HGNC Approved Gene Symbol: ITGB4
Cytogenetic location: 17q25.1 Genomic coordinates (GRCh38) : 17:75,721,459-75,757,818 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q25.1 | Epidermolysis bullosa, junctional 5A, intermediate | 619816 | Autosomal recessive | 3 |
| Epidermolysis bullosa, junctional 5B, with pyloric atresia | 226730 | Autosomal recessive | 3 |
Suzuki and Naitoh (1990) isolated a cDNA corresponding to integrin beta-4 (ITGB4). The integrin beta-4 protein contains a putative signal sequence as well as a transmembrane domain that divides the molecule into an extracellular domain at the N-terminal side and a cytoplasmic domain at the C-terminal side. The extracellular domain exhibits a 4-fold repeat of a cysteine-rich motif similar to those of other integrin beta subunits. The cytoplasmic domain is much larger than those of other beta subunits and has no significant homology with them. A protein homology search revealed that the integrin beta-4 cytoplasmic domain has 4 repeating units that are homologous to the type III repetition exhibited by fibronectin. Integrin beta-4 subunit mRNA was expressed primarily in epithelial cells.
Hogervorst et al. (1990) isolated an ITGB4 cDNA. They demonstrated that the ITGB4 extracellular domain shows 35% identify with other integrin beta subunits, but is the most different among this class of molecules. The transmembrane region is poorly conserved, whereas the cytoplasmic domain showed no substantial identity in any region to the cytoplasmic tails of other integrin beta sequences or to other protein sequences. Hogervorst et al. (1990) stated that the exceptionally long cytoplasmic domain suggests distinct interactions of the beta-4 subunit with cytoplasmic proteins.
Hogervorst et al. (1991) mapped the ITGB4 gene to 17q11-qter by analysis of human-rodent somatic cell hybrids.
Integrins are transmembrane glycoprotein receptors that mediate cell-matrix or cell-cell adhesion, and transduced signals that regulate gene expression and cell growth (Vidal et al., 1995). These heterodimeric molecules consist of noncovalently linked alpha and beta subunits. Different combinations of alpha and beta polypeptides form complexes that vary in their ligand-binding specificities. Both alpha and beta subunits display a cytoplasmic domain that interacts with the cytoskeleton (and possibly signaling molecules), a transmembrane region, and a large extracellular domain that interacts with the extracellular matrix. In the human epidermis, basal keratinocytes express integrins alpha-2 (192974)/beta-1 (135630), alpha-3 (605025)/beta-1, and alpha-6 (147556)/beta-4. The first 2 of these are located primarily at the lateral surface of these cells, suggesting a role in cell-cell interaction, whereas the third, alpha-6/beta-4, is restricted to the ventral surface opposed to the basal membrane zone, suggestive of its role in cell-matrix adhesion. Consistent with this possibility, alpha-6/beta-4 is found to be associated with the hemidesmosomes in stratified and transitional epithelia. Hemidesmosomes are dense cytoplasmic plaques that mediate the attachment of stratified squamous epithelium to the underlying dermis by connecting with the extracellular anchoring filaments of the basement membrane.
The integrin alpha-6/beta-4, a receptor for the laminins, is likely to play a pivotal role in the biology of invasive carcinoma. In the MDA-MB-435 breast carcinoma cell line, Shaw et al. (1997) demonstrated that the alpha-6/beta-4 integrin promotes carcinoma invasion through a preferential and localized targeting of phosphoinositide-3 OH kinase (PI3K) activity. Stable expression of alpha-6/beta-4 increased carcinoma invasion in a PI3K-dependent manner, and transient expression of a constitutively active PI3K increased invasion in the absence of alpha-6/beta-4. Ligation of alpha-6/beta-4 stimulated significantly more PI3K activity than ligation of beta-1 integrins, establishing specificity among integrins for PI3K activation. Alpha-6/beta-4-regulated PI3K activity was required for the formation of lamellae, dynamic sites of motility, in carcinoma cells. The small G protein Rac is required downstream of PI3K for invasion. Shaw et al. (1997) concluded that their studies defined a mechanism by which the alpha-6/beta-4 integrin promotes carcinoma invasion and invoke a novel function for PI3K signaling.
