| Gene Symbol |
HNRNPA2B1 |
| Full Name |
Heterogeneous Nuclear Ribonucleoprotein A2/B1 |
| Chromosomal Location |
7p15.2 |
| NCBI Gene ID |
3181 |
| Ensembl ID |
ENSG00000122566 |
| OMIM ID |
600124 |
| UniProt ID |
P22626 |
| Associated Diseases |
ALS, FTD, Multisystem Proteinopathy |
| Protein Family |
HnRNP A/B family |
Hnrnpa2B1 Heterogeneous Nuclear Ribonucleoprotein A2 B1 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
HNRNPA2B1 encodes a member of the heterogeneous nuclear ribonucleoprotein family with essential roles in RNA processing, stress granule formation, and RNA localization1. HNRNPA2B1 is one of the most abundant nuclear
RNA-binding proteins and plays critical roles in alternative splicing, mRNA stability, and translational regulation2. Like HNRNPA1, pathogenic mutations in HNRNPA2B1
cause familial ALS and multisystem proteinopathy (MSP), demonstrating the critical importance of hnRNP proteins in motor neuron survival3.
The protein contains two RNA recognition motifs (RRMs) and a glycine-rich low-complexity domain that undergoes liquid-liquid phase separation, enabling stress granule formation and
pathological aggregation in neurodegenerative disease4. HNRNPA2B1 is also recognized as an N6-methyladenosine (m6A) reader, participating in post-transcriptional RNA regulation5.
HNRNPA2B1 participates in multiple aspects of RNA metabolism:
- Alternative splicing: Regulation of splice site selection through binding to pre-mRNA6
- mRNA stability: Binding to AU-rich elements in target mRNAs to regulate degradation7
- RNA transport: Localizing specific mRNAs to subcellular compartments including neuronal processes8
- Translation: Modulating translational efficiency through interaction with translation initiation factors9
- miRNA processing: Involvement in microRNA biogenesis10
The glycine-rich low-complexity domain enables HNRNPA2B1 to undergo liquid-liquid phase separation (LLPS):
- Formation of stress granules under cellular stress conditions
- Dynamic exchange between membraneless organelles and cytoplasmic pool
- Pathological aggregation when prion-like domains mutate
- Sequestration of translation machinery and signaling proteins
HNRNPA2B1 functions as an m6A reader:
- Recognizes m6A-modified mRNA transcripts
- Regulates RNA splicing and nuclear export
- Influences mRNA stability and translation
- Dysregulation affects neuronal function and survival
¶ Domain Organization
HNRNPA2B1 contains several functional domains:
- RNA Recognition Motif 1 (RRM1): N-terminal RRM that binds single-stranded RNA
- **RNA Recognition Motif 2 (RRM2): C-terminal RRM for RNA binding specificity
- Glycine-rich low-complexity domain: Prion-like domain enabling phase separation
- Nuclear localization signal (NLS): Targets protein to the nucleus
The protein undergoes various modifications:
- Phosphorylation: Affects localization and RNA binding
- Methylation: Influences protein-protein interactions
- Sumoylation: Regulates stress granule dynamics
HNRNPA2B1 is ubiquitously expressed with high levels in:
- Brain (particularly cortex, hippocampus, and motor neurons)
- Skeletal muscle
- Heart
- Lung
- Testis
- Predominantly nuclear (speckles and nucleoplasm)
- Cytoplasmic localization during active RNA transport
- Stress granule localization under cellular stress
HNRNPA2B1 mutations cause familial ALS with typical clinical features:
- Progressive muscle weakness and atrophy
- Fasciculations and muscle cramps
- Bulbar involvement (dysarthria, dysphagia)
- Respiratory involvement in later stages
- Typical age of onset in 40s-60s3
The D262V mutation in the prion-like domain was the first identified pathogenic variant causing ALS11.
The HNRNPA2B1-related disorder presents with a triad of conditions:
- Inclusion body myopathy: Progressive muscle weakness, typically beginning in adulthood
- Paget disease of bone: Increased bone turnover with focal lesions
- Frontotemporal Dementia: Cognitive and behavioral changes
This rare autosomal dominant disorder demonstrates the link between muscle, bone, and neuronal pathology12.
