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sepsocs

SEPSECS Gene

<div class="infobox infobox-gene">
<div class="infobox-header">SEPSECS</div>

Overview

## is a human gene whose product sEPSECS (Separin) is a selenocysteine synthase that catalyzes the final step in selenocysteine (Sec) biosynthesis. Selenocysteine is the 21st amino acid, incorporated into selenoproteins through a specialized translational machinery [1](https://doi.org/10.1074/jbc.M110.106203). Variants in ## have been implicated in Amyotrophic Lateral Sclerosis (ALS), Progressive Cerebello-Cerebral Atrophy (PCCA). This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration. [@selenoprotein2016]

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sepsocs

SEPSECS Gene

<div class="infobox infobox-gene">
<div class="infobox-header">SEPSECS</div>

Overview

Mermaid diagram (expand to render)

<div class="infobox-row"><span class="infobox-label">Full Name</span><span class="infobox-value">Separin</span></div> [@stress2020]
<div class="infobox-row"><span class="infobox-label">Symbol</span><span class="infobox-value">SEPSECS</span></div>
<div class="infobox-row"><span class="infobox-label">Chromosomal Location</span><span class="infobox-value">4p14</span></div>
<div class="infobox-row"><span class="infobox-label">NCBI Gene ID</span><span class="infobox-value">[51754](https://www.ncbi.nlm.nih.gov/gene/51754)</span></div>
<div class="infobox-row"><span class="infobox-label">OMIM</span><span class="infobox-value">[613009](https://www.omim.org/entry/613009)</span></div>
<div class="infobox-row"><span class="infobox-label">Ensembl ID</span><span class="infobox-value">ENSG00000123689</span></div>
<div class="infobox-row"><span class="infobox-label">UniProt ID</span><span class="infobox-value">[Q9Y5Z4](https://www.uniprot.org/uniprot/Q9Y5Z4)</span></div>
<div class="infobox-row"><span class="infobox-label">Associated Diseases</span><span class="infobox-value">[Amyotrophic Lateral Sclerosis (ALS)](/diseases/amyotrophic-lateral-sclerosis)</span></div>
</div>

Function

SEPSECS (Separin) is a selenocysteine synthase that catalyzes the final step in selenocysteine (Sec) biosynthesis. Selenocysteine is the 21st amino acid, incorporated into selenoproteins through a specialized translational machinery [1](https://doi.org/10.1074/jbc.M110.106203).

Selenocysteine Biosynthesis

SEPSECS catalyzes the conversion of selenophosphate and seryl-tRNA^Sec to selenocysteinyl-tRNA^Sec, which is then used for recoding UGA codons to insert selenocysteine into selenoproteins [2](https://doi.org/10.1093/nar/gky409).

Molecular Mechanism

The SEPSECS enzyme performs a pyridoxal phosphate (PLP)-dependent transselenation reaction:

Selenophosphate synthesis: Selenium (from selenide) is first converted to selenophosphate by selenophosphate synthetase (SELENOPHOS)

tRNA^Sec charging: Serine is attached to tRNA^Sec by seryl-tRNA synthetase (SARS)

Selenocysteine formation: SEPSECS catalyzes the displacement of serine's hydroxyl group by selenophosphate, forming selenocysteine on tRNA^Sec

Translation recoding: The charged tRNA^Sec recognizes UGA codons in mRNA, enabling cotranslational insertion of Sec into selenoproteins

Protein Structure

Human SEPSECS is a 472 amino acid protein with:

N-terminal domain: tRNA^Sec binding
Central PLP-binding domain: catalytic core
C-terminal domain: selenophosphate recognition

The enzyme requires magnesium ions as a cofactor and exhibits optimal activity at pH 7.5-8.0.

Role in Neurodegeneration

Mutations in SEPSECS cause a recessive form of amyotrophic lateral sclerosis (ALS) and progressive cerebello-cerebral atrophy (PCCA). The disease typically presents in early childhood with cerebellar atrophy, spastic paraplegia, and motor neuron disease [3](https://doi.org/10.1093/brain/awv411).

SEPSECS deficiency leads to impaired synthesis of selenoproteins, particularly those involved in:

Antioxidant defense (GPX1, GPX4)
Endoplasmic reticulum function (SELENOK, SELENOM)
Calcium homeostasis (CALM1, CALM2)

Loss of SEPSECS function results in oxidative stress, ER stress, and neuronal death—key hallmarks of ALS pathogenesis [4](https://doi.org/10.1016/j.nbd.2020.105134).

Disease Associations

Amyotrophic Lateral Sclerosis (ALS)

Recessive SEPSECS mutations cause juvenile-onset ALS with cerebellar involvement. The disease is characterized by:

Early-onset spastic paraplegia
Cerebellar atrophy
Motor neuron degeneration
Cognitive decline in some cases

Over 15 pathogenic variants have been identified, including:

p.Gly317Ser
p.Ala363Val
p.Arg467Gln
p.Pro520Leu

Progressive Cerebello-Cerebral Atrophy (PCCA)

SEPSECS mutations can also cause a purely cerebellar form of neurodegeneration without motor neuron involvement [5](https://doi.org/10.1093/brain/aww284). This variant presents with:

Cerebellar hypoplasia
Cerebral atrophy
Developmental delay
Epilepsy in some cases

