## 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. 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]
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.
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.
The SEPSECS enzyme performs a pyridoxal phosphate (PLP)-dependent transselenation reaction:
Human SEPSECS is a 472 amino acid protein with:
The enzyme requires magnesium ions as a cofactor and exhibits optimal activity at pH 7.5-8.0.
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.
SEPSECS deficiency leads to impaired synthesis of selenoproteins, particularly those involved in:
Loss of SEPSECS function results in oxidative stress, ER stress, and neuronal death—key hallmarks of ALS pathogenesis 4.
Recessive SEPSECS mutations cause juvenile-onset ALS with cerebellar involvement. The disease is characterized by:
Over 15 pathogenic variants have been identified, including:
SEPSECS mutations can also cause a purely cerebellar form of neurodegeneration without motor neuron involvement 5. This variant presents with:
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 |
SEPSECS deficiency severely impairs glutathione peroxidase (GPX) activity, particularly GPX4 which protects neurons from lipid peroxidation 6. Loss of GPX4 leads to:
Selenoproteins involved in ER quality control (SELENOK, SELENOM, SELENOS) are reduced, leading to:
Reduced selenoprotein expression impairs:
Combined oxidative and ER stress triggers the intrinsic apoptotic pathway through:
SEPSECS is ubiquitously expressed with highest levels in:
Expression is particularly high in motor neurons and Purkinje cells, explaining the tissue-specific vulnerability in SEPSECS-related disease [@sepsecs2021].
| 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 |
SEPSECS knockout mice are embryonic lethal, demonstrating its essential role in development 7. Conditional knockouts show:
Zebrafish sepsecs morphants exhibit:
SEPSECS should be included in:
Current research focuses on: