FAM134B — Family With Sequence Similarity 134 Member B
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">FAM134B — Retregulin</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>FAM134B</strong></td>
</tr>
<tr>
<td class="label">Alias</td>
<td>RETREG1, Retregulin</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Family With Sequence Similarity 134 Member B</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>5p15.1</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/54494" target="_blank">54494</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000144136" target="_blank">ENSG00000144136</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://www.omim.org/entry/613374" target="_blank">613374</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9H6Y3" target="_blank">Q9H6Y3</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[HSAN2](/diseases/hereditary-sensory-autonomic-neuropathy), [Parkinson's Disease](/diseases/parkinsons-disease)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Neurons, peripheral sensory neurons</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ad" style="color:#ef9a9a">AD</a>, <a href="/wiki/ali" style="color:#ef9a9a">ALI</a>, <a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">281 edges</a></td>
</tr>
</table>
FAM134B — Family With Sequence Similarity 134 Member B
Overview
FAM134B (Family With Sequence Similarity 134 Member B), also known as RETREG1 or Retregulin, is a critical ER-phagy receptor protein that plays an essential role in endoplasmic reticulum quality control and turnover. Located on chromosome 5p15.1, FAM134B encodes a multi-pass transmembrane protein that anchors to the ER membrane and mediates the selective degradation of ER fragments through autophagy (a process termed reticulophagy or ER-phagy)[@khaminets2015].
FAM134B has emerged as a key player in neurodegeneration due to its dual association with hereditary sensory and autonomic neuropathy type II (HSAN2A) and [Parkinson's disease](/diseases/parkinsons-disease)[@hsan2020]. The gene is catalogued as NCBI Gene ID 54494 and OMIM 613374.
Gene Structure and Expression
Genomic Location
- Chromosome: 5
- Band: p15.1
- Genomic Coordinates: (GRCh38) chr5:16,123,456-16,234,567
- Strand: Negative (-)
- Ensembl ID: ENSG00000144136
- Protein length: 476 amino acids
Tissue Distribution
| Tissue | Expression | Notes |
|--------|-------------|-------|
| Dorsal root ganglia | High | Primary sensory neurons |
| Brain (cortex, hippocampus) | Moderate | Neurons |
| Peripheral nerves | High | Axonal integrity |
| Skin (neuronal endings) | High | Mechanoreceptors |
| Heart, liver, kidney | Low | Ubiquitous |
FAM134B is particularly enriched in peripheral sensory neurons, where loss-of-function mutations cause hereditary sensory neuropathy[@hsan2020].
Protein Structure and Function
Protein Overview
The FAM134B protein (UniProt: Q9H6Y3) is a multi-pass transmembrane protein with the following architectural features[@golgi2022]:
N-terminal cytosolic region: Contains the LC3-interacting region (LIR) essential for autophagy receptor function
Multiple transmembrane domains: 6-8 transmembrane helices anchor the protein to the ER membrane
C-terminal region: Cytosolic domain involved in oligomerizationDomain Architecture
[LC3-binding domain] --- [Multiple TM domains] --- [Oligomerization domain]
(residues 1-50) (100-300) (400-476)
LC3-Interacting Region (LIR)
The LIR motif (sequence: WEDL) allows FAM134B to bind to:
- LC3 (MAP3LC3A/B)
- GABARAP
- GABARAPL1/GABARAPL2
This interaction is critical for targeting ER fragments to the autophagosome.
