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EPG5
ectopic P-granules 5 autophagy tethering factor
The EPG5 gene provides instructions for a protein essential in cellular waste recycling (autophagy) and the immune system's response to infections. EPG5 encodes a protein that plays a key role in autophagy, a process where cells break down and recycle old or unneeded components.
EPG5 is located on the long (q) arm of chromosome 18, at band 18q12.3-q21.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The EPG5 gene, fully known as ectopic P-granules 5 autophagy tethering factor, is a critical component for several fundamental cellular processes. It produces a protein that is primarily involved in autophagy, a vital pathway for maintaining cellular health by clearing out damaged or superfluous cellular material. Beyond its role in cellular recycling, the EPG5 protein also participates in the body's immune defence mechanisms.
Pathogenic variants within the EPG5 gene can disrupt these essential functions, leading to complex health conditions that affect multiple organ systems. Understanding EPG5's role provides insight into the molecular basis of such inherited disorders.
What the gene does
The EPG5 gene directs the production of a protein that is integral to the cellular process of autophagy. Autophagy involves the recycling of worn-out or unnecessary cellular components and the degradation of proteins that are no longer required. This process is particularly important for efficient material usage when cells face high energy demands. During autophagy, cellular waste is enclosed within specialised compartments called autophagosomes, which then transport these materials to lysosomes for breakdown.
The EPG5 protein is crucial for facilitating the interaction between autophagosomes and lysosomes, enabling the efficient transfer of materials for degradation. In addition to its role in cellular housekeeping, the EPG5 protein supports the cell's capacity to detect and respond to foreign invaders such as bacteria and viruses. It helps transport molecules derived from these invaders within cells, allowing them to interact with immune system proteins and initiate protective immune responses.
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Chromosome location
The EPG5 gene is situated on chromosome 18, specifically within the long (q) arm, at the band designated 18q12.3-q21.1. This precise location helps geneticists identify and study the gene's position within the human genome. The EPG5 gene codes for a protein that is 2579 amino acids in length.
Protein structure
The EPG5 protein consists of 2579 amino acids. Its structure includes several notable regions. There are three identified Disordered (Region) segments: one near the N-terminus spanning amino acids 1-46, another from amino acids 92-132, and a third located between amino acids 535-564. Additionally, a Coiled coil (Coiled coil) domain is present from amino acids 1607-1633. These structural elements contribute to the protein's function and interactions within the cell.
Key variants
Variants in the EPG5 gene can lead to alterations in the structure or function of the EPG5 protein. These genetic changes can range from small alterations in the DNA sequence to larger deletions or duplications. The impact of a variant depends on its specific nature and location within the gene, potentially affecting protein production, stability, or its ability to perform its crucial roles in autophagy and immune signalling. Many pathogenic variants result in a shortened, non-functional protein.
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.102del | p.Ser35fs | Pathogenic | ★★☆☆ | Vici syndrome |
c.1576C>T | p.Arg526Ter | Pathogenic | ★★☆☆ | Vici syndrome |
c.2449del | p.Ser817fs | Pathogenic/Likely pathogenic | ★★☆☆ | Vici syndrome |
c.3200del | p.Leu1067fs | Pathogenic/Likely pathogenic | ★★☆☆ | Vici syndrome |
c.6541G>T | p.Glu2181Ter | Pathogenic | ★★☆☆ | Vici syndrome |
c.6724del | p.Met2242fs | Pathogenic | ★★☆☆ | Vici syndrome |
c.1187dup | p.Tyr396Ter | Pathogenic | ★☆☆☆ | Vici syndrome |
c.3132_3133dup | p.Leu1045fs | Pathogenic | ★☆☆☆ | Vici syndrome |
c.6004C>T | p.Gln2002Ter | Pathogenic | ★☆☆☆ | Vici syndrome |
c.7021C>T | p.Gln2341Ter | Pathogenic | ★☆☆☆ | Vici syndrome |
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
Variants in the EPG5 gene are primarily associated with Vici syndrome. This is a severe, inherited condition that affects multiple body systems, including the brain, immune system, heart, skin, and eyes. The disruption of EPG5 protein function in Vici syndrome can impair both cellular waste recycling and the immune system's ability to fight infections, leading to characteristic symptoms of the condition.
No disease links recorded for this gene in our reference set.
UK clinical status
The EPG5 gene is included on several panels within the UK's NHS Genomic Medicine Service (GMS) PanelApp. It has a 'green' rating, indicating strong evidence for its association with conditions on panels such as Clefting, Congenital myopathy (R81), Early onset or syndromic epilepsy, Foetal anomalies (R21), Intellectual disability, and Vici Syndrome and other autophagy disorders. It is also listed on panels for COVID-19 research, DDG2P, Dilated Cardiomyopathy and conduction defects, Likely inborn error of metabolism (R98), Paediatric or syndromic cardiomyopathy (R135), Primary immunodeficiency or monogenic inflammatory bowel disease (R15), and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the EPG5 gene?
The EPG5 gene provides instructions for making a protein that is crucial for autophagy, a cellular process that recycles old or unneeded cell parts. It also helps the immune system recognise and respond to foreign invaders like bacteria and viruses.
What condition is most commonly associated with EPG5 gene variants?
Variants in the EPG5 gene are most commonly associated with Vici syndrome. This is a severe condition that affects multiple body systems, including the brain, immune system, heart, skin, and eyes.
How does EPG5 affect the immune system?
The EPG5 protein assists cells in detecting infections by foreign invaders. It transports molecules from these invaders within cells so they can interact with immune system proteins, which then trigger responses to fight the infection.
References
- Piano Mortari E, Folgiero V, Marcellini V. The Vici syndrome protein EPG5 regulates intracellular nucleic acid trafficking linking autophagy to innate and adaptive immunity. Autophagy. 2018. PMID: 29130391
- Hori I, Otomo T, Nakashima M. Defects in autophagosome-lysosome fusion underlie Vici syndrome, a neurodevelopmental disorder with multisystem involvement. Scientific reports. 2017. PMID: 28615637
- Baron O, Boudi A, Dias C. Stall in Canonical Autophagy-Lysosome Pathways Prompts Nucleophagy-Based Nuclear Breakdown in Neurodegeneration. Current biology : CB. 2017. PMID: 29174892
- Wang Z, Miao G, Xue X. The Vici Syndrome Protein EPG5 Is a Rab7 Effector that Determines the Fusion Specificity of Autophagosomes with Late Endosomes/Lysosomes. Molecular cell. 2016. PMID: 27588602
- Cullup T, Kho AL, Dionisi-Vici C. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nature genetics. 2013. PMID: 23222957