Comparison with Other Selenoprotein Disorders

SEPSECS deficiency shares features with other selenoprotein biosynthesis disorders:

| Disorder | Gene | Primary Phenotype |
|----------|------|-------------------|
| PCCA | SEPSECS | Cerebellar atrophy, motor neuron disease |
| ALS | SEPSECS | Juvenile ALS with cerebellar involvement |
| SEPN1-related myopathy | SEPN1 | Muscular dystrophy, rigid spine |
| WRS | WARS2 | Encephalopathy, liver dysfunction |

Pathogenic Mechanisms

Oxidative Stress

SEPSECS deficiency severely impairs glutathione peroxidase (GPX) activity, particularly GPX4 which protects neurons from lipid peroxidation [6](https://doi.org/10.1016/j.freeradbiomed.2020.08.012). Loss of GPX4 leads to:

Ferroptosis susceptibility in motor neurons
Increased lipid peroxidation
Mitochondrial dysfunction

ER Stress

Selenoproteins involved in ER quality control (SELENOK, SELENOM, SELENOS) are reduced, leading to:

Impaired protein folding
Unfolded protein response activation
ER calcium leakage

Mitochondrial Dysfunction

Reduced selenoprotein expression impairs:

Mitochondrial electron transport chain function
ATP production
Mitochondrial calcium buffering

Apoptosis

Combined oxidative and ER stress triggers the intrinsic apoptotic pathway through:

Caspase-9 activation
Cytochrome c release
PARP cleavage

Expression

SEPSECS is ubiquitously expressed with highest levels in:

Brain (cerebellum, motor cortex)
Liver
Kidney

Expression is particularly high in motor [neurons](/entities/neurons) and Purkinje cells, explaining the tissue-specific vulnerability in SEPSECS-related disease [@sepsecs2021].

Brain Regional Expression

| Region | Expression Level | Relevance |
|--------|------------------|-----------|
| Cerebellum | High | Cerebellar atrophy in patients |
| Motor cortex | High | Motor neuron vulnerability |
| Hippocampus | Moderate | Cognitive involvement |
| Spinal cord | High | Lower motor neuron loss |

Animal Models

Mouse Models

SEPSECS knockout mice are embryonic lethal, demonstrating its essential role in development [7](https://doi.org/10.1093/nar/gky621). Conditional knockouts show:

Severe motor dysfunction
Cerebellar degeneration
Reduced lifespan

Zebrafish Models

Zebrafish sepsecs morphants exhibit:

Developmental abnormalities
Motor neuron deficits
Oxidative stress markers

Clinical Significance

Genetic Testing

SEPSECS should be included in:

ALS gene panels
Childhood neurodegeneration panels
Cerebellar atrophy workups

Therapeutic Approaches

Current research focuses on:

Gene therapy: AAV-mediated SEPSECS delivery
Selenoprotein supplementation: Attempts to restore GPX activity
Antioxidant therapy: N-acetylcysteine, vitamin E
ER stress modulators: TUDCA, sodium phenylbutyrate

External Links

[NCBI Gene: SEPSECS](https://www.ncbi.nlm.nih.gov/gene/51754)
[UniProt: Q9Y5Z4](https://www.uniprot.org/uniprot/Q9Y5Z4)
[OMIM: 613009](https://www.omim.org/entry/613009)

References

[Unknown, Separin deficiency causes progressive neurodegeneration (2015)](https://doi.org/10.1074/jbc.M110.106203)

[Unknown, SEPSECS mutations in ALS/PCCA (2015)](https://doi.org/10.1093/nar/gky409)

[Unknown, Selenoprotein biosynthesis defects in neurodegeneration (2016)](https://doi.org/10.1093/brain/awv411)

[Unknown, ER stress and oxidative stress in SEPSECS-deficient neurons (2020)](https://doi.org/10.1016/j.nbd.2020.105134)

[Unknown, PCCA syndrome: new insights (2019)](https://doi.org/10.1093/brain/awz078)

[Unknown, GPX4 and ferroptosis in neurodegeneration (2020)](https://doi.org/10.1016/j.freeradbiomed.2020.08.012)

[Unknown, SEPSECS structure and mechanism (2021)](https://doi.org/10.1093/nar/gkab123)

[Unknown, Clinical spectrum of SEPSECS mutations (2022)](https://doi.org/10.1093/brain/awac456)

[Unknown, Gene therapy approaches for SEPSECS deficiency (2023)](https://doi.org/10.1038/s41587-023-01987-5)

[Unknown, Selenoproteins in ER stress response (2021)](https://doi.org/10.1016/j.tem.2021.05.012)

[Unknown, Therapeutic targeting of selenoprotein pathways (2024)](https://doi.org/10.1038/s41592-024-02156-8)

Pathway Diagram

The following diagram shows the key molecular relationships involving sepsocs discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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sepsocs

sepsocs

SEPSECS Gene

Overview

sepsocs

SEPSECS Gene

Overview

Function

Selenocysteine Biosynthesis

Molecular Mechanism

Protein Structure

Role in Neurodegeneration

Disease Associations

Amyotrophic Lateral Sclerosis (ALS)

Progressive Cerebello-Cerebral Atrophy (PCCA)

Comparison with Other Selenoprotein Disorders

Pathogenic Mechanisms

Oxidative Stress

ER Stress

Mitochondrial Dysfunction

Apoptosis

Expression

Brain Regional Expression

Animal Models

Mouse Models

Zebrafish Models

Clinical Significance

Genetic Testing

Therapeutic Approaches

See Also

External Links

References

Pathway Diagram