Fig. 4 | Potential effects of mutations in RBP genes.
Only mutations in the transcribed regions of genes have been considered.
Mutations in non-coding regions (that is, untranslated regions (UTRs) and introns) or coding exons (open reading frames (ORFs)) of the pre-mRNA may lead to altered mRNA levels, defective intracellular localization of the transcript or alternative transcript isoforms.
For example, mutations in introns can lead to intron retention and subsequent nonsense-mediated decay of the transcript (top).
Mutations in the coding region may elicit various effects depending on the type and location of the mutation.
Nonsense mutations lead to protein truncation and defective activity.(pre-happened termination)
Missense mutations affecting sites of post-translational modification (PTM) may lead to altered signal perception.
perception：Perception is the recognition of things using your senses, especially the sense of sight.
Mutations in RNA-binding domains (RBDs) or in protein–protein interaction (PPI) domains lead to defects in ribonucleoprotein particle (RNP) assembly and function.
Mutations in low-complexity (LC) and disordered regions may lead to changes in the solubility of RNA-binding proteins (RBPs), ultimately resulting in accumulation of toxic aggregates.
For those RBPs that display dual roles as enzymes, mutations in the enzymatic (Enz) domain may lead to defective catalysis (bottom).
The consequences of mutations are not mutually exclusive.
For instance, mutations in PTMs may not only lead to altered signal perception but also modify the interaction of the RBP with partners and its localization, stability or solubility
Fig. 5 | Location and networks of disease-associated mutations.
Fig. 6 | RnA-binding proteins and phase transitions.
a | Physical states of ribonucleoprotein particle (RNP) assemblies. Soluble RNPs can undergo initial de-mixing, resulting in liquid-like condensates that may further transit into more viscous hydrogel-like states and solid-like pathological aggregates. Dynamic RNP assemblies within the cell are thought to interchange between the first two states, whereas the last state is largely irreversible and toxic.
b | Principles of FUS (fused in sarcoma) liquid de-mixing. Domain organization of FUS (top). Hotspots for mutations causing the neurodegenerative disorders amyotrophic lateral sclerosis and frontotemporal dementia are indicated. Contacts between tyrosine residues in the prion-like domain (PrLD) and arginine residues in the region rich in arginine and glycine residues (RGG) promote liquid–liquid phase separation, with mutations promoting aberrant transitions to toxic aggregates (bottom).
