Alternative titles; symbols
HGNC Approved Gene Symbol: ITGA6
Cytogenetic location: 2q31.1 Genomic coordinates (GRCh38) : 2:172,427,336-172,506,459 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q31.1 | Epidermolysis bullosa, junctional 6, with pyloric atresia | 619817 | Autosomal recessive | 3 |
Tamura et al. (1990) determined the complete primary structure of alpha-6, which is part of the integrin alpha-6/beta-4 (ITGB4; 147557) heterodimer expressed predominantly by epithelial cells. Hogervorst et al. (1991) isolated cDNAs encoding the alpha-6 subunit from a gamma-gt11 expression library from human keratinocytes. The alpha-6 subunit encoded by this cDNA consists of 1,050 amino acids with a 991-amino acid extracellular domain, a 23-amino acid transmembrane domain, and a 36-amino acid cytoplasmic domain. The alpha-6 subunit most closely resembles the alpha-3 subunit (ITGA3; 605025), which shows 40% identity. Hogervorst et al. (1991) stated that this high degree of similarity may be the basis for their functional resemblance, since both the alpha-3 and alpha-6 subunits, when associated with beta-1 (ITGB1; 135630), haven been shown to function as laminin receptors (150370) and to bind to the long arm of laminin (see 150320).
In mice, Yao et al. (2018) showed that acute lymphoblastic leukemia (ALL; 613065) cells in the circulation are unable to breach the blood-brain barrier; instead, they migrate into the central nervous system (CNS) along vessels that pass directly between vertebral or calvarial bone marrow and the subarachnoid space. The basement membrane of these bridging vessels is enriched in laminin (see 150320), which is known to coordinate pathfinding of neuronal progenitor cells in the CNS. The laminin receptor alpha-6 integrin is expressed in most cases of ALL. Yao et al. (2018) found that alpha-6 integrin-laminin interactions mediated the migration of ALL cells towards the cerebrospinal fluid in vitro. Mice with ALL xenografts were treated with either a PI3K-delta (PIK3CD; 602839) inhibitor, which decreased alpha-6 integrin expression on ALL cells, or specific alpha-6 integrin-neutralizing antibodies and showed significant reductions in ALL transit along bridging vessels, blast counts in the cerebrospinal fluid, and CNS disease symptoms despite minimally decreased bone marrow disease burden. Yao et al. (2018) concluded that alpha-6 integrin expression, which is common in ALL, allows cells to use neural migratory pathways to invade the CNS.
Hogervorst et al. (1991) mapped the ITGA6 gene to chromosome 2 by analysis of human-rodent somatic cell hybrids.
Using flow cytometry to track expression of adhesion molecules in human hematopoietic stem cells (HSCs), Notta et al. (2011) identified CD49F as a specific marker for CD34 (142230)-positive/THY1 (188230)-positive cells with high capacity to be long-term multipotent progenitors (MPPs). Single CD49F-positive/THY1-negative cells were highly efficient in generating long-term MPPs, whereas this potential was low in CD49F-negative/THY1-negative cells. Notta et al. (2011) concluded that CD49F is a marker for HSCs with MPP capacity.
Stumpf (2022) mapped the ITGA6 gene to chromosome 2q31.1 based on an alignment of the ITGA6 sequence (GenBank BC136456) with the genomic sequence (GRCh38).
Ruzzi et al. (1997, 1997) found a homozygous mutation in the ITGA6 gene (147556.0001) in a patient with junctional epidermolysis bullosa with pyloric atresia (JEB6; 619817). Mutations in the gene encoding a cognate protein, ITGB4 (147557), had been demonstrated in a patient with the same disorder. Their results indicated that, despite the ability of alpha-6 to associate with both the beta-1 and the beta-4 integrin subunits and its expression in tissues where beta-4 is not found, mutations in either alpha-6 or beta-4 lead to the same disease. Ruzzi et al. (1997) noted that mice with knockout of either of these genes also had extensive detachment of epidermis and other epithelia.
