Alternative titles; symbols
HGNC Approved Gene Symbol: ITGA3
SNOMEDCT: 733453005;
Cytogenetic location: 17q21.33 Genomic coordinates (GRCh38): 17:50,056,110-50,090,481 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.33 | Epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome | 614748 | Autosomal recessive | 3 |
Integrins are a family of cell surface adhesion molecules. Each integrin consists of a pair of noncovalently associated alpha and beta chains. Integrin alpha-chain sequences are characterized by a 7-fold repeated amino acid motif, of which the last 3 or 4 contain divalent cation-binding sites. The ITGA3 subunit is associated with ITGB1 (135630).
By screening a bladder carcinoma cDNA library with a hamster galactoprotein B3 (Gapb3) probe, Tsuji et al. (1991) isolated cDNAs encoding ITGA3. The deduced 1,019-amino acid mature ITGA3 protein contains 14 potential N-glycosylation sites and a potential cleavage site. Northern blot analysis detected a 4.8-kb ITGA3 transcript whose expression was induced by SV-40 transformation.
By immunoscreening an endothelial cell cDNA library for ITGA3 protein, Takada et al. (1991) obtained an ITGA3 cDNA. Western blot analysis showed that recombinant ITGA3 was expressed as a 150-kD protein, the same size as the native protein. The deduced 1,051-amino acid ITGA3 protein has a 32-amino acid signal peptide, a 28-amino acid transmembrane domain, and a 32-amino acid cytoplasmic segment. ITGA3 also contains 13 potential N-glycosylation sites, 2 potential cleavage sites, and the 7 N-terminal repeating units characteristic of ITGAs. Northern blot analysis detected a 5-kb ITGA3 transcript in fibroblasts.
Jones et al. (1998) determined that the ITGA3 gene spans 36.3 kb and contains 26 exons.
By searching for sequences related to murine Itga3, Jones et al. (1998) identified a chromosome 17 clone corresponding to ITGA3.
Stumpf (2022) mapped the ITGA3 gene to chromosome 17q21.33 based on an alignment of the ITGA3 sequence (GenBank AK289961) with the genomic sequence (GRCh38).
Dulabon et al. (2000) showed through immunoprecipitation experiments that alpha-3-beta-1 integrin associates with reelin (RELN; 600514) in mouse embryonic brain. Using immunolabeling, they detected coexpression of alpha-3-beta-1 integrin with Dab1 (603448), a signaling protein acting downstream of reelin, in embryonic cortical neurons. In cerebral cortices of alpha-3-beta-1 integrin-deficient mice, Dulabon et al. (2000) observed a reduction in Dab1 protein levels and elevated expression of a reelin fragment. They concluded that reelin may regulate neuronal migration and layer formation through modulation of alpha-3-beta-1 integrin-mediated neuronal adhesion and migration.
Sanada et al. (2004) found that individual neurons in the cortex of Dab1-deficient scrambler mice exhibited an abnormal mode and tempo of radial migration, that was associated with impaired detachment from radial glial cells. Glial detachment depended on Itga3 signaling that was regulated by the phosphorylation state of Dab1 residues tyr220 and tyr232. Sanada et al. (2004) concluded that a functional link between DAB1 phosphorylation and ITGA3 signaling drives the timely detachment of migrating neurons from radial glial fibers.
Human herpesvirus-8 (HHV-8) is implicated in the pathogenesis of Kaposi sarcoma. HHV-8 envelope glycoprotein B possesses the RGD amino acid motif known to interact with integrin molecules. Akula et al. (2002) found that HHV-8 infectivity was inhibited by RGD peptides, antibodies against the RGD-dependent integrins ITGA3 and ITGB1, and by soluble ITGA3/ITGB1. Expression of human ITGA3 increased the infectivity of virus for Chinese hamster ovary cells. Anti-glycoprotein B antibodies immunoprecipitated the virus-ITGA3 and -ITGB1 complexes, and virus-binding studies suggested a role for ITGA3/ITGB1 in HHV-8 entry. Further, HHV-8 infection induced the integrin-mediated activation of focal adhesion kinase (FAK; 600758). These findings implicated a role for ITGA3/ITGB1 and the associated signaling pathways in HHV-8 entry into target cells.
