sepsocs

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]

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]

<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:

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

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)

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

• 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

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

See Also

• Amyotrophic Lateral Sclerosis (ALS)
• Selenocysteine biosynthesis pathway
• GPX4 Protein - selenoenzyme affected
• [ER stress pathway](/mechanisms/er-stress-pathway)
• [Oxidative stress in neurodegeneration](/mechanisms/oxidative-stress-in-neurodegeneration)

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

Pathway Diagram

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