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ITGB4
integrin subunit beta 4
The ITGB4 gene provides instructions for the beta-4 subunit of integrin, a protein vital for cell adhesion, signalling, and maintaining the structural integrity of the skin. ITGB4 encodes a component of the cell adhesion protein alpha-6-beta-4 integrin, which is primarily found in epithelial cells.
ITGB4 is located on the long (q) arm of chromosome 17, at band 17q25.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The ITGB4 gene, or integrin subunit beta 4, contains the genetic blueprint for the beta-4 subunit of the alpha-6-beta-4 integrin protein. Integrins are a class of proteins that facilitate cell-to-cell adhesion and cell attachment to the extracellular matrix, a network of proteins and molecules surrounding cells. Beyond structural roles, integrins also transmit chemical signals that influence cellular processes like growth and gene activity.
The alpha-6-beta-4 integrin is predominantly located in epithelial cells, which form linings and coverings throughout the body. Its primary function involves strengthening and stabilising skin layers by forming part of hemidesmosomes. These microscopic structures are essential for anchoring the outer skin layer, the epidermis, to the layers beneath it.
What the gene does
The ITGB4 gene product, the beta-4 subunit, combines with an alpha-6 subunit to form alpha-6-beta-4 integrin. This integrin is a key component of hemidesmosomes, which are specialised adhesion complexes found in epithelial cells. Hemidesmosomes effectively connect the intracellular cytoskeleton to the extracellular matrix, providing mechanical stability to tissues, particularly the skin.
Within hemidesmosomes, alpha-6-beta-4 integrin functions as a transmembrane receptor, linking intermediate filaments inside the cell to components like laminin in the basement membrane outside the cell. This connection is critical for maintaining tissue integrity and preventing separation of cell layers. Integrins also participate in cell signalling pathways, influencing cell survival, proliferation, and differentiation by transducing signals from the extracellular environment into the cell. The interaction of the beta-4 subunit with other proteins and its structural role contribute to its importance in epithelial tissue homeostasis.
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Chromosome location
The ITGB4 gene is located on chromosome 17 at position q25.1. This means it resides on the long arm (q) of chromosome 17, within region 25, band 1. This genomic location is consistent across human populations.
Protein structure
The ITGB4 protein comprises 1822 amino acids and features several distinct domains and regions. Key structural elements include an N-terminal PSI domain (amino acids 29-73) and a VWFA domain (amino acids 131-329). A specific region involved in NRG1- and IGF1-binding is located at amino acids 194-199. The protein also contains four I-EGF domains: I-EGF 1 (amino acids 457-491), I-EGF 2 (amino acids 492-537), I-EGF 3 (amino acids 538-574), and I-EGF 4 (amino acids 575-615).
Further into the protein, it is palmitoylated on several cysteines within a region spanning amino acids 732-749. A Calx-beta domain is found between amino acids 979-1084. There are also fibronectin type-III domains, specifically Fibronectin type-III 1 (amino acids 1129-1218) and Fibronectin type-III 2 (amino acids 1222-1321). Additionally, several disordered regions are present (amino acids 1113-1140, 1400-1444, and 1495-1525). An extended region from amino acids 1451-1752 is known to interact with ARHGEF40.
