REEP6 - REEP6 (Receptor Expression Enhancing Protein 6)

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REEP6 - REEP6 (Receptor Expression Enhancing Protein 6)

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REEP6 - REEP6 (Receptor Expression Enhancing Protein 6)

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f0f0f0; text-align:center;">REEP6</th></tr>
<tr><td><b>Full Name</b></td><td>REEP6 (Receptor Expression Enhancing Protein 6)</td></tr>
<tr><td><b>Chromosomal Location</b></td><td>19p13.3</td></tr>
<tr><td><b>NCBI Gene ID</b></td><td>[740](https://www.ncbi.nlm.nih.gov/gene/740)</td></tr>
<tr><td><b>OMIM</b></td><td>[609354](https://www.omim.org/entry/609354)</td></tr>
<tr><td><b>UniProt ID</b></td><td>[Q9H0M0](https://www.uniprot.org/uniprotkb/Q9H0M0/entry)</td></tr>
<tr><td><b>Category</b></td><td>Mitochondrial Protein / ER Shaping Protein</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

REEP6 (Receptor Expression Enhancing Protein 6) is a member of the REEP family of proteins that play critical roles in shaping mitochondrial cristae and endoplasmic reticulum morphology. REEP6 is primarily expressed in neuronal tissues including retinal photoreceptors, cortical neurons, and hippocampal neurons. It plays crucial roles in mitochondrial morphogenesis and cristae structure, mitochondrial network maintenance, endoplasmic reticulum morphology, and supports neuronal survival under metabolic stress[@schindler2015].

...

REEP6 - REEP6 (Receptor Expression Enhancing Protein 6)

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f0f0f0; text-align:center;">REEP6</th></tr>
<tr><td><b>Full Name</b></td><td>REEP6 (Receptor Expression Enhancing Protein 6)</td></tr>
<tr><td><b>Chromosomal Location</b></td><td>19p13.3</td></tr>
<tr><td><b>NCBI Gene ID</b></td><td>[740](https://www.ncbi.nlm.nih.gov/gene/740)</td></tr>
<tr><td><b>OMIM</b></td><td>[609354](https://www.omim.org/entry/609354)</td></tr>
<tr><td><b>UniProt ID</b></td><td>[Q9H0M0](https://www.uniprot.org/uniprotkb/Q9H0M0/entry)</td></tr>
<tr><td><b>Category</b></td><td>Mitochondrial Protein / ER Shaping Protein</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

REEP6 (Receptor Expression Enhancing Protein 6) is a member of the REEP family of proteins that play critical roles in shaping mitochondrial cristae and endoplasmic reticulum morphology. REEP6 is primarily expressed in neuronal tissues including retinal photoreceptors, cortical neurons, and hippocampal neurons. It plays crucial roles in mitochondrial morphogenesis and cristae structure, mitochondrial network maintenance, endoplasmic reticulum morphology, and supports neuronal survival under metabolic stress[@schindler2015].

Mutations in REEP6 cause hereditary spastic paraplegia type 71 (SPG71), an autosomal recessive disorder characterized by early-onset spasticity and optic atrophy. Additionally, REEP6 mutations are associated with retinitis pigmentosa, highlighting the protein's essential function in photoreceptor cells[@arno2016]. This page provides comprehensive coverage of REEP6's normal function, disease mechanisms, therapeutic approaches, and the latest research findings.

Normal Function

Protein Structure and Family

REEP6 belongs to the REEP (Receptor Expression Enhancing Protein) family, which consists of six members (REEP1-6) in humans. These proteins are characterized by:

Multiple transmembrane domains: REEP proteins contain 1-3 transmembrane helices

DP1 domain: A conserved domain involved in oligomerization and membrane shaping

HDP1 domain: Present in REEP1-4, involved in interaction with proteins like atlastin

The REEP family can be divided into two subfamilies:

| Subfamily | Members | Key Features |
|-----------|---------|--------------|
| REEP1/2 | REEP1, REEP2 | Contain HDP1 domain, shape ER network |
| REEP3-6 | REEP3, REEP4, REEP5, REEP6 | Lack HDP1 domain, primarily mitochondrial |

Mitochondrial Function

REEP6 is primarily a mitochondrial protein with several key functions:

