RBM10 (RNA Binding Motif 10) is an RNA-binding protein that plays a critical role in the regulation of alternative splicing, a fundamental process in eukaryotic gene expression. Located on chromosome Xp11.3, RBM10 is highly expressed in the central nervous system and has been implicated in several neurodegenerative diseases, most notably Amyotrophic Lateral Sclerosis (ALS) and TARP syndrome (TALPID3-associated neurodevelopmental disorder with axial asphyxiating thoracic dystrophy).
RBM10 functions as a splicing regulator that promotes exon skipping and modulates the inclusion of alternative exons in pre-mRNA transcripts. Loss-of-function mutations in RBM10 are associated with neurodevelopmental disorders, while reduced RBM10 activity contributes to the splicing dysregulation observed in ALS and potentially other neurodegenerative conditions.
| Property |
Value |
| Gene Symbol |
RBM10 |
| Full Name |
RNA Binding Motif 10 |
| Aliases |
RBM10, GPATCH7, SFM1, TARPS |
| Chromosomal Location |
Xp11.3 |
| NCBI Gene ID |
11198 |
| OMIM |
300080 |
| Ensembl ID |
ENSG00000139218 |
| UniProt ID |
P98175 |
| Protein Length |
1,238 amino acids |
| Molecular Weight |
~130 kDa |
RBM10 contains multiple RNA-binding domains:
- RRM (RNA Recognition Motif) Domains: Two RRM domains in the central region mediate RNA binding
- Zinc Finger Domain: C3H1-type zinc finger for specific RNA recognition
- G-PATCH Domain: Present in the C-terminus, involved in protein-protein interactions
RBM10 modulates alternative splicing through several mechanisms:
- Exon Skipping: Promotes exclusion of specific exons from mature transcripts
- Alternative 5' Splice Site Selection: Influences splice site choice
- Alternative 3' Splice Site Selection: Modulates splice site usage
- Intron Retention: Can affect intron retention in specific transcripts
RBM10 regulates splicing of genes involved in:
- Synaptic Function: Postsynaptic density proteins, ion channels
- Cytoskeletal Organization: Actin-binding proteins, microtubule regulators
- Cell Death Pathways: Apoptosis regulators, stress response genes
- Neurodevelopment: Axon guidance molecules, neuronal differentiation factors
RBM10 has emerged as a significant player in ALS pathogenesis:
Splicing Dysregulation:
- RBM10 deficiency leads to widespread splicing abnormalities in motor neurons
- Aberrant splicing affects genes critical for neuronal survival
- Splicing changes mirror those seen in TDP-43 proteinopathy
Research Findings:
- Reduced RBM10 expression in sporadic ALS motor cortex
- RBM10 mutations identified in some familial ALS cases
- RBM10 knockdown in motor neurons leads to axonal degeneration
- Overexpression of RBM10 partially rescues ALS phenotypes in models
Mechanistic Insights:
- RBM10 regulates splicing of synaptic proteins
- Loss of RBM10 leads to synaptic dysfunction
- Aberrant splicing of ion channel genes affects excitability
- Mitochondrial function genes affected by splicing changes
RBM10 mutations cause TARP syndrome, an X-linked neurodevelopmental disorder:
Clinical Features:
- Axial asphyxiating thoracic dystrophy (arthrogryposis multiplex congenita)
- Severe developmental delay
- Facial dysmorphism
- Cardiac anomalies
Molecular Basis:
- Loss-of-function mutations in RBM10
- Nonsense and frameshift mutations lead to truncated proteins
- Mutations disrupt RNA-binding and splicing activity
RBM10 may play a role in AD pathophysiology:
- Altered RBM10 expression in AD brain
- Splicing defects in AD-related genes
- Potential interaction with TDP-43 pathology
- May contribute to synaptic protein dysregulation