Key variants
Variants in the ITGB4 gene can alter the structure and function of the beta-4 integrin subunit, potentially affecting cell adhesion and tissue integrity. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions within the gene sequence. The impact of a specific variant depends on its location within the gene and how it alters the resulting 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.1135C>T | p.Arg379Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Epidermolysis bullosa, junctional 5A, intermediate |
c.1614del | p.Glu537_Tyr538insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Junctional epidermolysis bullosa with pyloric atresia |
c.1860G>A | p.Ala620= | Pathogenic/Likely pathogenic | ★★☆☆ | Junctional epidermolysis bullosa with pyloric atresia |
c.2254+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Junctional epidermolysis bullosa with pyloric atresia |
c.3719G>A | p.Trp1240Ter | Pathogenic | ★★☆☆ | Epidermolysis bullosa, junctional 5A, intermediate |
c.614del | p.Asn205fs | Pathogenic/Likely pathogenic | ★★☆☆ | Junctional epidermolysis bullosa with pyloric atresia |
c.658del | p.Leu220fs | Pathogenic | ★★☆☆ | Junctional epidermolysis bullosa with pyloric atresia |
c.754C>T | p.Arg252Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Epidermolysis bullosa, junctional 5A, intermediate |
c.794dup | p.Ala266fs | Pathogenic | ★★☆☆ | Epidermolysis bullosa, junctional 5A, intermediate |
c.884_885del | p.Thr295fs | Pathogenic/Likely pathogenic | ★★☆☆ | Epidermolysis bullosa, junctional 5A, intermediate |
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 ITGB4 gene are primarily associated with inherited conditions affecting skin integrity. These include forms of epidermolysis bullosa, a group of genetic disorders characterised by fragile skin that blisters easily. Specifically, ITGB4 variants are a significant cause of epidermolysis bullosa with pyloric atresia, a severe form that also involves an obstruction of the digestive tract.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic ITGB4 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 ITGB4 gene is recognised within the NHS Genomic Medicine Service, indicating its clinical relevance in the UK. It is currently listed on several NHS Genomic Test Directories panels, including those for Epidermolysis bullosa, Epidermolysis bullosa and congenital skin fragility (R164), and Foetal anomalies (R21). Inclusion on these panels signifies that testing for ITGB4 variants may be available for diagnostic purposes in relevant clinical contexts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the ITGB4 gene?
The ITGB4 gene provides instructions for making the beta-4 subunit of the alpha-6-beta-4 integrin protein. This protein is crucial for cell adhesion, particularly in epithelial cells, where it helps anchor the outer layer of the skin to underlying tissues, maintaining structural stability.
What health conditions are associated with ITGB4 gene variants?
Variants in the ITGB4 gene are primarily associated with forms of epidermolysis bullosa, a group of genetic disorders that cause the skin to be fragile and blister easily. Specifically, it is a known cause of epidermolysis bullosa with pyloric atresia, which involves skin blistering and an obstruction in the digestive tract.
How does the ITGB4 protein contribute to skin structure?
The ITGB4 protein is a key component of hemidesmosomes, which are microscopic structures found in skin cells. These hemidesmosomes act like anchors, connecting the epidermis (outer skin layer) to the basement membrane and deeper layers, thus strengthening and stabilising the skin's structure.
References
- Dang N, Klingberg S, Rubin AI. Differential expression of pyloric atresia in junctional epidermolysis bullosa with ITGB4 mutations suggests that pyloric atresia is due to factors other than the mutations and not predictive of a poor outcome: three novel mutations and a review of the literature. Acta dermato-venereologica. 2008. PMID: 18779879
- Yoon SO, Shin S, Lipscomb EA. A novel mechanism for integrin-mediated ras activation in breast carcinoma cells: the alpha6beta4 integrin regulates ErbB2 translation and transactivates epidermal growth factor receptor/ErbB2 signaling. Cancer research. 2006. PMID: 16510594
- Guo W, Pylayeva Y, Pepe A. Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis. Cell. 2006. PMID: 16901783
- Lipscomb EA, Mercurio AM. Mobilization and activation of a signaling competent alpha6beta4integrin underlies its contribution to carcinoma progression. Cancer metastasis reviews. 2005. PMID: 16258729
- 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
- Nakano A, Pulkkinen L, Murrell D. Epidermolysis bullosa with congenital pyloric atresia: novel mutations in the beta 4 integrin gene (ITGB4) and genotype/phenotype correlations. Pediatric research. 2001. PMID: 11328943
- Pulkkinen L, Kim DU, Uitto J. Epidermolysis bullosa with pyloric atresia: novel mutations in the beta4 integrin gene (ITGB4). The American journal of pathology. 1998. PMID: 9422533
- Pulkkinen L, Rouan F, Bruckner-Tuderman L. Novel ITGB4 mutations in lethal and nonlethal variants of epidermolysis bullosa with pyloric atresia: missense versus nonsense. American journal of human genetics. 1998. PMID: 9792864