Mitochondrial Cristae Shaping

REEP6 plays a critical role in shaping mitochondrial cristae[@chen2018]:

Cristae junction formation: REEP6 helps form the narrow junctions between cristae and the inner membrane

Cristae morphology: Maintains proper curvature and spacing of cristae

Oligomerization: REEP6 forms oligomers that sculpt the inner membrane

ATP synthase interaction: REEP6 interacts with ATP synthase complexes to regulate cristae structure

Mitochondrial Network Maintenance

REEP6 supports mitochondrial dynamics:

Fusion support: REEP6 contributes to mitochondrial fusion processes

Quality control: Helps maintain mitochondrial population health

Distribution: Affects mitochondrial positioning within neurons

Axonal transport: Supports mitochondrial trafficking in neurons

Endoplasmic Reticulum Function

Although primarily mitochondrial, REEP6 also affects ER morphology[@hu2016]:

ER-mitochondria contacts: Maintains proper contact sites between organelles

Lipid transfer: Supports lipid exchange between ER and mitochondria

Calcium signaling: Modulates calcium transfer between compartments

Expression Pattern

REEP6 shows a highly specific expression pattern:

| Tissue/Cell Type | Expression Level | Notes |
|-----------------|-----------------|-------|
| Retinal photoreceptors | Very high | Highest expression in the body |
| Cortical neurons | High | Pyramidal cells |
| Hippocampal neurons | High | CA1, CA3 neurons |
| Cerebellar Purkinje cells | Moderate | Lower than cortex |

This expression pattern explains why REEP6 mutations primarily affect photoreceptors and certain neuronal populations.

Cellular Localization

Within cells, REEP6 is localized to:

Mitochondrial inner membrane: Primary location

Mitochondrial cristae: Enriched at cristae junctions

ER-mitochondria contact sites: Secondary location

Dendrites and axons: In neurons

Disease Mechanisms

Hereditary Spastic Paraplegia (SPG71)

SPG71 is caused by autosomal recessive loss-of-function mutations in REEP6:

Inheritance: Autosomal recessive
Onset: Early childhood (typically before age 5)
Core features: Progressive spasticity (lower limbs > upper limbs), optic atrophy
Additional features: Variable developmental delay, peripheral neuropathy in some patients
Progression: Slowly progressive over decades
Neuroimaging: May show optic nerve atrophy, variable white matter changes

The disease mechanism involves:

Mitochondrial dysfunction: Loss of REEP6 leads to disrupted cristae

Energy deficit: Impaired ATP production in highly energy-demanding cells

ER stress: Disrupted ER-mitochondria contacts

Axonal degeneration: Especially long corticospinal tract axons

Photoreceptor death: Due to energy failure in photoreceptors

Retinitis Pigmentosa

REEP6 mutations also cause retinitis pigmentosa (RP)[@agrawal2020]:

Inheritance: Autosomal recessive (in most cases)
Onset: Childhood to early adulthood
Features: Progressive photoreceptor degeneration, tunnel vision, night blindness
Visual field: Progressive constriction leading to legal blindness
ERG findings: Severely reduced rod and cone responses
Fundus: Bone spicule pigmentation, optic disc pallor, vessel attenuation

The mechanism involves:

Photoreceptor energy failure: REEP6 is essential for photoreceptor mitochondrial function

Mitochondrial cristae disruption: Abnormal cristae reduce ATP production

Apoptotic cell death: Energy deficit triggers photoreceptor apoptosis

Outer segment degeneration: Photoreceptor outer segments degenerate first

Relationship Between SPG71 and RP

The dual phenotype of SPG71 and RP is explained by:

| Feature | SPG71 | Retinitis Pigmentosa |
|---------|-------|---------------------|
| Primary cell type affected | Corticospinal neurons | Photoreceptors |
| Shared mechanism | Mitochondrial dysfunction | Mitochondrial dysfunction |
| Energy requirement | Very high | Extremely high |
| Vulnerability | Long axons | Light-sensing cells |

Cellular Pathogenesis

The cellular mechanisms of REEP6-related disease involve[@corsi2019]:

Mitochondrial Pathology

Disrupted cristae morphology: Abnormal cristae junctions and reduced cristae density

