by coordinated networks of splicing regulators (Ule and Blencowe, 2019). The importance of alternative splicing in craniofacial development is demonstrated by the observation that abnormalities in spliceosome or splicing regulators occur in several human birth defects often involving the craniofacial complex (Bain et al, 2016;Marques et al, 2016;Loiselle and Sutherland, 2018;Berube-Simard and Pilon, 2019;Beauchamp et al, 2020;Griffin and Saint-Jeannet, 2020). Two splicing regulators involved in promoting differential splicing in the ectoderm -Esrp1/2 -are known to cause mouse orofacial clefting of the lip and palate when deleted (Warzecha et al, 2009;Bebee et al, 2015;Lee et al, 2020).…”

Mis-splicing ofMdm2leads to Increased P53-Activity and Craniofacial Defects in a MFDMEftud2Mutant Mouse Model

“…Patients with MFDM exhibit a variety of clinical findings and the most common are craniofacial defects such as microcephaly, developmental delay, mandibular and malar hypoplasia as well as external ear anomalies. In addition, as no correlation is found between patient`s genotypes and their clinical characteristics, these mutations are predicted to be loss-of-function mutations and suggest that the developing craniofacial region is more sensitive to reduced levels of EFTUD2 when compared to other embryonic cell types (reviewed in (Beauchamp et al, 2020)). Here, we report that altered splicing caused by the loss of Eftud2 results in the reduced inclusion of exon 3 of Mdm2 and nuclear accumulation of P53 in the neural crest cells.…”

“…Furthermore, homozygous Eftud2 (Eftud2 -/-) mutant blastocysts failed to implant, precluding analysis of the role of Eftud2 during craniofacial development. These and other past studies confirmed that Eftud2 is an essential gene, but its role in neural crest cells, the precursors of bones and cartilages affected in the head and face of MFDM patients, has not been examined (Beauchamp et al, 2020;Deml et al, 2015;Lei et al, 2017;Wu et al, 2019). Therefore, we have generated a conditional Eftud2 knock-out mouse (Eftud2 loxP/+ ) in which exon 2 is flanked by loxP sequences to study the role of Eftud2 during craniofacial development.…”

“…The sequential steps in splicing include recognition of a 5'-splice site via the U1/U11 snRNP, binding of U2/U12 snRNP to the branch site on the intron, recruitment of the preassembled U4/U6.U5 or U4atac/U6atac/U5 snRNPs, cleavage of the intervening intron, and ligation of the two exons. This process is ubiquitous and yet, mutations in components of the spliceosome can result in tissue-specific abnormalities ranging from retinitis pigmentosa to craniofacial malformations (Beauchamp et al, 2020;Daguenet et al, 2015;Griffin and Saint-Jeannet, 2020;Lehalle et al, 2015).…”

Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells

“…BMKS is one of five developmental craniofacial disorders caused by variants in core spliceosome components [6,17]. Given the universality of pre-mRNA splicing in the processing of all human pre-mRNAs, the very specific and tissue-restricted craniofacial phenotypes of these disorders are remarkable.…”