Dajee et al. (2003) showed that human keratinocytes lacking laminin-5 (LAMB3; 150310) and ITGB4 failed to form tumors on coexpression with RAS (190020) and IKBA (NFKBIA; 164008); however, introduction of wildtype LAMB3 and ITGB4 restored tumor-forming capacity, suggesting that these 2 proteins are required for human squamous cell carcinoma tumorigenesis.
Using expression profiling, Yang et al. (2008) found that ITGB4 was upregulated 6-fold by ZKSCAN3 (612791) in transfected human colon cancer cells compared with parental cells. They confirmed that ZKSCAN3 bound the promoter of ITGB4 in vitro and in vivo. ITGB4 knockdown by short hairpin RNA countered ZKSCAN3-augmented anchorage-independent colony formation in the colon cancer cell lines. Yang et al. (2008) concluded that ZKSCAN3 regulates expression of genes favoring tumor progression, including ITGB4.
The integrin beta-4 subunit is characterized by an unusually long cytoplasmic domain that harbors 4 fibronectin type III (FNIII) repeats, residing in 2 pairs separated by a connecting segment. A fragment of beta-4 containing the first pair of FNIII repeats and the first 36 amino acids of the connecting segment is crucial for the recruitment of plectin (601282) in hemidesmosomes (Niessen et al., 1997; Nievers et al., 1998). Geerts et al. (1999) demonstrated that this fragment of beta-4 contains a binding site for plectin and that this interaction depends in the presence of the actin-binding domain of plectin. Two mutations in ITGB4, arg1281 to trp (R1281W; 147557.0014) and arg 1225 to his (R1225H; 147557.0015), are located in the second FNIII repeat; R1281W is localized in the loop region that connects 2 beta strands, whereas R1225H is located in the N-terminal end of the second FNIII repeat. Koster et al. (2001) demonstrated that these mutations render beta-4 unable to interact with plectin and prevent the localization of plectin in hemidesmosomes.
Intermediate Junctional Epidermolysis Bullosa 5A
Inoue et al. (2000) studied a 68-year-old Japanese man with typical features of non-Herlitz JEB without pyloric atresia (JEB5A; 618716) who had a homozygous missense mutation in the ITGB4 gene (G931D; 147557.0012). He had lifelong trauma-induced skin fragility, but no history of gastrointestinal symptoms or previous abdominal surgery.
In a 49-year-old woman with mild blistering of hands and feet from birth, dystrophy of the nails with onychogryposis, and enamel hypoplasia, without pyloric atresia, Jonkman et al. (2002) identified a heterozygous 2-bp deletion in the ITGB4 gene (147557.0013). She was also expected to be heterozygous for a null allele, as no full-size protein was detected in vitro and the epitope 450-11 A was absent in vivo.
Junctional Epidermolysis Bullosa 5B with Pyloric Atresia
Vidal et al. (1995) identified 2 mutations in compound heterozygosity (147557.0001 and 147557.0002) in a patient with junctional epidermolysis bullosa associated with pyloric atresia (JEB5B; 226730).
Improvement with aging has been reported in a few cases of epidermolysis bullosa with pyloric atresia. In a patient who improved from severe to mild JEB-PA, Chavanas et al. (1999) found compound heterozygosity for 2 splice site mutations in the ITGB4 gene (147557.0011 and 147557.0007). Analysis of the mRNA showed that 1 of the mutations prevented legitimate splicing of the beta-4 pre-mRNA. Functional splicing could be restored in vitro by seeding the patient's keratinocytes on feeders of irradiated fibroblasts. Study of mRNA in wildtype keratinocytes transfected with ITGB4 minigenes containing intron 31 with or without the mutation confirmed the causative role in JEB-PA.
Nakano et al. (2001) identified 11 novel mutations in ITGB4 in patients with epidermolysis bullosa with congenital pyloric atresia. Four mutations predicted a premature termination codon and 7 were missense mutations. Of the 33 mutations reported to that time, those causing premature termination codons were associated with the lethal variant, whereas missense mutations were more prevalent in nonlethal forms. In general, indirect immunofluorescent studies of affected skin revealed negative staining for beta-4 integrin in lethal cases and positive, but attenuated, staining in nonlethal cases and correlated with clinical phenotype.