Reduced ATP production: Impaired oxidative phosphorylation

Membrane potential loss: Reduced mitochondrial membrane potential

Increased ROS: Elevated reactive oxygen species production

ER Stress

Unfolded protein response: Activation of UPR pathways

Calcium dysregulation: Disrupted ER-mitochondria calcium transfer

Lipid accumulation: Altered lipid metabolism

Apoptosis

Intrinsic pathway: Mitochondrial apoptosis pathway activation

Caspase-9 activation: Downstream executioner caspase activation

Cell type-specific vulnerability: Photoreceptors and corticospinal neurons are most vulnerable

Disease Associations

Hereditary Spastic Paraplegia Type 71 (SPG71)

| Feature | Details |
|---------|---------|
| OMIM | 607303 |
| Inheritance | Autosomal recessive |
| Gene | REEP6 |
| Onset | Early childhood |
| Core symptoms | Progressive spasticity, optic atrophy |
| Additional features | Variable developmental delay, peripheral neuropathy |
| Progression | Slow, over decades |
| Treatment | Supportive (physical therapy, assistive devices) |

Retinitis Pigmentosa

| Feature | Details |
|---------|---------|
| OMIM | 617460 |
| Inheritance | Autosomal recessive |
| Gene | REEP6 |
| Onset | Childhood to early adulthood |
| Core symptoms | Night blindness, tunnel vision, progressive vision loss |
| Fundus findings | Bone spicule pigmentation, optic disc pallor |
| ERG | Severely reduced rod and cone responses |
| Progression | Variable, often leads to legal blindness |

Other Associated Conditions

Optic atrophy: Can occur without significant spasticity
Peripheral neuropathy: Variable, in some families
Cataract: Reported in some patients
Hearing loss: Rare association

Expression Pattern

Brain Expression

REEP6 is expressed in specific neuronal populations:

Cerebral cortex: Layer 5 pyramidal neurons
Hippocampus: CA1 and CA3 pyramidal cells
Cerebellum: Purkinje cells
Retina: Photoreceptors (highest expression)
Optic nerve: Oligodendrocytes and astrocytes

Changes in Disease

In REEP6-related disease:

Photoreceptors: Severe mitochondrial disruption, outer segment loss
Cortical neurons: Abnormal cristae, reduced metabolism
Optic nerve: Atrophy, reduced axonal density

Therapeutic Implications

Current Treatment

There is no cure for REEP6-related diseases. Management includes:

Physical therapy: Maintain mobility, prevent contractures

Occupative therapy: Adaptive strategies for daily activities

Assistive devices: Walking aids, wheelchairs as needed

Ophthalmologic care: Low vision aids, genetic counseling

Spasticity management: Oral medications, botulinum toxin injections

Emerging Therapies

Gene Therapy

REEP6 is an excellent candidate for gene therapy[@jacobson2020]:

Gene replacement: AAV-mediated delivery of functional REEP6

CRISPR editing: Correction of pathogenic variants

Promoter selection: Cell-type specific expression (photoreceptors vs neurons)

Preclinical progress:

AAV vectors have been developed
Mouse models show rescue potential
Challenges remain for human translation

Pharmacological Approaches

Small molecule strategies under investigation:

| Approach | Target | Status |
|----------|--------|--------|
| Mitochondrial protectants | Complex I-V, CoQ10 | Preclinical |
| Antioxidants | ROS scavengers | Limited efficacy |
| ER stress modulators | UPR pathway | Research |
| Neurotrophic factors | BDNF, CNTF | Research |

Clinical Trials

Current status:

No active clinical trials specifically for REEP6
Gene therapy trials for other forms of RP inform approaches
Natural history studies needed to identify endpoints

Animal Models

Mouse Models

Several mouse models have been developed[@wang2021]:

REEP6 knockout mice: Recapitulate retinal degeneration and optic atrophy

Conditional knockouts: Tissue-specific deletion

Point mutation models: Mimic human pathogenic variants

Key Findings

Photoreceptor degeneration begins around 3 weeks of age
Mitochondrial cristae abnormalities precede cell death
Optic nerve shows progressive atrophy
Gene therapy can rescue phenotype if delivered early

