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ITGA6
integrin subunit alpha 6
The ITGA6 gene provides instructions for the alpha-6 subunit of integrin proteins, which are essential for cell adhesion and communication with the extracellular matrix, playing a critical role in tissue structure and signalling. The ITGA6 gene is responsible for producing a key component of integrin proteins.
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, or integrin subunit alpha 6, encodes a crucial component of integrin proteins. These proteins are transmembrane receptors that mediate cell-cell and cell-matrix adhesion, meaning they help cells attach to one another and to the surrounding structural network of proteins and other molecules [PMID:17953285]. Integrins also play a role in signal transduction, influencing various cellular processes such as growth and gene expression. Variants in the ITGA6 gene can affect these vital cellular functions, leading to certain health conditions.
What the gene does
The ITGA6 gene provides instructions for synthesising the alpha-6 subunit, which combines with other subunits to form two main integrin proteins: alpha-6-beta-4 integrin and alpha-6-beta-1 integrin [PMID:24606132]. Alpha-6-beta-4 integrin is predominantly found in epithelial cells, which form the lining of body surfaces and cavities. This integrin is a key component of hemidesmosomes, specialised structures that anchor the epidermis (outer layer of skin) to the underlying layers, thereby contributing significantly to skin strength and stability. Alpha-6-beta-1 integrin is involved in the formation of organs and tissues during development before birth, though its role is not as extensively studied as alpha-6-beta-4 integrin. Both integrins facilitate the transmission of chemical signals that regulate cell growth and influence the activity of specific genes.
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Chromosome location
The ITGA6 gene is located on chromosome 2 at position 2q31.1. This position indicates that the gene resides on the long arm (q) of chromosome 2, within region 3, band 1, and sub-band 1. The ITGA6 gene spans a specific segment of the human genome and contains the genetic blueprint for a protein of 1130 amino acids.
Protein structure
The ITGA6 protein is composed of 1130 amino acids and features several distinct domains crucial for its function. It contains seven FG-GAP repeats, 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, there is a specific region for interaction with HPS5 (amino acids 1077-1083) and a GFFKR motif (amino acids 1079-1083), which are involved in protein interactions and potentially in intracellular signalling.
Key variants
Genetic variations within the ITGA6 gene can alter the production or function of the alpha-6 integrin subunit. These changes may disrupt the normal cell adhesion processes and signalling pathways that integrins are involved in. Variants can range from single nucleotide changes to larger deletions or duplications, each potentially impacting the stability or activity of the resulting integrin proteins. The clinical implications of ITGA6 variants can vary depending on their specific nature and location within the gene.
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
Variants in the ITGA6 gene are associated with inherited conditions primarily affecting the skin and other epithelial tissues. One such condition is epidermolysis bullosa with pyloric atresia, where individuals experience severe skin blistering and a life-threatening obstruction of the digestive tract [PMID:24606132]. Researchers also suggest that alpha-6-beta-1 and alpha-6-beta-4 integrins may have significant roles in the progression of various carcinomas, which are cancers originating in epithelial cells, including those of the breast, lung, liver, prostate, and skin [PMID:24606132].
No disease links recorded for this gene in our reference set.
UK clinical status
The ITGA6 gene is recognised within the NHS Genomic Medicine Service due to its association with several conditions. It is listed on the 'Epidermolysis bullosa' and 'Epidermolysis bullosa and congenital skin fragility' panels, both currently rated green, indicating that there is strong evidence for the gene's association with these conditions. Furthermore, ITGA6 is also part of the 'Foetal anomalies' panel, also rated green, highlighting its relevance in prenatal diagnostics.
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 creating the alpha-6 subunit of integrin proteins. These integrins are crucial for cell adhesion, helping cells attach to each other and to the surrounding tissue matrix, and for transmitting signals within cells.
How does ITGA6 relate to skin health?
The alpha-6-beta-4 integrin, formed with the ITGA6 subunit, is a vital part of hemidesmosomes in epithelial cells. These structures anchor the outer skin layer to underlying tissues, which is essential for maintaining skin strength and preventing blistering.
What conditions are associated with ITGA6 gene variants?
Variants in the ITGA6 gene are linked to epidermolysis bullosa with pyloric atresia, a condition characterised by skin blistering and a digestive tract obstruction. Research also suggests a role for ITGA6-related integrins in the progression of various epithelial cancers.
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