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DDRGK1
DDRGK domain containing 1
The DDRGK1 gene provides instructions for making a protein involved in the addition of a small protein called UFM1 to other proteins, a process crucial for various cellular functions. The DDRGK1 gene encodes a protein that plays a key role in ufmylation, a type of post-translational modification where the UFM1 protein is attached to target proteins.
DDRGK1 is located on the short (p) arm of chromosome 20, at band 20p13. Arm ratio per GRCh38 - banding schematic.
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Overview
The DDRGK1 gene, formally known as DDRGK domain containing 1, is crucial for cellular function, particularly in a process known as ufmylation. This process involves the attachment of a small protein modifier, UFM1, to other proteins, which can alter their activity, stability, or localisation. The DDRGK1 protein acts as a scaffold or an activator for the enzymes involved in ufmylation.
Research into DDRGK1 highlights its importance in maintaining proper cellular processes, and disruptions to its function may have implications for human health. Understanding DDRGK1's role is therefore vital for comprehending the broader mechanisms of protein regulation within the cell.
What the gene does
The DDRGK1 protein's primary function is to facilitate ufmylation, a post-translational modification system. It interacts directly with components of the ufmylation pathway, acting as an essential cofactor for the UFL1 ligase, which is responsible for attaching UFM1 to target proteins. DDRGK1 appears to stabilise UFL1 and enhance its enzymatic activity, thereby promoting efficient ufmylation.
This modification is involved in diverse cellular processes, including protein quality control in the endoplasmic reticulum, stress responses, and potentially cell development and differentiation. The protein's interaction with TRIP4 and UFL1, mediated by specific regions, underscores its scaffolding role in assembling the ufmylation machinery. The UFM1-interacting motif (UFIM) within DDRGK1 is also critical for its ability to bind and recruit UFM1 for subsequent conjugation to substrates.
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Chromosome location
The DDRGK1 gene is located on chromosome 20 at position 20p13. This specific location refers to the p-arm (short arm) of chromosome 20, within region 1, band 3. Genes situated in this chromosomal area contribute to various biological functions, and their disruption can sometimes lead to genetic conditions.
Protein structure
The DDRGK1 protein consists of 314 amino acids and features several distinct functional regions and domains. The N-terminal region, specifically amino acids 1-114, mediates interaction with CDK5RAP3. Other regions, spanning amino acids 31-75 and 100-186, are classified as disordered, indicating flexibility in their structure. From amino acid 118-216, a region critical for interaction with TRIP4 is found. A key functional element, the UFM1-interacting motif (UFIM), is located between amino acids 195 and 209, enabling binding to UFM1. Further towards the C-terminus, a region spanning amino acids 216-314 mediates interaction with UFL1. Lastly, a PCI domain is present from amino acids 229-273.
Key variants
Genetic variations within the DDRGK1 gene can influence its function. These variants may include single nucleotide changes, insertions, or deletions that alter the protein sequence or affect gene expression. While the impact of many DDRGK1 variants is still under investigation, some may affect the protein’s ability to participate in ufmylation, potentially leading to altered cellular processes. The clinical significance of any identified variant requires careful interpretation by healthcare professionals.
Sample of pathogenic variants
2 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.391C>T | p.Arg131Ter | Pathogenic | ★★☆☆ | Spondyloepimetaphyseal dysplasia, Shohat type |
c.408+1G>A | - | Pathogenic | - | Spondyloepimetaphyseal dysplasia, Shohat type |
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
While no specific conditions are directly and widely attributed to DDRGK1 variants across all populations, research indicates its involvement in pathways that affect aspects of human development. For instance, in a clinical diagnostic context, the gene is considered relevant for disorders such as skeletal dysplasia and foetal anomalies. This suggests that certain genetic changes in DDRGK1 could contribute to, or be associated with, the presentation of these developmental conditions.
No disease links recorded for this gene in our reference set.
UK clinical status
In the UK, the DDRGK1 gene is included on specific diagnostic panels within the NHS Genomic Medicine Service. It is categorised as a 'green' gene on the Foetal anomalies (R21) and Skeletal dysplasia (R104) panels. A 'green' status indicates that there is strong evidence for a gene's association with the respective condition, making it clinically actionable for diagnostic testing within these specific contexts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is ufmylation?
Ufmylation is a post-translational modification process where the small protein modifier UFM1 is covalently attached to other proteins. This can alter the target protein's function, stability, or cellular location, impacting various cellular activities.
Why is the DDRGK1 gene important for cellular function?
The DDRGK1 gene is important because it encodes a protein that facilitates ufmylation. This process is crucial for protein quality control, cellular stress responses, and maintaining overall cellular health and homeostasis.
What does it mean for DDRGK1 to be 'green' on an NHS PanelApp panel?
A 'green' status on an NHS PanelApp panel means there is strong evidence supporting a pathogenic role for variants in the DDRGK1 gene in the context of the specific condition, such as Foetal anomalies or Skeletal dysplasia.