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ITGA6
integrin subunit alpha 6
The ITGA6 gene provides instructions for a protein subunit integral to integrins, which are cell surface receptors vital for cell-to-cell and cell-to-matrix adhesion, influencing skin integrity and development. ITGA6 encodes the alpha 6 subunit of integrin proteins, specifically alpha 6 beta 4 and alpha 6 beta 1 integrins.
ITGA6 is located on the long (q) arm of chromosome 2, at band 2q31.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The ITGA6 gene provides the genetic blueprint for the alpha 6 subunit, a component of two important proteins: alpha 6 beta 4 integrin and alpha 6 beta 1 integrin. Integrins are a class of proteins that facilitate the attachment of cells to each other and to the extracellular matrix, the network of proteins and other molecules surrounding cells. They are also involved in transmitting signals that regulate cell growth and gene activity.
What the gene does
Integrins play a fundamental role in cell-matrix adhesion, acting as crucial links between a cell's internal cytoskeleton and its external environment. The alpha 6 subunit, encoded by ITGA6, is a key part of both alpha 6 beta 4 and alpha 6 beta 1 integrins. Alpha 6 beta 4 integrin is predominantly found in epithelial cells, which line the body's surfaces and cavities. Within these cells, it is a vital component of hemidesmosomes, microscopic structures that anchor the epidermis (outer skin layer) to underlying layers, thereby contributing significantly to skin strength and stability. The other integrin, alpha 6 beta 1, is involved in the formation of organs and tissues during foetal development, though its functions are less extensively studied compared to alpha 6 beta 4 integrin.
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Chromosome location
The ITGA6 gene is located on chromosome 2 at band 2q31.1. This specific position on the long arm of chromosome 2 indicates its address within the human genome.
Protein structure
The ITGA6 protein, consisting of 1130 amino acids, exhibits a complex domain architecture. It contains multiple FG-GAP (Repeat) domains, specifically FG-GAP 1 (amino acids 30-95), FG-GAP 2 (amino acids 101-166), FG-GAP 3 (amino acids 176-229), FG-GAP 4 (amino acids 283-339), FG-GAP 5 (amino acids 340-402), FG-GAP 6 (amino acids 403-458), and FG-GAP 7 (amino acids 459-518). Additionally, an Interaction with HPS5 (Region) is found between amino acids 1077-1083, which overlaps with the GFFKR motif (Motif) located at amino acids 1079-1083.
Key variants
Genetic variations within the ITGA6 gene can affect its function, potentially leading to altered protein structure or reduced production of the alpha 6 subunit. These changes may impact the integrity of cell adhesion and signalling pathways where integrins are involved. The spectrum of variants can range from single nucleotide changes to larger deletions or insertions.
Sample of pathogenic variants
4 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 |
|---|---|---|---|---|
g.(?_173292517)_(173292718_?)del | - | Pathogenic | ★☆☆☆ | not provided |
g.(?_173330247)_(173330411_?)del | - | Pathogenic | ★☆☆☆ | not provided |
g.(?_173332189)_(173332308_?)del | - | Pathogenic | ★☆☆☆ | not provided |
c.88G>T | p.Glu30Ter | Pathogenic | ★☆☆☆ | not provided |
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 ITGA6 gene are associated with epidermolysis bullosa with pyloric atresia (EB-PA). Individuals with EB-PA typically experience skin blistering alongside a life-threatening obstruction in the digestive tract known as pyloric atresia. ITGA6 gene mutations are responsible for a proportion of EB-PA cases. Research also suggests that both alpha 6 beta 1 and alpha 6 beta 4 integrins may play critical roles in the progression of various carcinomas, including those affecting the breast, lung, liver, prostate, and skin.
No disease links recorded for this gene in our reference set.
UK clinical status
The ITGA6 gene is recognised within the UK's NHS Genomic Medicine Service. It is listed as 'green' on PanelApp for its association with Epidermolysis Bullosa, indicating strong evidence for this gene's role in the condition. It is also green-listed for Epidermolysis Bullosa and congenital skin fragility (R164) and Foetal anomalies (R21).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the ITGA6 gene?
The ITGA6 gene provides instructions for making the alpha 6 subunit of integrin proteins, which are crucial for cell adhesion, helping cells attach to each other and to their surrounding environment.
Which health condition is most commonly associated with ITGA6 gene variants?
Variants in the ITGA6 gene are most commonly associated with epidermolysis bullosa with pyloric atresia (EB-PA), a condition characterised by skin blistering and a digestive tract obstruction.
Are ITGA6 gene variants linked to cancer?
Research suggests that both alpha 6 beta 1 and alpha 6 beta 4 integrins, which incorporate the ITGA6 gene product, may play important roles in the development and progression of various carcinomas.
References
- Lipscomb EA, Mercurio AM. Mobilization and activation of a signaling competent alpha6beta4integrin underlies its contribution to carcinoma progression. Cancer metastasis reviews. 2005. PMID: 16258729
- Chung J, Mercurio AM. Contributions of the alpha6 integrins to breast carcinoma survival and progression. Molecules and cells. 2004. PMID: 15179031
- Chung J, Yoon S, Datta K. Hypoxia-induced vascular endothelial growth factor transcription and protection from apoptosis are dependent on alpha6beta1 integrin in breast carcinoma cells. Cancer research. 2004. PMID: 15256436
- Allegra M, Gagnoux-Palacios L, Gache Y. Rapid decay of alpha6 integrin caused by a mis-sense mutation in the propeller domain results in severe junctional epidermolysis bullosa with pyloric atresia. The Journal of investigative dermatology. 2003. PMID: 14675179
- Ashton GH, Sorelli P, Mellerio JE. Alpha 6 beta 4 integrin abnormalities in junctional epidermolysis bullosa with pyloric atresia. The British journal of dermatology. 2001. PMID: 11251584
- Nejjari M, Hafdi Z, Dumortier J. alpha6beta1 integrin expression in hepatocarcinoma cells: regulation and role in cell adhesion and migration. International journal of cancer. 1999. PMID: 10508489
- Gache Y, Romero-Graillet C, Spadafora A. A novel homozygous mutation affecting integrin alpha6 in a case of junctional epidermolysis bullosa with pyloric atresia detected in utero by ultrasound examination. The Journal of investigative dermatology. 1998. PMID: 9804362
- Pulkkinen L, Kimonis VE, Xu Y. Homozygous alpha6 integrin mutation in junctional epidermolysis bullosa with congenital duodenal atresia. Human molecular genetics. 1997. PMID: 9158140
- Ruzzi L, Gagnoux-Palacios L, Pinola M. A homozygous mutation in the integrin alpha6 gene in junctional epidermolysis bullosa with pyloric atresia. The Journal of clinical investigation. 1997. PMID: 9185503