FAM134B — Family With Sequence Similarity 134 Member B

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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">A

...

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 oligomerization

Domain 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 integrity

Known 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 susceptibility

Other 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)

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