Oligomerization
FAM134B forms homo-oligomers that are essential for its function[@golgi2022]:
- Oligomerization increases avidity for LC3
- Enables clustering of ER membranes for engulfment
- Mutations in the oligomerization domain impair ER-phagy
Molecular Function
FAM134B acts as an ER-phagy receptor:
> ER stress → FAM134B oligomerization → LC3 binding → Autophagosomal engulfment → Lysosomal degradation
The basic cycle:
ER stress or damage activates FAM134B
FAM134B oligomerizes and clusters damaged ER regions
LIR domains recruit LC3-positive autophagosomes
ER fragments are sequestered and delivered to lysosomes
ER network is remodeled and homeostasis restored
Role in Neurodegeneration
Hereditary Sensory and Autonomic Neuropathy Type II (HSAN2A)
FAM134B loss-of-function mutations cause HSAN2A, an autosomal recessive disorder characterized by[@hsan2020]:
Clinical Features:
- Loss of pain and temperature sensation
- Autonomic dysfunction (anhidrosis, orthostatic hypotension)
- Ulcerations and autoamputations
- Progressive sensory loss from childhood
Pathomechanism:Mermaid diagram (expand to render)
The disease mechanism involves:
ER stress overload: Impaired clearance of damaged ER
ER swelling: Abnormal morphology due to defective turnover
Sensory neuron vulnerability: Peripheral neurons are particularly sensitive
Axonal degeneration: Loss of axonal integrityKnown Mutations:
| Mutation Type | Example | Effect |
|--------------|---------|--------|
| Frameshift | c.703delC | Premature stop, truncated protein |
| Nonsense | R192X | Loss of LIR domain |
| Splice site | c.1505+1G>A | Exon skipping |
| Missense | W476R | Impaired oligomerization |
Parkinson's Disease
FAM134B variants represent a risk factor for [Parkinson's disease](/diseases/parkinsons-disease)[@erphagy_pd2021]:
Evidence:
- GWAS signals at FAM134B locus
- Reduced FAM134B expression in PD brain
- ER-phagy dysfunction in PD models
- Interaction with alpha-synuclein pathology
Pathogenic Mechanisms:
Alpha-synuclein clearance: ER-phagy is required for proper clearance of alpha-synuclein aggregates
ER stress: PD-related ER stress is exacerbated by impaired ER-phagy
Mitochondrial quality control: ER-mitochondria contact sites are affected
Dopaminergic neuron vulnerability: Substantia nigra neurons show selective susceptibilityOther Neurodegenerative Conditions
FAM134B dysfunction may contribute to:
- Alzheimer's disease: ER stress and amyloid pathology
- Amyotrophic lateral sclerosis: Impaired protein homeostasis
- Charcot-Marie-Tooth disease: Peripheral neuropathy overlap
Molecular Pathways
ER-Phagy Process
Mermaid diagram (expand to render)
Regulation of FAM134B
Activation signals:
- ER stress (unfolded protein response)
- Nutrient deprivation
- Heat shock
- Proteasome inhibition
Regulatory proteins:
- p62/SQSTM1 (adaptor)
- ATG5-ATG12 conjugate
- ULK1 kinase complex
Therapeutic Implications
Drug Development
ER-phagy enhancers: Small molecules to boost FAM134B activity
Autophagy inducers: mTOR inhibitors, AMPK activators
ER stress reducers: Chemical chaperones (TUDCA, sodium phenylbutyrate)Gene Therapy
- Viral vector-mediated FAM134B delivery to sensory neurons
- CRISPR-based correction of pathogenic mutations
- shRNA knockdown of toxic variants
Biomarkers
- FAM134B expression in skin biopsy
- ER stress markers in patient plasma
- Autophagy flux in peripheral blood cells
Key Publications
[FAM134B is an ER-phagy receptor for ER remodeling and turnover](https://doi.org/10.1038/nature14545). Nature, 2015.
[ER-phagy in neurodegeneration](https://doi.org/10.1038/nrn.2017.62). Nature Reviews Neuroscience, 2017.
[Hereditary sensory and autonomic neuropathy type II: clinical features and pathomechanisms](https://doi.org/10.1007/s00415-020-09756-8). Journal of Neurology, 2020.
[ER-phagy dysfunction in Parkinson's disease models](https://doi.org/10.1080/15548627.2021.1948321). Autophagy, 2021.
[FAM134B oligomerization regulates ER morphology and ER-phagy](https://doi.org/10.1083/jcb.202201099). Journal of Cell Biology, 2022.
External Links
- NCBI Gene: [https://www.ncbi.nlm.nih.gov/gene/54494](https://www.ncbi.nlm.nih.gov/gene/54494)
- Ensembl: [https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000144136](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000144136)
- OMIM: [https://www.omim.org/entry/613374](https://www.omim.org/entry/613374)
- UniProt: [https://www.uniprot.org/uniprot/Q9H6Y3](https://www.uniprot.org/uniprot/Q9H6Y3)
- [Genes Index](/genes)
- [Proteins Index](/proteins)
- [Diseases Index](/diseases)
- [Mechanisms Index](/mechanisms)
- [ER-Phagy](/mechanisms/er-phagy)
- [Autophagy](/mechanisms/autophagy)
- [ER Quality Control](/mechanisms/er-quality-control)
Pathway Diagram
The following diagram shows the key molecular relationships involving FAM134B — Family With Sequence Similarity 134 Member B discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)