In addition to promoting cell adhesion and cytoskeletal organization, basement membranes influence the proliferation and differentiation of cells. The effects of basement membranes on cellular behavior are likely to be mediated by integrins. The cytoplasmic domain of the integrin beta-4 subunit mediates both association with the hemidesmosomal cytoskeleton and recruitment of the signaling adaptor protein SHC (600560). To examine the significance of these interactions during development, Murgia et al. (1998) generated mice carrying a targeted deletion of the beta-4 cytoplasmic domain. Analysis of homozygous mutant mice indicated that the tail-less alpha-6/beta-4 binds efficiently to laminin-5 (see 600805), but is unable to integrate with the cytoskeleton. Accordingly, these mice displayed extensive epidermal detachment at birth and died immediately thereafter from a syndrome resembling junctional epidermolysis bullosa with pyloric atresia in humans. In addition, Murgia et al. (1998) found a significant proliferative defect. Specifically, the number of precursor cells in the intestinal epithelium, which remains adherent to the basement membrane, and in intact areas of the skin was reduced, and postmitotic enterocytes displayed increased levels of the cyclin-dependent kinase inhibitor p27(Kip) (600778). These findings indicated that the interactions mediated by the beta-4 tail are crucial for stable adhesion of stratified epithelia to the basement membrane and for proper cell cycle control of the proliferative compartments of both stratified and simple epithelia.
Amplification of ERBB2 (164870) is common in aggressive breast tumors and correlates with poor prognosis. Guo et al. (2006) found that deletion of the signaling domain of beta-4 integrin suppressed tumor onset and invasive growth in a mouse model of Erbb2-induced mammary carcinoma. Ex vivo studies showed that beta-4 formed a complex with Erbb2 and enhanced activation of Stat3 (102582) and Jun (165160). Stat3 contributed to disruption of epithelial adhesion and polarity, whereas Jun was required for hyperproliferation. Deletion of the beta-4 signaling domain enhanced the efficacy of Erbb2-targeted therapy. Guo et al. (2006) concluded that beta-4 integrin promotes tumor progression by amplifying ERBB2 signaling and is a potential target for breast cancer therapy.
Vidal et al. (1995) found compound heterozygosity for mutations in the ITGB4 gene in an infant with junctional epidermolysis bullosa associated with pyloric atresia (JEB5B; 226730). The parents were unaffected and unrelated. At birth, the infant presented with pyloric atresia and cutaneous aplasia of the left hand. Perioral blistering and erosions of the mucosa of the mouth, upper esophagus, and cornea were noted shortly after birth. Pyloric atresia was treated surgically at the age of 2 weeks. During a surgical procedure at the age of 8 weeks, erosions of the gastric epithelium were found. At the age of 8 months, infection of skin blisters resulted in generalized infection and death of the infant. In the allele inherited from the mother, an insertion of a T was found after the second base at the 5-prime end of the intron after nucleotide 3801. This was predicted to result in shortening of the cytoplasmic domain of the integrin beta-4 subunit. The mutation was designated 3801+2insT.
In a patient with JEB associated with pyloric atresia (JEB5B; 226730), Vidal et al. (1995) found that the mutant allele inherited from the father had deletion of the ITGB4 cDNA sequence. This mutation, 1150delG, resulted in a premature termination codon 168-bp downstream from the deletion, predicting a truncated beta-4 polypeptide terminating at residue 409.
