Nonsense-mediated mRNA decay and associated splicing patterns in neurodevelopmental disorders

Abstract

Nonsense-mediated mRNA decay (NMD) is a basic post-transcriptional mechanism ensuring the fidelity of many biological processes including brain development. Together with alternative splicing, it regulates the inclusion of poison exons. NMD is involved in the control of multiple processes during brain development such as neural progenitor proliferation and differentiation, neuronal migration, axonal guidance, and synaptic plasticity. Under physiological conditions, this mechanism safeguards neuronal identity and the functional maturation of the brain. When disrupted, the consequences range from structural cerebral anomalies to cognitive impairment and epilepsy. This review examines NMD-mediated regulatory mechanisms across different stages of brain development. Special emphasis is placed on how dysfunction in NMD pathway components—specifically core degradation factors, the exon junction complex, and neuron-specific splicing regulators—underpins an extensive array of neurodevelopmental disorders (NDDs). Furthermore, we delineate the relationship between the position of a premature termination codon (PTC) within a transcript and the resulting molecular outcome. While the degradation of aberrant mRNAs often leads to haploinsufficiency, their escape from NMD might result in the accumulation of truncated proteins with dominant-negative effects, thereby causing specific clinical phenotypes in affected patients. Elucidating these mechanisms is essential for both the interpretation of variant pathogenicity and the development of targeted therapeutic strategies.