REEP6 - REEP6 (Receptor Expression Enhancing Protein 6)
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<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>
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<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
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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 atlastinThe 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 structureMitochondrial 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 neuronsEndoplasmic 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 compartmentsExpression 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 neuronsDisease 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 photoreceptorsRetinitis 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 firstRelationship 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 productionER Stress
Unfolded protein response: Activation of UPR pathways
Calcium dysregulation: Disrupted ER-mitochondria calcium transfer
Lipid accumulation: Altered lipid metabolismApoptosis
Intrinsic pathway: Mitochondrial apoptosis pathway activation
Caspase-9 activation: Downstream executioner caspase activation
Cell type-specific vulnerability: Photoreceptors and corticospinal neurons are most vulnerableDisease 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 injectionsEmerging 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 variantsKey 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)
See Also
- [Hereditary Spastic Paraplegia](/diseases/hereditary-spastic-paraplegia)
- [Mitochondrial Disorders](/diseases/mitochondrial-disorders)
- [Retinitis Pigmentosa](/diseases/retinitis-pigmentosa)
- [Neurodegeneration](/diseases/neurodegeneration)
- [White Matter Disorders](/diseases/white-matter-disorders)
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/)