Mutation in the ITGA6 and ITGB4 genes had been demonstrated in patients with a lethal form of epidermolysis bullosa with congenital pyloric atresia (JEB5B; 226730). Pulkkinen et al. (1998) provided the first demonstration of ITGB4 mutations in nonlethal epidermolysis bullosa with congenital pyloric atresia. The patient was compound heterozygous for a missense mutation (L156P) and a nonsense mutation (R554X; 147557.0004). The leucine substitution by proline affected a residue conserved in different human, rodent, and Drosophila integrin-beta polypeptides and disrupts the alpha-helix formation of the polypeptide segment. The nonsense mutation was accompanied by undetectable levels of the corresponding mRNA transcript, as determined by RT-PCR. The presence of a missense mutation, when combined with a premature termination codon mutation, may explain the milder blistering tendency of the skin in this patient. The proband was an 18-month-old male, the product of a nonconsanguineous union. Pyloric atresia was diagnosed at birth and treated surgically at the age of 3 days. Following the operation, skin blistering was noted at sites exposed to mechanical trauma, and the blisters healed without apparent scarring, milia, or pigmentary changes. Later on, however, only occasional blisters developed, mostly at the sites of trauma such as the knees and toes, and dystrophy of some toenails developed. The mucous membranes were not involved.
For discussion of the arg554-to-ter (R554X) mutation in the ITGB4 gene that was found in compound heterozygous state in a patient with lethal epidermolysis bullosa with congenital pyloric atresia (JEB5B; 226730) by Pulkkinen et al. (1998), see 147557.0003.
Pulkkinen et al. (1998) pointed out that patients with the lethal variant of epidermolysis bullosa with pyloric atresia (JEB5B; 226730) usually have mutations leading to premature termination of the protein, whereas missense mutations may lead to nonlethal phenotypes. A missense mutation that resulted in a lethal phenotype involved a cysteine residue (C61Y).
Pulkkinen et al. (1998) found 1 of 3 patients with a nonlethal form of epidermolysis bullosa with pyloric atresia (JEB5B; 226730) to be homozygous for a cys562-to-arg (C562R) missense mutation in the ITGB4 gene.
Mellerio et al. (1998) reported 2 unrelated patients with junctional epidermolysis bullosa with pyloric atresia (JEB5B; 226730) who survived into early childhood with mild cutaneous involvement. One patient was compound heterozygous for a splice site mutation in exon 30 (3793+1G-A) and a nonsense mutation in exon 36 (W1478X; 147557.0008). The second patient was compound heterozygous with a missense mutation in exon 3 (C38R; 147557.0009) and a 1-bp deletion in exon 36 (4776delG; 147557.0010). Although the nonsense and deletion mutations were predicted to result in markedly reduced beta-4 integrin mRNA levels, the presence of the missense or splice site mutation on the second allele may enable the synthesis of some functional, albeit perturbed, beta-4 polypeptide.
For discussion of the trp1478-to-ter (W1478X) mutation in the ITGB4 gene that was found in compound heterozygous state in a patient with junctional epidermolysis bullosa with pyloric atresia (JEB5B; 226730) by Mellerio et al. (1998), see 147557.0007.
For discussion of the cys38-to-arg (C38R) mutation in the ITGB4 gene that was found in compound heterozygous state in a patient with junctional epidermolysis bullosa with pyloric atresia (JEB5B; 226730) by Mellerio et al. (1998), see 147557.0007.
For discussion of the 1-bp deletion in the ITGB4 gene (4776delG) that was found in compound heterozygous state in a patient with junctional epidermolysis bullosa with pyloric atresia (JEB5B; 226730) by Mellerio et al. (1998), see 147557.0007.
Chavanas et al. (1999) reported a patient who represented the rare instance in which epidermolysis bullosa with pyloric atresia (JEB5B; 226730) shows improvement with age. The proband was a 14-year-old boy, the child of nonconsanguineous parents, who at birth presented all the hallmarks of severe PA-JEB, including extensive skin blistering, pyloric atresia, and urethrovesical occlusion. As the child grew, however, the blistering tendency decreased and his skin and epithelia acquired resistance to trauma. At the age of 14, induction of blisters required prolonged rubbing of the skin. In this patient, Chavanas et al. (1999) found compound heterozygosity for the intron 30 splice donor site mutation (3802+1G-A; 147557.0007) and a novel T-to-A transversion at nucleotide 3986-19 in intron 31 of the ITGB4 gene.