In a male infant with JEB-PA born of unaffected consanguineous Emirate Arabian parents, Allegra et al. (2003) identified homozygosity for a ser47-to leu mutation (S47L; 147556.0002) in the beta-propeller domain of ITGA6. Functional studies indicated that the S47L mutation triggers instability of alpha-6 integrin that was at least partially mediated by the lysosomal degradation pathway.
Schumann et al. (2013) studied 8 epidermolysis bullosa patients with alpha-6/beta-4 mutations, 7 with homozygous or compound heterozygous mutations in ITGB4 and 1 with homozygous mutation in ITGA6 (147556.0003). This patient had pyloric atresia and a severe phenotype.
In a Japanese infant with lethal JEB-PA, Masunaga et al. (2017) detected compound heterozygosity for splicing mutations in the ITGA6 gene (147556.0004 and 147556.0005). Both mutations resulted in exon skipping, with in-frame deletion or premature termination of the protein.
Georges-Labouesse et al. (1996) produced mice that were deficient in alpha-6 integrin through a targeted disruption of the alpha-6 integrin gene. The mice developed normally before birth but died shortly thereafter with severe blistering of the skin and other epithelia. The phenotype was reminiscent of human epidermolysis bullosa (see 226700). Hemidesmosomes were absent from the mutant tissue.
In an infant with junctional epidermolysis bullosa with pyloric atresia and esophageal stenosis (JEB6; 619817), Ruzzi et al. (1997, 1997) identified a homozygous 1-bp deletion (791delC) in the ITGA6 gene, resulting in a frameshift, premature termination, and with complete absence of alpha-6 integrin. Both parents were healthy, heterozygous carriers of the mutation. The child was born with extensive aplasia cutis and with multiple blisters and erosions over the trunk and limbs. Successful prenatal diagnosis was achieved in a later pregnancy with allele-specific oligonucleotide (ASO) analysis; skin biopsy at 16 weeks' gestation showed that the fetus was a heterozygous carrier.
In a male infant with junctional epidermolysis bullosa-6 with pyloric atresia (JEB6; 619817), born of unaffected consanguineous Emirate Arabian parents, Allegra et al. (2003) identified a homozygous c.286C-T transition in exon 1 of the ITGA6 gene, resulting in a ser47-to leu (S47L) substitution in a highly conserved region of the first beta-strand of the 7-bladed beta-propeller structure in the extracellular head of alpha-6-integrin. The mutation was not detected among 100 healthy control individuals. Functional studies demonstrated that the mutation generated an unstable alpha-6 precursor that underwent rapid proteolysis involving the lysosomal degradation pathway.
In a 3-month-old Turkish boy (patient 8) with junctional epidermolysis bullosa-6 with pyloric atresia (JEB6; 619817), Schumann et al. (2013) detected homozygosity for a splice site mutation in the ITGA6 gene (c.388-5T-G, NM_000210.2). No expression of alpha-6-integrin was detected by immunofluorescence of patient keratinocytes. The mutation, which occurred in the extracellular domain, was presumed to result in mRNA decay. The patient died at 3 months of age.
In a Japanese infant with lethal junctional epidermolysis bullosa-6 with pyloric atresia (JEB6; 619817) Masunaga et al. (2017) identified compound heterozygosity for splicing mutations in the ITGA6 gene. The maternal allele carried a c.387G-T transition at the last nucleotide of exon 3; the paternal allele carried a G-to-C transversion at the acceptor site of intron 19 (c.2506-1G-C; 147556.0005). The mutations resulted in exon skipping leading to in-frame deletion or premature termination and malfunctional integrin-beta-6.
For discussion of a splice mutation (c.2506-1G-C) in the ITGA6 gene that was found in compound heterozygous state in a patient with junctional epidermolysis bullosa-6 with pyloric atresia (JEB6; 619817) by Masunaga et al. (2017), see 147556.0004.
