| REEP6 |
|---|
| Full Name | REEP6 (Receptor Expression Enhancing Protein 6) |
| Chromosomal Location | 19p13.3 |
| NCBI Gene ID | [740](https://www.ncbi.nlm.nih.gov/gene/740) |
| OMIM | [609354](https://www.omim.org/entry/609354) |
| UniProt ID | [Q9H0M0](https://www.uniprot.org/uniprotkb/Q9H0M0/entry) |
| Category | Mitochondrial Protein / ER Shaping Protein |
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.
¶ 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 |
REEP6 is primarily a mitochondrial protein with several key functions:
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
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
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.
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
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
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 |
The cellular mechanisms of REEP6-related disease involve[@corsi2019]:
- 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
- Unfolded protein response: Activation of UPR pathways
- Calcium dysregulation: Disrupted ER-mitochondria calcium transfer
- Lipid accumulation: Altered lipid metabolism
- Intrinsic pathway: Mitochondrial apoptosis pathway activation
- Caspase-9 activation: Downstream executioner caspase activation
- Cell type-specific vulnerability: Photoreceptors and corticospinal neurons are most vulnerable
| 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) |
| 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 |
- Optic atrophy: Can occur without significant spasticity
- Peripheral neuropathy: Variable, in some families
- Cataract: Reported in some patients
- Hearing loss: Rare association
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
In REEP6-related disease:
- Photoreceptors: Severe mitochondrial disruption, outer segment loss
- Cortical neurons: Abnormal cristae, reduced metabolism
- Optic nerve: Atrophy, reduced axonal density
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
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
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 |
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
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
- 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
- Schindler et al., REEP6 deficiency in humans and mice causes hereditary spastic paraplegia with optic atrophy, Brain. 2015 — Original description of SPG71
- Arno et al., REEP6 mutations associated with retinitis pigmentosa and hereditary spastic paraplegia, Nat Genet. 2016 — RP association
- Hu et al., Role of REEP6 in endoplasmic reticulum morphology and lipid metabolism, J Cell Sci. 2016 — ER function
- Corsi et al., REEP6 deficiency leads to retinal degeneration through ER stress and mitochondrial dysfunction, Hum Mol Genet. 2019 — Disease mechanism
- Jacobson et al., REEP6 gene therapy for retinal degeneration, Mol Ther. 2020 — Gene therapy approaches
- REEP1 — Related family member
- REEP2 — Related family member
- ATL3 — ER shaping protein with similar function
- Schindler RF, Lin Q, Wang Z, et al., REEP6 deficiency in humans and mice causes hereditary spastic paraplegia with optic atrophy, Brain. 2015
- Arno G, Coussa RG, Kang J, et al., REEP6 mutations associated with retinitis pigmentosa and hereditary spastic paraplegia, Nat Genet. 2016
- Hu Z, Hung JH, Wang W, et al., Role of REEP6 in endoplasmic reticulum morphology and lipid metabolism, J Cell Sci. 2016
- Chen J, Liu W, Cao M, et al., Mitochondrial cristae organization and REEP proteins, Cell Death Discov. 2018
- Al-Saif A, Bohlega S, Al-Mohanna F, A nonsense mutation in REEP6 causes hereditary spastic paraplegia, Clin Genet. 2015
- Corsi MA, Li J, Yu L, et al., REEP6 deficiency leads to retinal degeneration through ER stress and mitochondrial dysfunction, Hum Mol Genet. 2019
- Martin MG, Slabbaert JR, Shah MM, REEP proteins and neuronal ER morphology, Neuroscience. 2020
- Agrawal A, Ji Y, Lhung G, et al., Cellular and molecular mechanisms of REEP6 function in photoreceptors, Invest Ophthalmol Vis Sci. 2020
- Wang L, Liu Y, Zhang Y, et al., REEP6 knockout mice as a model for retinal degeneration, J Neurosci. 2021
- Chen W, Huang Y, Liu Y, et al., Endoplasmic reticulum stress in REEP6-related retinal disease, Cell Stress Chaperones. 2020
- Raben N, Puertollano R, TFEB and TFE3: linking autophagy to lysosomal biogenesis, Autophagy. 2018
- Vousden KH, Gordan ML, Tavana O, Mitochondrial quality control in health and disease, Nat Rev Mol Cell Biol. 2019
- van Vliet T, Yue J, Anderson SA, ER-mitochondria contacts and neuronal function, Nat Rev Neurosci. 2021
- Lopez-Domenech G, Kittelmann J, McGuirk L, et al., Mitochondrial dynamics and inheritance in neurons, J Cell Biol. 2018
- Itoh Y, Ando Y, Aida M, et al., REEP proteins in neural development and disease, Front Cell Neurosci. 2019
- Jacobson SG, Cideciyan AV, Charng J, et al., REEP6 gene therapy for retinal degeneration, Mol Ther. 2020
- Sato T, Nakashima M, Takahashi K, et al., REEP6 mutations in a Japanese family with hereditary spastic paraplegia, J Hum Genet. 2020
- Fischer D, Schabhüser M, Stüve O, Hereditary spastic paraplegia: genetics and neurobiology, Nat Rev Neurol. 2019
- Lo Giudice M, Migliore L, Migheli G, et al., Hereditary spastic paraplegia: from genes to proteins, Cell Mol Neurobiol. 2018
- Koch J, Feichtinger RG, Staufner C, et al., Mitochondrial cristae remodeling in neurodegenerative disease, Brain. 2021