HGNC Approved Gene Symbol: ITGA7
SNOMEDCT: 771267003;
Cytogenetic location: 12q13.2 Genomic coordinates (GRCh38): 12:55,684,568-55,716,400 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.2 | Muscular dystrophy, congenital, due to ITGA7 deficiency | 613204 | Autosomal recessive | 3 |
Integrins are heterodimeric membrane glycoproteins that mediate a wide spectrum of cell-cell and cell-matrix interactions. They have preeminent roles in cell migration and morphologic development, differentiation, and metastasis. The diversity and specificity of functions mediated by integrins rest in the structural diversity of the different integrin alpha and beta chains and in their ligand-binding and signal transduction capacities. Alternate splicing increases the structural diversity in the cytoplasmic domains of several integrin alpha and beta chains. The alpha-7 (ITGA7)/beta-1 (ITGB1; 135630) integrin is a specific cellular receptor for the basement membrane protein laminin-1 (see 150320), as well as for laminin-2 (see 156225) and -4. The alpha-7 subunit is expressed mainly in skeletal and cardiac muscle and may be involved in differentiation and migration processes during myogenesis (summary by Wang et al. (1995) and Mayer et al. (1997)).
Mayer et al. (1997) noted that 3 cytoplasmic and 2 extracellular splice variants of integrin alpha-7 are developmentally regulated and expressed in different sites in muscle. In adult muscle, the alpha-7A and alpha-7B subunits are concentrated in myotendinous junctions, but they can also be detected in neuromuscular junctions and along the sarcolemmal membrane.
From examining the rat and human genomes by Southern blot analysis and in situ hybridization, Wang et al. (1995) determined that both genomes contain a single alpha-7 gene. Using FISH, they mapped the human ITGA7 gene to chromosome 12q13.
In 3 unrelated patients with congenital muscular dystrophy due to integrin alpha-7 deficiency (613204), Hayashi et al. (1998) identified compound heterozygosity for mutations in the ITGA7 gene (600536.0001-600536.0003). All had normal laminin alpha-2 chain expression (LAMA2; 156225) in skeletal muscle. The findings in the 3 patients corresponded well with the findings in Itga7 knockout mice reported by Mayer et al. (1997) (see ANIMAL MODEL). Hayashi et al. (1998) noted that deficiency of LAMA2 causes congenital muscular dystrophy (MDC1A; 607855), and a secondary deficiency of integrin alpha-7 can be observed in some cases. Another patient with congenital myopathy and marked deficiency of ITGA7 mRNA showed hypotonia and torticollis from birth. No mutation was identified in the ITGA7 cDNA. The patients were identified from a larger cohort of 117 patients with unclassified congenital myopathy and congenital muscular dystrophy by immunocytochemistry.
Wang et al. (1995) noted that 1 structural difference in the integrin alpha chains appears to divide them into 2 subgroups. The I-integrin alpha chains have an insertion of about 180 amino acids in the extracellular region, whereas the non-I-integrins do not. Phylogenetic analysis of the integrin alpha-chain sequences by Wang et al. (1995) suggested that the early integrin genes evolved in 2 pathways to form the I-integrins and the non-I-integrins. The I-integrin alpha chains apparently arose as a result of an early insertion into the non-I-gene. The I-chain subfamily further evolved by duplications within the same chromosome. The non-I-integrin alpha-chain genes are located in clusters on chromosomes 2, 12, and 17, which coincides closely with the localization of the human homeobox gene clusters. Non-I-integrin alpha-chain genes appear to have evolved in parallel and in proximity to the HOX clusters. Thus, the HOX genes that underlie the design of body structure and the integrin genes that underlie informed cell-cell and cell-matrix interactions appear to have evolved in parallel and coordinate fashions.
To study the involvement of alpha-7 integrin during myogenesis and its role in muscle integrity and function, Mayer et al. (1997) generated a null allele of the Itga7 gene in the germline of mice by homologous recombination in embryonic stem (ES) cells. Mice homozygous for the mutation were viable and fertile, indicating that the gene is not essential for myogenesis. However, histologic analysis of skeletal muscle showed typical signs of progressive muscular dystrophy starting soon after birth, but with a distinct variability in different muscle types. The histopathologic changes indicated an impairment of function of the myotendinous junctions. Thus, ITGA7 represents an indispensable linkage between the muscle fiber and extracellular matrix that is independent of the dystrophin-dystroglycan complex-mediated interaction of the cytoskeleton with the muscle basement membrane.
Nawrotzki et al. (2003) reported that beta-1D integrin coimmunoprecipitated and colocalized with the alpha-5 integrin subunit (ITGA5; 135620) at myotendinous junctions in alpha-7-deficient mice, but did not associate with alpha-3 (ITGA3; 605025), alpha-6 (ITGA6; 147556), or alpha-V (ITGAV; 193210) integrins. Immunogold labeling showed that the basement membranes of integrin alpha-7-deficient muscles recruited abnormally high levels of fibronectin (FN1; 135600), the ligand of alpha-5-beta-1D. Alpha-5-beta-1D was downregulated at the normal postnatal junction and was displaced by alpha-7-beta-1D. The authors suggested that the alpha-7 subunit may be responsible for downregulation of alpha-5-beta-1D and also for removal of fibronectin from the maturing myotendinous junction, thus providing an alpha-7-beta-1D-based link to laminin. The authors proposed that persistence of alpha-5-beta-1D in alpha-7-deficient mice may not be compatible with normal muscle function and may lead to muscle wasting.