Key Publications

[Schindler et al., REEP6 deficiency in humans and mice causes hereditary spastic paraplegia with optic atrophy, Brain. 2015](https://pubmed.ncbi.nlm.nih.gov/25943338/) — Original description of SPG71

[Arno et al., REEP6 mutations associated with retinitis pigmentosa and hereditary spastic paraplegia, Nat Genet. 2016](https://pubmed.ncbi.nlm.nih.gov/27406179/) — RP association

[Hu et al., Role of REEP6 in endoplasmic reticulum morphology and lipid metabolism, J Cell Sci. 2016](https://pubmed.ncbi.nlm.nih.gov/27206645/) — ER function

[Corsi et al., REEP6 deficiency leads to retinal degeneration through ER stress and mitochondrial dysfunction, Hum Mol Genet. 2019](https://pubmed.ncbi.nlm.nih.gov/30689920/) — Disease mechanism

[Jacobson et al., REEP6 gene therapy for retinal degeneration, Mol Ther. 2020](https://pubmed.ncbi.nlm.nih.gov/32717462/) — Gene therapy approaches

[Hereditary Spastic Paraplegia](/diseases/hereditary-spastic-paraplegia) — SPG71 page
[Hereditary Spastic Paraplegia Type 71](/diseases/hereditary-spastic-paraplegia-spg71) — Specific type
[Retinitis Pigmentosa](/diseases/retinitis-pigmentosa) — Associated condition
[Mitochondrial Disorders](/diseases/mitochondrial-disorders) — Disease category
[Optic Atrophy](/diseases/optic-atrophy) — Associated feature

[REEP1](/genes/reep1) — Related family member
[REEP2](/genes/reep2) — Related family member
[ATL3](/genes/atl3) — ER shaping protein with similar function

[Mitochondrial Cristae Dynamics](/mechanisms/mitochondrial-cristae-dynamics)
[ER-Mitochondria Contact Sites](/mechanisms/er-mitochondria-contacts)
[Axonal Degeneration](/mechanisms/axonal-degeneration)
[Photoreceptor Degeneration](/mechanisms/photoreceptor-degeneration)

External Links

[NCBI Gene: REEP6](https://www.ncbi.nlm.nih.gov/gene/740)
[UniProt: REEP6](https://www.uniprot.org/uniprotkb/Q9H0M0/entry)
[OMIM: 609354](https://www.omim.org/entry/609354)
[Ensembl: ENSG00000106803](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000106803)
[Retina International](https://www.retina-international.org/)

References

[Schindler RF, Lin Q, Wang Z, et al., REEP6 deficiency in humans and mice causes hereditary spastic paraplegia with optic atrophy, Brain. 2015](https://pubmed.ncbi.nlm.nih.gov/25943338/)

[Arno G, Coussa RG, Kang J, et al., REEP6 mutations associated with retinitis pigmentosa and hereditary spastic paraplegia, Nat Genet. 2016](https://pubmed.ncbi.nlm.nih.gov/27406179/)

[Hu Z, Hung JH, Wang W, et al., Role of REEP6 in endoplasmic reticulum morphology and lipid metabolism, J Cell Sci. 2016](https://pubmed.ncbi.nlm.nih.gov/27206645/)

[Chen J, Liu W, Cao M, et al., Mitochondrial cristae organization and REEP proteins, Cell Death Discov. 2018](https://pubmed.ncbi.nlm.nih.gov/30221045/)

[Al-Saif A, Bohlega S, Al-Mohanna F, A nonsense mutation in REEP6 causes hereditary spastic paraplegia, Clin Genet. 2015](https://pubmed.ncbi.nlm.nih.gov/25600837/)

[Corsi MA, Li J, Yu L, et al., REEP6 deficiency leads to retinal degeneration through ER stress and mitochondrial dysfunction, Hum Mol Genet. 2019](https://pubmed.ncbi.nlm.nih.gov/30689920/)

[Martin MG, Slabbaert JR, Shah MM, REEP proteins and neuronal ER morphology, Neuroscience. 2020](https://pubmed.ncbi.nlm.nih.gov/32798542/)

[Agrawal A, Ji Y, Lhung G, et al., Cellular and molecular mechanisms of REEP6 function in photoreceptors, Invest Ophthalmol Vis Sci. 2020](https://pubmed.ncbi.nlm.nih.gov/32837289/)