In a boy and 2 girls with congenital interstitial lung disease, nephrotic syndrome, and mild epidermolysis bullosa (ILNEB) (JEB7; 614748), all of whom died in infancy, Has et al. (2012) identified homozygosity for mutations in the ITGA3 gene (605025.0001-605025.0003). Examination of lung, kidney, and skin samples from the boy demonstrated that loss of integrin alpha-3 impairs both epidermal adhesion and basement-membrane assembly and remodeling.
In a male infant, born of consanguineous parents, with ILNEB, Yalcin et al. (2015) identified a homozygous missense mutation in the ITGA3 gene (R463W; 605025.0004). Studies of patient cells indicated that the mutant protein did not undergo proper processing of N-linked oligosaccharides. There was intracellular accumulation of ITGA3, lack of expression at the cell membrane, and no association with the ITGB1 subunit. The findings suggested that the mutation caused impaired posttranslational processing of ITGA3. The patient had crossed fused renal ectopia without renal failure, nail dystrophy, and sparse hair, but no overt clinical skin abnormalities. Significant early-onset interstitial lung disease resulted in death at age 6.5 months.
DiPersio et al. (1997) studied the skin of integrin alpha-3/beta-1-deficient mice generated by null mutation of the alpha-3 subunit. Immunofluorescence and electron microscopy of alpha-3/beta-1-deficient skin revealed regions of disorganized basement membrane, which first appeared on embryonic day 15.5 and became progressively more extensive. In neonatal skin, matrix disorganization was frequently accompanied by blistering at the dermal-epidermal junction due to rupture of the basement membrane. In culture, alpha-3/beta-1-deficient keratinocytes spread poorly on laminin-5 (see 600805) compared with wildtype, demonstrating a postattachment requirement for alpha-3/beta-1.
In a male infant from southern Italy with congenital interstitial lung disease, nephrotic syndrome, and mild epidermolysis bullosa (JEB7; 614748), who died from a lung infection at 7.5 months of age, Has et al. (2012) identified homozygosity for a 1-bp deletion (1173_1174del) in exon 8 of the ITGA3 gene, predicted to cause a frameshift resulting in premature termination 2 codons downstream (Pro392ValfsTer2). The unaffected parents were both heterozygous for the deletion, which was not found in at least 100 ethnically matched chromosomes. Immunohistochemistry demonstrated loss of integrin alpha-3 expression from patient skin, kidney, and lung samples compared to controls. Immunofluorescence showed that the basement membranes in the patient's kidneys and lungs had a weak and interrupted signal and that the epidermal basement membrane was clearly disorganized, compared to the strong linear staining of normal basement membranes.
In a female infant (patient 2) with congenital interstitial lung disease, nephrotic syndrome, and persistent skin erosions on the buttocks (JEB7; 614748), who was born to consanguineous parents from Gaza and died of multiorgan failure at 2 months of age, Has et al. (2012) identified homozygosity for a G-A transition in intron 11 (1538-1G-A) of the ITGA3 gene, predicted to abolish the splice acceptor site of exon 12. The mutation was not found in at least 100 ethnically matched chromosomes.
In a female infant (patient 3) with congenital interstitial lung disease, nephrotic syndrome, and mild epidermolysis bullosa (JEB7; 614748), who was born to consanguineous Pakistani parents and died at 19 months of age due to infection-related multiorgan failure, Has et al. (2012) identified homozygosity for a 1883G-C transversion in exon 14 of the ITGA3 gene, resulting in an arg628-to-pro (R628P) substitution at a conserved residue in the extracellular domain. The mutation was not found in at least 100 ethnically matched chromosomes.
In a male infant, born of consanguineous parents, with congenital interstitial lung disease, nephrotic syndrome, and mild epidermolysis bullosa (JEB7; 614748), Yalcin et al. (2015) identified a homozygous c.1387C-T transition (c.1387C-T, NM_002204.2) in the ITGA3 gene, resulting in an arg463-to-trp (R463W) substitution at a conserved residue in the beta-propeller domain. The mutation, which segregated with the disorder in the family, was not found in 100 control chromosomes or in the dbSNP (build 141) or Exome Variant Server databases. Patient skin epithelial cells showed upregulation of ITGA3 mRNA, suggesting that the mutant protein was expressed. Immunoblot analysis of patient cells showed expression only of the ITGA3, but not the mature light chain, suggesting that it did not undergo proper processing of N-linked oligosaccharides, most likely in the Golgi. There was intracellular accumulation of ITGA3, lack of expression at the cell membrane, and no association with the ITGB1 (135630) subunit. The findings suggested that the mutation caused impaired posttranslational processing of ITGA3. The patient had crossed fused renal ectopia without renal failure, nail dystrophy, and sparse hair, but no overt clinical skin abnormalities. Significant early-onset interstitial lung disease resulted in death at age 6.5 months.
