Intellectual development disorders (IDD) affect 2 to 3 per cent of the population and are characterized by impaired cognitive functions, impacting learning. TDI thus has an impact on coping skills with implications for daily life and is a major public health issue.
An often genetic but still poorly elucidated origin
The origin of TDI is often genetic, with great heterogeneity. Despite the identification of more than 1 500 genes involved in TDI, more than 50% of affected children remain without a genetic diagnosis, with each gene accounting for only a small proportion of cases.
Until now, research into the genetic causes of neurodevelopmental disorders has focused mainly on protein genes, about 1.5% of the total DNA, while the non-coding part (98.5% of the total DNA) remains largely unexplored and difficult to interpret.
Major breakthrough in 2024: RNU4-2 gene identification
In 2024, de novo (non-parental) variants of the RNU4-2 gene, located on chromosome 12, were identified as responsible for severe TDI, often associated with hypotonia, microcephaly, nutritional difficulties and epilepsy. Unlike most of the genes studied, RNU4-2 does not produce a protein, but a small RNA essential to a key process in our cells: splicing, which transforms pre-messenger RNAs into mature RNAs used for to make proteins.
The RNU-Splice project: deepening the understanding of the pathologies related to small non-coding nuclear RNAs.
The RNU-Splice project has several objectives:
- Specifically describe the clinical spectrum associated with pathogenic variants of RNU4-2 and correlate symptom severity with their location in the gene.
- To understand the impact of variants on the structure of U4 RNA and its interaction with other small non-coding RNAs involved in splicing.
- Continue to explore the non-coding genome by studying other small RNAs involved in splicing in patients with TDI or other pathologies.
- To characterize pathophysiological mechanisms through the study of RNAs extracted from blood samples and iPSCs (induced pluripotent stem cells) differentiated into neural progenitors.
The RNU-Splice project (“Neurodevelopmental pathology associated with small nuclear RNAs involved in the spliceosome: clinical, genetic and pathophysiological exploration”), carried out by Caroline Nava within the team of Stéphanie Baulac, has been selected within the framework of a call for projects launched by the patronage of Mutuelles AXA, alongside 13 new health projects carried out by 11 French institutions that will collectively benefit from a financing of EUR 13.9 million from 3 years. This is the second project supported by AXA Mutuals since 2023.
Thanks to its innovative nature, the RNU-Splice project will be financed by the Mutuelles AXA, for a period of 3 years, as part of its programme dedicated to supporting innovative research initiatives in France.