While primarily associated with ALS, HNRNPA2B1 mutations can cause FTD without Motor Neuron Disease:
- Behavioral variant FTD (bvFTD)
- Language variant (primary progressive aphasia)
- Progressive Supranuclear Palsy phenotype
HNRNPA2B1 aggregates in a prion-like manner:
- Mutant protein misfolds and forms oligomers
- Oligomers seed aggregation of wild-type protein
- Aggregates spread through neural networks
- Progressive loss of neuronal function
Pathogenic mutations disrupt stress granule dynamics:
- Excessive phase separation
- Impaired disassembly of stress granules
- Sequestration of essential cellular proteins
- Disruption of RNA metabolism
ALS-associated mutations cause:
- Altered splicing of survival motor neuron (SMN) transcripts
- Dysregulated translation of neuronal proteins
- Impaired RNA transport to synaptic terminals
- Knock-in and overexpression models recapitulate key features
- Motor dysfunction and reduced lifespan observed
- Stress granule accumulation in neurons
- Transgenic mice with mutant HNRNPA2B1 show:
- Motor neuron degeneration
- Muscle denervation
- Gliosis in spinal cord
- Behavioral deficits
- Antisense oligonucleotides (ASOs): Reduce mutant allele expression
- CRISPR-based approaches: Correct mutations or allele-specific silencing
- AAV delivery: Target CNS motor neurons
- Phase separation modulators: Normalize LLPS dynamics
- Protein aggregation inhibitors: Prevent toxic oligomer formation
- RNA metabolism modulators: Restore proper RNA processing
- Elevated HNRNPA2B1 in cerebrospinal fluid of ALS patients
- Potential for disease progression monitoring
- Utility in clinical trial enrollment
The study of Hnrnpa2B1 Heterogeneous Nuclear Ribonucleoprotein A2 B1 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Beyer AL, Christensen ME, Walker BW, LeStourgeon WM. "Identification and characterization of the packaging proteins of core 40S hnRNP particles." Cell. 1977;11(1):127-138. DOI
- Mayeda A, Krainer AR. "Regulation of alternative pre-mRNA splicing by hnRNP A1/A2B1." Cell. 1992;68(2):365-375. DOI
- Kim HJ, Kim NC, Wang YD, et al. "Mutations in prion-like domains in hnRNPA1 and hnRNPA2B1 cause amyotrophic lateral sclerosis and Frontotemporal Dementia." Nature. 2013;495(7442):467-473. DOI PubMed
- Molliex A, Taylor J, Fare CM, et al. "Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization." Cell. 2015;163(1):123-133. DOI
- Liu N, Zhou KI, Zhang W, et al. "Direct detection of N6-methyladenosine in RNA by digital enzyme-free sequencing." Nat Biotechnol. 2022;40(10):1541-1550. DOI
- Martinez-Contreras R, Cloutier P, Shkreta L, et al. "hnRNP proteins and splicing." Biopolymers. 2003;66(4):223-249. DOI
- Shenkman M, Brill M, Dromi M, et al. "HNRNPA2B1 controls diet-induced obesity via regulation of lipid metabolism in adipose tissue." Mol Metab. 2020;42:101077. DOI
- Glinka M, Herrmann R, Hausmann M, et al. "HNRNPA2B1 localizes to dendritic RNA granules." J Cell Sci. 2020;133(17):jcs249342. DOI
- Kim J, Park R, Yoo J, et al. "HNRNPA2B1 regulates alternative splicing in neuronal development." Neuron. 2021;109(11):1812-1828. DOI
- Alarcon CR, Lee H, Goodarzi H, et al. "HNRNPA2B1 is an m6A reader that governs nuclear RNA processing and export." Cell. 2015;161(6):1378-1390. DOI
- Liu Q, Shu S, Wang MS, et al. "ALS-associated D262V mutation in HNRNPA2B1 disrupts stress granule dynamics and nucleocytoplasmic transport." Acta Neuropathol Commun. 2019;7(1):184. DOI
- Benatar M, Wuu J, McHale J, et al. "Multisystem proteinopathy: evidence for phenotypic heterogeneity in ALS-FTD." Neurology. 2020;95(10):e1401-e1413. DOI