ITGB4 Gene

The ITGB4 gene (ITGB4 stands for "Integrin Subunit Beta 4") is a protein coding gene that is loaclized on chromosome 17q25.1. The ITGB4 gene encodes integrin alpha-6/beta-4, which is a receptor protein for laminin. Several alternatively spliced transcript variants encoding different isoforms have been found for ITGB4. The "integrin alpha-6/beta-4" encoded by this gene plays a crucial structural role in hemidesmosomes of epithelial cells and is required for the regulation of the polarity and motility of keratinocytes (see also ITGA6 gene).

Integrins are heterodimers consisting of alpha and beta subunits. They are non-covalently linked transmembrane glycoprotein receptors. Different combinations of alpha and beta polypeptides form complexes that differ in their ligand binding specificity.

Integrins mediate cell-matrix or cell-cell adhesion and relay signals that regulate gene expression and cell growth. Other proteins play important roles in these interactions:

• Cadherins
• CAMs(cell adhesion molecules, e.g. ICAM-1 )
• Selectins.

The extracellular, portion (protein domain) of these transmembrane proteins has binding sites with the"RGD" recognition feature (Arg-Gly-Asp) (RGD sequence) such as fibronectin (in fibroblasts), or the "non-RGD" recognition feature such as intercellular adhesion molecules (ICAMs), collagens and laminins (in epithelial cells).

Chemically, an integrin consists of two subunits (alpha and beta subunits) that are linked together. For the alpha and beta subunits there are again different subtypes (e.g. beta 1, beta 2 and others).

The ITGB4 gene encodes the integrin beta 4 subunit, a receptor for laminins. This subunit tends to associate with the alpha 6 subunit and probably plays a central role in the biology of invasive carcinoma.

Diseases associated with ITGB4 include:

• Epidermolysis Bullosa Junctionalis with Pyloric Atresia (OMIM:226730). Mutations in ITGA6 and ITGB4, usually result in junctional epidermolysis bullosa (JEB) with pyloric atresia. Versch. However, reports suggest that integrin-associated JEB can also occur without pyloric atresia, but with other dysplasias of epithelial tissue (e.g., genitourinary tract) (Zhou X et al. 2021).
• Epidermolysis bullosa junctionalis, localized (traditional name: Non-Herlitz type). (OMIM:226650)
• Colon carcinoma: Integrin β4 (ITGB4) expression plays a role in carcinomas, so in colon carcinoma. It was shown that mRNA expressions of ITGB4 were significantly upregulated in colon cancer. High ITGB4 expression is associated with higher disease age, proximal tumor location, and high microsatellite instability (MSH) status. This is associated with unfavorable overall survival (Li M et al. 2019).

1. Dang N et al. (2008) 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 Derm Venereol 88:438-448.
2. Huang W et al. 82021) A Pan-Cancer Analysis of the Oncogenic Role of Integrin Beta4 (ITGB4) in Human Tumors. Int J Gen Med 14:9629-9645.
3. Li M et al (2019) ITGB4 is a novel prognostic factor in colon cancer. J Cancer 10: 5223-5233.
4. Stoevesandt J et al (2012) Lethal junctional epidermolysis bullosa with pyloric atresia due to compound heterozygosity for two novel mutations in the integrin β4 gene. Clin Padiatr 224:8-11.
5. Zhou X et al. (2021) Identification of novel compound heterozygous ITGB4 mutations in a Chinese woman with junctional epidermolysis bullosa without pylori atresia but profound urinary symptoms: A case report and review of the literature. J Dermatol 48:1780-1785