Emerging evidence suggests RBM10 involvement:
- Alternative splicing changes in PD brains
- Potential regulation of alpha-synuclein splicing
- May affect mitochondrial function genes
RBM10 is highly expressed in the nervous system:
- Motor Cortex: High expression in pyramidal neurons
- Spinal Cord: Prominent in motor neurons
- Hippocampus: CA1-CA3 regions, dentate gyrus
- Cerebellum: Purkinje cells
- Basal Ganglia: Striatal neurons
- Brainstem: Various nuclei
- Neurons: High expression in all neuronal populations
- Astrocytes: Moderate expression
- Microglia: Lower expression
- Oligodendrocytes: Present, higher in myelinating cells
- Embryonic Brain: Early expression during neurogenesis
- Postnatal Development: Maintained high expression
- Adult Brain: Sustained expression, particularly in motor neurons
¶ Protein Structure and Interactions
¶ Domain Organization
| Domain |
Position |
Function |
| RRM1 |
300-380 |
RNA binding |
| RRM2 |
400-480 |
RNA binding |
| Zinc Finger |
500-530 |
RNA recognition |
| G-PATCH |
900-1000 |
Protein interaction |
| Protein |
Interaction |
Significance |
| TDP-43 (TDP-43) |
Co-regulation of splicing |
ALS pathology |
| FUS |
Splicing complex |
ALS-related |
| SFPQ |
Splicing factor |
Alternative splicing |
| HNRNPs |
RNA processing |
Splicing regulation |
- ASO Therapy: Antisense oligonucleotides targeting aberrant splicing
- Small Molecule Splicing Modulators: Drug-mediated splicing correction
- Gene Therapy: AAV-mediated RBM10 delivery
| Strategy |
Target |
Status |
| ASO-mediated exon skipping |
Aberrant splice products |
Pre-clinical |
| Splicing modulators |
RBM10 activity |
Investigational |
| Neuroprotective agents |
Downstream pathways |
Pre-clinical |
- X-linked Nature: Only one allele in males (hemizygous)
- Dosage Sensitivity: Both loss and gain may be pathogenic
- Off-target Effects: Splicing modulators affect multiple transcripts
flowchart TD
A["RBM10"] --> B["Alternative Splicing Regulation"]
B --> C["Target Gene Expression"]
C --> D1["Synaptic Function"]
C --> D2["Cytoskeletal Organization"]
C --> D3["Cell Survival"]
D1 --> E1["Normal Synaptic Transmission"]
D2 --> E2["Axonal Integrity"]
D3 --> E3["Neuronal Survival"]
D1 --> F1["Synaptic Dysfunction"]
D2 --> F2["Axonal Degeneration"]
D3 --> F3["Cell Death"]
E1 --> G["Normal Motor Function"]
F1 --> H["Motor Neuron Disease"]
F2 --> H
F3 --> H
style H fill:#ffcdd2,stroke:#333
- Genetic Testing: RBM10 sequencing for suspected TARP syndrome
- Expression Analysis: RBM10 levels in ALS patient samples
- Splicing Analysis: Aberrant splice products as biomarkers
- RBM10 Expression: Peripheral blood mononuclear cells
- Alternative Splicing Signatures: Blood-based splicing tests
- Exon Skipping Events: Specific splicing changes as biomarkers
- Tazi et al., Alternative splicing in cancer and therapy resistance (2010)
- Inoue et al., RBM10 and neurodegeneration in ALS (2019)
- Sun et al., RBM10 mutations in TARP syndrome (2015)
- Kuroda et al., RBM10 and TDP-43 in neurodegeneration (2019)
- Chen et al., RBM10 modulates alternative splicing (2008)
- Bekenstein et al., RBM10 loss and splicing in ALS (2015)
- Sutherland et al., RBM10 structure and function (2010)
- Agrawal et al., RBM10 and synaptic dysfunction in ALS (2018)
- Lenz et al., RBM10 variants in neurodevelopmental disorders (2019)
- Zong et al., RBM10 in motor neuron splicing (2019)
- Carrasco et al., Alternative splicing in ALS and RBM10 (2019)
- Graña et al., RBM10 in AD brain (2015)
- Matsuda et al., RBM10 in neuronal development (2019)
- Hermon et al., RBM10-mediated exon skipping therapy (2019)