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CUL7
cullin 7
The CUL7 gene provides instructions for producing the cullin-7 protein, a crucial component of the cell's ubiquitin-proteasome system, which is vital for protein breakdown and cellular regulation. The CUL7 gene plays a key role in maintaining cellular health by directing the synthesis of cullin-7.
CUL7 is located on the short (p) arm of chromosome 6, at band 6p21.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The CUL7 gene encodes the cullin-7 protein, which is an important part of the cellular machinery responsible for breaking down proteins. This process, known as the ubiquitin-proteasome system, acts as a quality control mechanism within cells by disposing of damaged, misfolded, or excess proteins. The proper functioning of the CUL7 gene and its protein is essential for regulating critical cellular activities, including cell division and growth.
What the gene does
The cullin-7 protein encoded by the CUL7 gene participates in the ubiquitin-proteasome system. Within this system, cullin-7 helps assemble an E3 ubiquitin ligase complex. This complex's primary role is to attach ubiquitin molecules to specific proteins, effectively tagging them for degradation. These ubiquitin-tagged proteins are then recognised and broken down by proteasomes, which are specialised cellular structures. This process is fundamental for clearing damaged and excess proteins, maintaining cellular homeostasis, and regulating protein levels involved in various cellular functions, including the body's response to growth hormones, although the precise mechanism is still under investigation.
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Chromosome location
The CUL7 gene is situated on chromosome 6, specifically at position 6p21.1. This genomic location indicates its position on the short arm of chromosome 6.
Protein structure
The cullin-7 protein is composed of 1698 amino acids. It features several distinct regions and domains crucial for its function. These include a Disordered region spanning amino acids 315-357, a CPH (Cullin-PH) Domain from amino acids 357-433, another Disordered region between amino acids 601-623, a DOC (DDB1-binding OB-fold-like Cullin-binding) Domain from amino acids 814-993, and a final Disordered region located between amino acids 1345-1370.
Key variants
Variants within the CUL7 gene can impact the production or function of the cullin-7 protein. These genetic changes may lead to the synthesis of an abnormally short, non-functional protein or result in a protein with altered amino acid composition. Such changes can disrupt the crucial role of cullin-7 in the ubiquitin-proteasome system, potentially affecting cellular protein degradation and regulation.
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.1144C>T | p.Arg382Ter | Pathogenic | ★★☆☆ | 3M syndrome 1 |
c.1392G>A | p.Trp464Ter | Pathogenic/Likely pathogenic | ★★☆☆ | CUL7-related disorder |
c.2213_2235del | p.Val738fs | Pathogenic/Likely pathogenic | ★★☆☆ | 3M syndrome 1 |
c.2660+1G>C | - | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.2988G>A | p.Trp996Ter | Pathogenic | ★★☆☆ | 3M syndrome 1 |
c.3129G>A | p.Trp1043Ter | Pathogenic | ★★☆☆ | 3M syndrome 1 |
c.3136del | p.Leu1046fs | Pathogenic | ★★☆☆ | 3M syndrome 1 |
c.3907C>T | p.Gln1303Ter | Pathogenic | ★★☆☆ | not provided |
c.3924_3931del | p.Leu1308_Ser1309insTer | Pathogenic/Likely pathogenic | ★★☆☆ | 3M syndrome 1 |
c.3991_3992del | p.Leu1331fs | Pathogenic | ★★☆☆ | 3-M 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
Pathogenic variants in the CUL7 gene are primarily associated with 3-M syndrome. This condition is an inherited disorder characterised by skeletal anomalies, including short stature and distinctive facial features. Research has identified numerous CUL7 gene variants in individuals affected by 3-M syndrome.
Inheritance pattern
Conditions caused by pathogenic CUL7 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The CUL7 gene is recognised within several NHS Genomic Medicine Service (GMS) approved clinical panels in the UK, indicating its importance in diagnostic testing. It is currently listed as 'green' in the DDG2P, Foetal anomalies (R21), IUGR and IGF abnormalities, Monogenic short stature (R453), and Skeletal dysplasia (R104) panels, signifying that there is strong evidence for its association with these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the CUL7 gene?
The CUL7 gene provides instructions for the cullin-7 protein, which is a vital part of the ubiquitin-proteasome system. This system is responsible for tagging unwanted or damaged proteins for degradation, helping to maintain cellular quality control and regulate cell processes.
Which genetic condition is associated with CUL7 gene variants?
Variants in the CUL7 gene are primarily associated with 3-M syndrome. This is an inherited disorder characterised by distinctive skeletal abnormalities, including short stature, and specific facial features.
How does the cullin-7 protein contribute to cellular health?
The cullin-7 protein helps to assemble an E3 ubiquitin ligase complex. This complex marks specific proteins with ubiquitin molecules, signalling them for breakdown by proteasomes. This process ensures the removal of damaged or excess proteins, which is crucial for proper cell function and growth regulation.
References
- Clayton PE, Hanson D, Magee L. Exploring the spectrum of 3-M syndrome, a primordial short stature disorder of disrupted ubiquitination. Clinical endocrinology. 2012. PMID: 22624670
- Hanson D, Murray PG, Coulson T. Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling. Journal of molecular endocrinology. 2012. PMID: 23018678
- Hanson D, Murray PG, Black GC. The genetics of 3-M syndrome: unravelling a potential new regulatory growth pathway. Hormone research in paediatrics. 2011. PMID: 22156540
- Maksimova N, Hara K, Miyashia A. Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia. Journal of medical genetics. 2007. PMID: 17675530
- Huber C, Dias-Santagata D, Glaser A. Identification of mutations in CUL7 in 3-M syndrome. Nature genetics. 2005. PMID: 16142236
- Adam MP, Bick S, Mirzaa GM. 3-M Syndrome. 1993. PMID: 20301654