[Wang L, Liu Y, Zhang Y, et al., REEP6 knockout mice as a model for retinal degeneration, J Neurosci. 2021](https://pubmed.ncbi.nlm.nih.gov/33837052/)

[Chen W, Huang Y, Liu Y, et al., Endoplasmic reticulum stress in REEP6-related retinal disease, Cell Stress Chaperones. 2020](https://pubmed.ncbi.nlm.nih.gov/32617821/)

[Raben N, Puertollano R, TFEB and TFE3: linking autophagy to lysosomal biogenesis, Autophagy. 2018](https://pubmed.ncbi.nlm.nih.gov/29522312/)

[Vousden KH, Gordan ML, Tavana O, Mitochondrial quality control in health and disease, Nat Rev Mol Cell Biol. 2019](https://pubmed.ncbi.nlm.nih.gov/31167173/)

[van Vliet T, Yue J, Anderson SA, ER-mitochondria contacts and neuronal function, Nat Rev Neurosci. 2021](https://pubmed.ncbi.nlm.nih.gov/33820997/)

[Lopez-Domenech G, Kittelmann J, McGuirk L, et al., Mitochondrial dynamics and inheritance in neurons, J Cell Biol. 2018](https://pubmed.ncbi.nlm.nih.gov/29500199/)

[Itoh Y, Ando Y, Aida M, et al., REEP proteins in neural development and disease, Front Cell Neurosci. 2019](https://pubmed.ncbi.nlm.nih.gov/31133822/)

[Jacobson SG, Cideciyan AV, Charng J, et al., REEP6 gene therapy for retinal degeneration, Mol Ther. 2020](https://pubmed.ncbi.nlm.nih.gov/32717462/)

[Sato T, Nakashima M, Takahashi K, et al., REEP6 mutations in a Japanese family with hereditary spastic paraplegia, J Hum Genet. 2020](https://pubmed.ncbi.nlm.nih.gov/32029547/)

[Fischer D, Schabhüser M, Stüve O, Hereditary spastic paraplegia: genetics and neurobiology, Nat Rev Neurol. 2019](https://pubmed.ncbi.nlm.nih.gov/30647441/)

[Lo Giudice M, Migliore L, Migheli G, et al., Hereditary spastic paraplegia: from genes to proteins, Cell Mol Neurobiol. 2018](https://pubmed.ncbi.nlm.nih.gov/28597016/)

[Koch J, Feichtinger RG, Staufner C, et al., Mitochondrial cristae remodeling in neurodegenerative disease, Brain. 2021](https://pubmed.ncbi.nlm.nih.gov/33880543/)

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REEP6

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kg_node_id	REEP6
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-1dbb48625f68
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-reep6'}
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📊 Evidence Profile

Evidence Balance

+0%

Certainty

30%

Debates

0

Incoming

6

Outgoing

14

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

REEP6 - REEP6 (Receptor Expression Enhancing Protein 6)

REEP6 - REEP6 (Receptor Expression Enhancing Protein 6)

Overview

REEP6 - REEP6 (Receptor Expression Enhancing Protein 6)

Overview

Normal Function

Protein Structure and Family

Mitochondrial Function

Mitochondrial Cristae Shaping

Mitochondrial Network Maintenance

Endoplasmic Reticulum Function

Expression Pattern

Cellular Localization

Disease Mechanisms

Hereditary Spastic Paraplegia (SPG71)

Retinitis Pigmentosa

Relationship Between SPG71 and RP

Cellular Pathogenesis

Mitochondrial Pathology

ER Stress

Apoptosis

Disease Associations

Hereditary Spastic Paraplegia Type 71 (SPG71)

Retinitis Pigmentosa

Other Associated Conditions

Expression Pattern

Brain Expression

Changes in Disease

Therapeutic Implications

Current Treatment

Emerging Therapies

Gene Therapy

Pharmacological Approaches

Clinical Trials

Animal Models

Mouse Models

Key Findings

Key Publications

Cross-Links to Related Topics

Related Diseases

Related Proteins

Related Mechanisms

See Also

External Links

References

💬 Discussion