In a 68-year-old male with typical non-Herlitz junctional epidermolysis bullosa (JEB5A; 619816) without pyloric atresia, Inoue et al. (2000) reported a homozygous ITGB4 gly931-to-asp (G931D) mutation. The patient, who was the product of a consanguineous mating, had a history of congenital blisters, recurrent urethral stenosis since age 12 years, progressive alopecia since childhood, loss of permanent dentition by age 30 years, nail dystrophy, and absence of pubic and axillary hair. There was no history of gastrointestinal symptoms or previous abdominal surgery. The mutation, a G-to-A transition at nucleotide 2792, created a novel BsmF1 cut site.
Jonkman et al. (2002) reported a patient with predominant features of epidermolysis bullosa simplex confined to the hands and feet (JEB5A; 619816) due to a heterozygous 2-bp deletion (4733delCT) in the ITGB4 gene, resulting in in-frame skipping of exon 36 and a deduced 50-amino acid deletion (1450-1499) within the third fibronectin type III repeat in the cytoplasmic domain of integrin beta-4. Although mutation in exon 36 of the ITGB4 gene had been reported in epidermolysis bullosa with pyloric atresia (226730) (see 147557.0007), this patient had no history of pyloric atresia. The patient, a 49-year-old female, had mild blistering of hands and feet from birth, dystrophy of the nails with onychogryposis, and enamel hypoplasia. Electron microscopy and antigen mapping of a skin blister revealed that the level of separation was intraepidermal, low in the basal keratinocytes through the attachment plaque of the hemidesmosome. Immunofluorescence microscopy revealed absent binding of monoclonal antibody 450-11 A against the third fibronectin III repeat on the intracellular domain of integrin beta-4, whereas binding was reduced with monoclonal antibodies recognizing epitopes on amino-terminal and carboxy-terminal ends of the polypeptide. Immunoblot analysis demonstrated a 5-kD shorter beta-4 polypeptide. The patient was also expected to be heterozygous for a null allele, as no full-size protein was detected in vitro and the epitope 450-11 A was absent in vivo. These data showed that deletion of the third fibronectin type III repeat in the cytoplasmic domain of integrin beta-4, which is thought to interact with BP180/type XVII collagen (113811), is clinically pathogenic and results in a mild phenotype. Although Jonkman et al. (2002) stated that the level of skin separation was intraepidermal (i.e., consistent with that seen in epidermolysis bullosa simplex), they pointed out that 'pseudojunctional' splits very low in the basal cells had been reported in patients with JEB with pyloric atresia carrying mutations in the ITGB4 gene (e.g., Pulkkinen et al. (1998), Mellerio et al. (1998)).
In 2 patients with epidermolysis bullosa with pyloric atresia (JEB5B; 226730), Pulkkinen et al. (1998) described an arg1281-to-trp (R1281W) mutation in the ITGB4 gene. In 1 patient the mutation was homozygous, and in the other compound heterozygous with another missense mutation. Koster et al. (2001) reported that this mutation renders integrin beta-4 unable to interact with plectin (601282) and prevents the localization of plectin in hemidesmosomes.
In an individual with epidermolysis bullosa with pyloric atresia (JEB5B; 226730), Nakano et al. (2001) found an arg1225-to-his (R1225H) mutation in the ITGB4 gene. The mutation occurred in compound heterozygosity. The blistering tendency of the patient improved with time. Koster et al. (2001) reported that this mutation renders integrin beta-4 unable to interact with plectin (601282) and prevents the localization of plectin in hemidesmosomes.
In affected members of the original Bedouin kindred from southern Israel with epidermolysis bullosa with pyloric atresia and aplasia cutis congenita (JEB5B; 226730), described by Carmi et al. (1982) and Maman et al. (1998), Birnbaum et al. (2008) identified a homozygous 2,279-bp in-frame deletion in part of exon 27 and all of exons 28-30 of the ITGB4 gene in 3 affected family members. The deletion includes the authentic 5-prime splice site of exon 27 that creates a new cryptic 5-prime splice site leading to a 570-bp deletion within the integrin beta-4 final transcript. The mutation generates an in-frame deletion of 190 amino acids (1075-1266). The ITGB4 fragment deleted in this family encodes the first pair of fibronectin type III (FNIII) repeats. Birnbaum et al. (2008) suggested that the deletion affected the integrity of the basement membrane and the assembly of hemidesmosomes, consequently abrogating the control of normal skin structure.
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