Allegra, M., Gagnoux-Palacios, L., Gache, Y., Roques, S., Lestringant, G., Ortonne, J. P., Meneguzzi, G. Rapid decay of alpha-6 integrin caused by a mis-sense mutation in the propeller domain results in severe junctional epidermolysis bullosa with pyloric atresia. J. Invest. Derm. 121: 1336-1343, 2003. [PubMed: 14675179] [Full Text: https://doi.org/10.1111/j.1523-1747.2003.12625.x]
Georges-Labouesse, E., Messaddeq, N., Yehia, G., Cadalbert, L., Dierich, A., Le Meur, M. Absence of integrin alpha-6 leads to epidermolysis bullosa and neonatal death in mice. Nature Genet. 13: 370-373, 1996. [PubMed: 8673141] [Full Text: https://doi.org/10.1038/ng0796-370]
Hogervorst, F., Kuikman, I., Geurts van Kessel, A., Sonnenberg, A. Molecular cloning of the human alpha-6 integrin subunit: alternative splicing of alpha-6 mRNA and chromosomal localization of the alpha-6 and beta-4 genes. Europ. J. Biochem. 199: 425-433, 1991. [PubMed: 2070796] [Full Text: https://doi.org/10.1111/j.1432-1033.1991.tb16140.x]
Masunaga, T., Ogawa, J., Akiyama, M., Nishikawa, T., Shimizu, H., Ishiko, A. Compound heterozygosity for novel splice site mutations of ITGA6 in lethal junctional epidermolysis bullosa with pyloric atresia. J. Derm. 44: 160-166, 2017. [PubMed: 27607025] [Full Text: https://doi.org/10.1111/1346-8138.13575]
Notta, F., Doulatov, S., Laurenti, E., Poeppl, A., Jurisica, I., Dick, J. E. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science 333: 218-221, 2011. [PubMed: 21737740] [Full Text: https://doi.org/10.1126/science.1201219]
Ruzzi, L., Gagnoux-Palacios, L., Pinola, M., Belli, S., Meneguzzi, G., D'Alessio, M., Zambruno, G. A homozygous mutation in the integrin alpha-6 gene in junctional epidermolysis bullosa with pyloric atresia. J. Clin. Invest. 99: 2826-2831, 1997. [PubMed: 9185503] [Full Text: https://doi.org/10.1172/JCI119474]
Ruzzi, L., Gagnoux-Palacios, L., Pinola, M., Belli, S., Meneguzzi, G., Zambruno, G., D'Alessio, M. A homozygous mutation in the gene encoding integrin alpha6 in junctional epidermolysis bullosa with pyloric atresia. (Abstract) Medizinische Genetik 9: 13-14, 1997.
Schumann, H., Kiritsi, D., Pigors, M., Hausser, I., Kohlhase, J., Peters, J., Ott, H., Hyla-Klekot, L., Gacka, E., Sieron, A. L., Valari, M., Bruckner-Tuderman, L., Has, C. Phenotypic spectrum of epidermolysis bullosa associated with alpha-6-beta-4 integrin mutations. Brit. J. Derm. 169: 115-124, 2013. [PubMed: 23496044] [Full Text: https://doi.org/10.1111/bjd.12317]
Stumpf, A. M. Personal Communication. Baltimore, Md. 03/28/2022.
Tamura, R. N., Rozzo, C., Starr, L., Chambers, J., Reichardt, L. F., Cooper, H. M., Quaranta, V. Epithelial integrin alpha-6/beta-4: complete primary structure of alpha-6 and variant forms of beta-4. J. Cell Biol. 111: 1593-1604, 1990. [PubMed: 1976638] [Full Text: https://doi.org/10.1083/jcb.111.4.1593]
Yao, H., Price, T. T., Cantelli, G., Ngo, B., Warner, M. J., Olivere, L., Ridge, S. M., Jablonski, E. M., Therrien, J., Tannheimer, S., McCall, C. M., Chenn, A., Sipkins, D. A. Leukemia hijacks a neural mechanism to invade the central nervous system. Nature 560: 55-60, 2018. [PubMed: 30022166] [Full Text: https://doi.org/10.1038/s41586-018-0342-5]