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ITGB4
integrin subunit beta 4
The ITGB4 gene encodes the beta-4 subunit of an integrin protein, crucial for cell-cell and cell-matrix adhesion, particularly in maintaining skin integrity. The ITGB4 gene provides the blueprint for the β4 subunit of the α6β4 integrin protein.
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 contains instructions for producing integrin beta-4, a protein subunit. This subunit forms part of integrins, which are proteins crucial for cellular attachment to each other and to the extracellular matrix-the supportive network surrounding cells. Integrins also help relay signals that influence cell growth and gene activity.
The α6β4 integrin, which incorporates the beta-4 subunit, is predominantly located in epithelial cells, which form the linings of body surfaces. It is particularly important for the strength and stability of the skin, where it is a component of hemidesmosomes. These microscopic structures are responsible for anchoring the outer layer of skin (epidermis) to deeper connective tissues.
What the gene does
The principal role of the ITGB4 gene is to code for the β4 subunit, which is an essential part of the α6β4 integrin protein. This integrin is vital for hemidesmosomes, which are specialised adhesion complexes. Hemidesmosomes mechanically connect the basal keratinocytes of the epidermis to the underlying basement membrane. The α6β4 integrin facilitates adhesion between cells and the extracellular matrix, which is critical for maintaining tissue structure and integrity, especially in the skin.
Beyond its structural function, integrins like α6β4 also act as signal transducers, relaying information between the cell's interior and its external environment. This signalling pathway can influence various cellular processes, including cell proliferation, differentiation, and survival. Impaired function of the ITGB4 gene due to pathogenic changes can lead to weakened cell adhesion and related clinical symptoms.
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Chromosome location
The ITGB4 gene is situated on chromosome 17 at position 17q25.1. This specifies its exact address on the long arm (q) of chromosome 17, within region 25, band 1. The gene consists of multiple exons, which are the coding segments that are translated into protein.
Protein structure
The ITGB4 protein is substantial, comprising 1822 amino acids. Its structure includes several distinct domains critical for its function. Near the N-terminus, the protein features a PSI domain (amino acids 29-73) and a VWFA domain (amino acids 131-329). A region within the VWFA domain, from amino acids 194-199, is involved in NRG1- and IGF1-binding. Further along, there are 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). A region between amino acids 732-749 is noted to be palmitoylated on several cysteines. A Calx-beta domain is present from amino acids 979-1084. There are also several disordered regions, including one at amino acids 1113-1140, another at 1400-1444, and a third at 1495-1525. Additionally, the protein contains four fibronectin type-III domains: Fibronectin type-III 1 (amino acids 1129-1218), Fibronectin type-III 2 (amino acids 1222-1321), Fibronectin type-III 3 (amino acids 1530-1625), and Fibronectin type-III 4 (amino acids 1643-1739). A segment spanning amino acids 1451-1752 is implicated in interaction with ARHGEF40.
Key variants
Variants within the ITGB4 gene can alter the production or function of the integrin beta-4 subunit. These genetic changes can range from small point mutations to larger deletions or insertions within the gene sequence. Pathogenic variants can lead to a compromised or non-functional protein, affecting its ability to facilitate cell adhesion and signalling, particularly in the skin and digestive tract.
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 | ★★☆☆ | ITGB4-related disorder |
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 | ★★☆☆ | Epidermolysis bullosa, junctional 5A, intermediate |
c.754C>T | p.Arg252Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Junctional epidermolysis bullosa with pyloric atresia |
c.794dup | p.Ala266fs | Pathogenic | ★★☆☆ | ITGB4-related disorder |
c.884_885del | p.Thr295fs | Pathogenic/Likely pathogenic | ★★☆☆ | Junctional epidermolysis bullosa with pyloric atresia |
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 characterised by fragile skin. These include epidermolysis bullosa, a group of genetic disorders that cause the skin to be very fragile and blister easily. Specifically, variants in ITGB4 are a known cause of epidermolysis bullosa with pyloric atresia, a severe form that also involves an obstruction in the digestive system. At least 60 identified mutations in the ITGB4 gene are associated with epidermolysis bullosa with pyloric atresia (EB-PA). These variants impair the structural integrity provided by the α6β4 integrin, leading to the clinical manifestations.
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 in the UK's NHS Genomic Medicine Service, with several green light entries in PanelApp. This indicates that there is sufficient evidence for its association with specific conditions to be routinely considered in diagnostic testing. It is included on panels for 'Epidermolysis bullosa', '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 ITGB4 gene?
The ITGB4 gene provides instructions for making the beta-4 subunit of an integrin protein. This protein is essential for cell adhesion, helping cells to attach to each other and to the surrounding extracellular matrix, particularly in epithelial tissues like the skin.
Which conditions are associated with ITGB4 gene variants?
Pathogenic variants in the ITGB4 gene are primarily linked to epidermolysis bullosa, particularly epidermolysis bullosa with pyloric atresia. These conditions are characterised by extreme skin fragility and blistering.
How does the ITGB4 protein function in the skin?
In the skin, the ITGB4 protein is a crucial component of hemidesmosomes. These structures act as anchors, connecting the outer layer of the skin (epidermis) to the underlying layers, thereby providing stability and strength to the skin tissue.
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