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SEPSECS
Sep (O-phosphoserine) tRNA:Sec (selenocysteine) tRNA synthase
The SEPSECS gene provides instructions for an enzyme essential in the synthesis of selenocysteine, a critical amino acid for various cellular functions, including antioxidant defence and brain development. SEPSECS encodes an enzyme called SepSecS, which plays a vital role in forming a specialised transfer RNA molecule necessary for producing selenocysteine.
SEPSECS is located on the short (p) arm of chromosome 4, at band 4p15.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The SEPSECS gene, full name Sep (O-phosphoserine) tRNA:Sec (selenocysteine) tRNA synthase, is responsible for producing the SepSecS enzyme. This enzyme is crucial for the synthesis of selenocysteine, an amino acid containing selenium, which is an essential nutrient obtained from the diet. Selenocysteine is a building block for a group of proteins known as selenoproteins, which are vital for numerous bodily functions.
What the gene does
The SepSecS enzyme, encoded by the SEPSECS gene, facilitates the creation of a specific transfer RNA (tRNA) molecule. This tRNA is indispensable for the incorporation of selenocysteine into proteins during their synthesis. Selenoproteins, which contain selenocysteine, carry out diverse roles within the body. These roles include participating in antioxidant reactions, which help protect cells from damage caused by reactive oxygen species. Selenoproteins also contribute to the activation of thyroid hormones, immune system function, and the production of sperm cells. Furthermore, they are considered critical for normal brain development and the proper functioning of nerve cells, known as neurons.
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Chromosome location
The SEPSECS gene is located on the short arm of chromosome 4, specifically at position 4p15.2. This genomic location positions SEPSECS within a region that has been studied for its involvement in various genetic conditions.
Protein structure
The SEPSECS protein consists of 501 amino acids and features several distinct functional regions. The Tetramerization region spans amino acids 1-44, which is likely involved in the assembly of multiple protein units. A Phosphate loop (P-loop) is found between amino acids 96-106, a motif often associated with binding phosphate-containing molecules like ATP. Additionally, an SLA/LP epitope is present from amino acids 474-493, which may be relevant for immune recognition.
Key variants
Variations within the SEPSECS gene can alter the function of the SepSecS enzyme, potentially affecting the synthesis of selenocysteine and subsequently the function of selenoproteins. The impact of these variants can range from mild to severe, depending on the specific change and its effect on protein activity.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1023_1026del | p.Glu343fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pontocerebellar hypoplasia type 2D |
c.1148dup | p.His383fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pontocerebellar hypoplasia type 2D |
c.1169_1173del | p.Gln390fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pontocerebellar hypoplasia type 2D |
c.1178C>A | p.Ser393Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Pontocerebellar hypoplasia type 2D |
c.163_164del | p.Leu55fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pontocerebellar hypoplasia type 2D |
c.466C>T | p.Arg156Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Pontocerebellar hypoplasia type 2D |
c.482del | p.Lys161fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pontocerebellar hypoplasia type 2D |
c.505C>T | p.Arg169Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Pontocerebellar hypoplasia type 2D |
c.811C>T | p.Arg271Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Pontocerebellar hypoplasia type 2D |
c.919del | p.Ser307fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pontocerebellar hypoplasia type 2D |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Mutations in the SEPSECS gene have been identified in individuals with certain neurological conditions. Notably, at least three mutations in SEPSECS have been linked to pontocerebellar hypoplasia, a disorder affecting brain development. This condition, specifically designated as pontocerebellar hypoplasia type 2 (PCH2), is characterised by developmental delays, difficulties with movement, and intellectual disability.
No disease links recorded for this gene in our reference set.
UK clinical status
The SEPSECS gene is included in several NHS Genomic Medicine Service national test panels. These include panels for conditions such as Ataxia and cerebellar anomalies - childhood onset, Cerebellar hypoplasia, Early onset or syndromic epilepsy, Foetal anomalies (R21), Hereditary ataxia, Hereditary ataxia, adult onset, and Intellectual disability. Its inclusion indicates clinical relevance for these conditions within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is selenocysteine?
Selenocysteine is a unique amino acid that contains selenium, an essential trace element. It is often referred to as the 21st amino acid and is crucial for the function of selenoproteins, which are involved in various bodily processes.
What are selenoproteins?
Selenoproteins are a family of proteins that incorporate selenocysteine into their structure. They play critical roles in antioxidant defence, thyroid hormone metabolism, immune responses, and nervous system function.
What is pontocerebellar hypoplasia?
Pontocerebellar hypoplasia is a group of rare neurological disorders characterised by underdeveloped structures in the brain, particularly the pons and cerebellum. It can lead to developmental delays, movement difficulties, and intellectual disability.
References
- Agamy O, Ben Zeev B, Lev D. Mutations disrupting selenocysteine formation cause progressive cerebello-cerebral atrophy. American journal of human genetics. 2010. PMID: 20920667
- Palioura S, Sherrer RL, Steitz TA. The human SepSecS-tRNASec complex reveals the mechanism of selenocysteine formation. Science (New York, N.Y.). 2009. PMID: 19608919
- Brown KM, Arthur JR. Selenium, selenoproteins and human health: a review. Public health nutrition. 2001. PMID: 11683552