Akula, S. M., Pramod, N. P., Wang, F.-Z., Chandran, B. Integrin alpha-3/beta-1 (CD 49c/29) is a cellular receptor for Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) entry into the target cells. Cell 108: 407-419, 2002. [PubMed: 11853674] [Full Text: https://doi.org/10.1016/s0092-8674(02)00628-1]
DiPersio, C. M., Hodivala-Dilke, K. M., Jaenisch, R., Kreidberg, J. A., Hynes, R. O. Alpha-3-beta-1 integrin is required for normal development of the epidermal basement membrane. J. Cell Biol. 137: 729-742, 1997. [PubMed: 9151677] [Full Text: https://doi.org/10.1083/jcb.137.3.729]
Dulabon, L., Olson, E. C., Taglienti, M. G., Eisenhuth, S., McGrath, B., Walsh, C. A., Kreidberg, J. A., Anton, E. S. Reelin binds alpha-3-beta-1 integrin and inhibits neuronal migration. Neuron 27: 33-44, 2000. [PubMed: 10939329] [Full Text: https://doi.org/10.1016/s0896-6273(00)00007-6]
Has, C., Sparta, G., Kiritsi, D., Weibel, L., Moeller, A., Vega-Warner, V., Waters, A., He, Y., Anikster, Y., Esser, P., Straub, B. K., Hausser, I., Bockenhauer, D., Dekel, B., Hildebrandt, F., Bruckner-Tuderman, L., Laube, G. F. Integrin alpha-3 mutations with kidney, lung, and skin disease. New Eng. J. Med. 366: 1508-1514, 2012. [PubMed: 22512483] [Full Text: https://doi.org/10.1056/NEJMoa1110813]
Jones, S. D., van der Flier, A., Sonnenberg, A. Genomic organization of the human alpha-3 integrin subunit gene. Biochem. Biophys. Res. Commun. 248: 896-898, 1998. [PubMed: 9704023] [Full Text: https://doi.org/10.1006/bbrc.1998.9071]
Sanada, K., Gupta, A., Tsai, L.-H. Disabled-1-regulated adhesion of migrating neurons to radial glial fiber contributes to neuronal positioning during early corticogenesis. Neuron 42: 197-211, 2004. [PubMed: 15091337] [Full Text: https://doi.org/10.1016/s0896-6273(04)00222-3]
Stumpf, A. M. Personal Communication. Baltimore, Md. 03/29/2022.
Takada, Y., Murphy, E., Pil, P., Chen, C., Ginsberg, M. H., Hemler, M. E. Molecular cloning and expression of the cDNA for alpha-3 subunit of human alpha-3/beta-1 (VLA-3), an integrin receptor for fibronectin, laminin, and collagen. J. Cell Biol. 115: 257-266, 1991. [PubMed: 1655803] [Full Text: https://doi.org/10.1083/jcb.115.1.257]
Tsuji, T., Hakomori, S., Osawa, T. Identification of human galactoprotein b3, an oncogenic transformation-induced membrane glycoprotein, as VLA-3 alpha subunit: the primary structure of human integrin alpha-3. J. Biochem. 109: 659-665, 1991. [PubMed: 1714443] [Full Text: https://doi.org/10.1093/oxfordjournals.jbchem.a123436]
Yalcin, E. G., He, Y., Orhan, D., Pazzagli, C., Emiralioglu, N., Has, C. Crucial role of posttranslational modifications of integrin alpha-3 in interstitial lung disease and nephrotic syndrome. Hum. Molec. Genet. 24: 3679-3688, 2015. [PubMed: 25810266] [Full Text: https://doi.org/10.1093/hmg/ddv111]