Both dystrophin (DMD; 300377) and alpha-7/beta-1 integrin have critical roles in the maintenance of muscle integrity by providing mechanical links between muscle fibers and the basement membrane. Guo et al. (2006) created Dmd/Itga7 double-knockout mice (DKO), which appeared normal at birth, but died within the first month of life with severe muscular dystrophy, endomysial fibrosis, and ectopic calcification. Progressive muscle wasting in the DKO mice was likely due to inadequate muscle regeneration, and the premature death appeared to be due to cardiac and/or respiratory failure.
In a 4-year-old Japanese boy with congenital muscular dystrophy (613204), Hayashi et al. (1998) observed compound heterozygosity for 2 splicing mutations in the ITGA7 gene: one was an A-to-G transition at -2 in a splice acceptor site (nucleotide 1506) that caused a 21-bp insertion in the conserved cysteine-rich region, and the other was a T-to-C transition at +2 in a splice donor site (nucleotide 2712) (600536.0002) that resulted in a 98-bp frameshift deletion and a premature termination codon 12 bp downstream. The latter mutation was found in the unaffected father, whereas the former was not detected in either parent, suggesting a new mutation. The child's psychomotor milestones were delayed; he acquired the ability to roll over at 9 months, and walked at 2.5 years. He could not jump or run. Mental retardation was also observed, and verbal abilities were limited to only a few words. Serum creatine kinase (CK) activity was mildly elevated. Brain MRI and EEG were normal. It was unclear whether mental retardation was caused by alpha-7 deficiency, but Hayashi et al. (1998) observed that alpha-7 is also expressed in the developing nervous system. Muscle biopsy at 15 months showed changes consistent with congenital myopathy.
For discussion of the splice site mutation at nucleotide 2712 in the ITGA7 gene that was found in compound heterozygous state in a patient with congenital muscular dystrophy due to alpha-7 deficiency (613204) by Hayashi et al. (1998), see 600536.0001.
In an 11-year-old Japanese girl with nonconsanguineous parents and signs of congenital myopathy (613204), Hayashi et al. (1998) found compound heterozygosity for 2 mutations in the ITGA7 gene: IVS+2T-C (600536.0002) and a 1-bp frameshift deletion (1204delG) that created a premature termination codon at amino acid 505. At 2 months of age, the girl was diagnosed with congenital dislocation of the hip and torticollis, which required surgical intervention. She acquired independent ambulation at 2 years, and Gowers sign and waddling gait were observed. She had never been able to climb stairs without support and could not run. There was no cognitive impairment. Serum CK was mildly elevated. Muscle biopsy showed changes consistent with congenital myopathy, with substantial fatty replacement and fiber size variation.
Guo, C., Willem, M., Werner, A., Raivich, G., Emerson, M., Neyses, L., Mayer, U. Absence of alpha-7 integrin in dystrophin-deficient mice causes a myopathy similar to Duchenne muscular dystrophy. Hum. Molec. Genet. 15: 989-998, 2006. [PubMed: 16476707] [Full Text: https://doi.org/10.1093/hmg/ddl018]
Hayashi, Y. K., Chou, F.-L., Engvall, E., Ogawa, M., Matsuda, C., Hirabayashi, S., Yokochi, K., Ziober, B. L., Kramer, R. H., Kaufman, S. J., Ozawa, E., Goto, Y., Nonaka, I., Tsukahara, T., Wang, J., Hoffman, E. P., Arahata, K. Mutations in the integrin alpha-7 gene cause congenital myopathy. Nature Genet. 19: 94-97, 1998. [PubMed: 9590299] [Full Text: https://doi.org/10.1038/ng0598-94]
Mayer, U., Saher, G., Fassler, R., Bornemann, A., Echtermeyer, F., von der Mark, H., Miosge, N., Poschl, E., von der Mark, K. Absence of integrin alpha-7 causes a novel form of muscular dystrophy. Nature Genet. 17: 318-323, 1997. [PubMed: 9354797] [Full Text: https://doi.org/10.1038/ng1197-318]
Nawrotzki, R., Willem, M., Miosge, N., Brinkmeier, H., Mayer, U. Defective integrin switch and matrix composition at alpha 7-deficient myotendinous junctions precede the onset of muscular dystrophy in mice. Hum. Molec. Genet. 12: 483-495, 2003. [PubMed: 12588796] [Full Text: https://doi.org/10.1093/hmg/ddg047]
Wang, W., Wu, W., Desai, T., Ward, D. C., Kaufman, S. J. Localization of the alpha-7 integrin gene (ITGA7) on human chromosome 12q13: clustering of integrin and Hox genes implies parallel evolution of these gene families. Genomics 26: 563-570, 1995.