ITGA7

ITGA7
Identifiers
Aliases	ITGA7, integrin subunit alpha 7
External IDs	MGI: 102700 HomoloGene: 37592 GeneCards: ITGA7
Gene location (Human) Chr. Chromosome 12 (human)[1] Band No data available Start 55,684,568 bp[1] End 55,716,043 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band No data available Start 128,933,818 bp[2] End 128,958,282 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • protein binding • metal ion binding Cellular component • integral component of membrane • cell surface • integrin complex • plasma membrane • membrane Biological process • integrin-mediated signaling pathway • heterotypic cell-cell adhesion • muscle organ development • cell-matrix adhesion • extracellular matrix organization • cell adhesion • endodermal cell differentiation • regulation of cell shape Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	3679	16404
Ensembl	ENSG00000135424	ENSMUSG00000025348
UniProt	Q13683	Q61738
RefSeq (mRNA)	NM_001144996 NM_001144997 NM_002206	NM_008398 NM_001330160
RefSeq (protein)	NP_001138468 NP_001138469 NP_002197	n/a
Location (UCSC)	Chr 12: 55.68 – 55.72 Mb	Chr 10: 128.93 – 128.96 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Alpha-7 integrin is a protein that in humans is encoded by the ITGA7 gene.^[5][6] Alpha-7 integrin is critical for modulating cell-matrix interactions. Alpha-7 integrin is highly expressed in cardiac muscle, skeletal muscle and smooth muscle cells, and localizes to Z-disc and costamere structures. Mutations in ITGA7 have been associated with congenital myopathies and noncompaction cardiomyopathy, and altered expression levels of alpha-7 integrin have been identified in various forms of muscular dystrophy.

Structure

ITGA7 encodes the protein alpha-7 integrin. Alpha-7 integrin is 128.9 kDa in molecular weight and 1181 amino acids in length.^[7] Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. Alpha-7 integrin undergoes post-translational cleavage within the extracellular domain to yield disulfide-linked light and heavy chains that join with beta 1 to form an integrin that binds to the extracellular matrix protein laminin-1. The primary binding partners of alpha-7 integrin are laminin-1 (alpha1-beta1-gamma1), laminin-2 (alpha2-beta1-gamma1) and laminin-4 (alpha2-beta2-gamma1).^[8] Alpha-7/beta-1 is the major integrin complex expressed in differentiated muscle cells.

Splice variants of alpha-7 integrin that differ in both the extracellular and cytoplasmic domains exist in the mouse^[9] and are developmentally regulated in mouse and rat muscle tissue.^{[9][10][11][12][13]} The X1/X2 alternative splicing region lies in the extracellular domain and alters the ligand binding site; specifically, the conserved homology repeat domains 3 and 4.^[9] The first identified human transcript contains extracellular and cytoplasmic domains corresponding to the mouse X2 and B variants, respectively. A unique extracellular splice variant was also identified in human.^[6][14] The differentially spliced variants detected in rodents have also been detected in humans. Major cytoplasmic, developmentally regulated variants, alpha-7A and alpha-7B, as well as extracellular variants, X1 and X2 were identified in humans. Moreover, the D variant, but not the C variant was detected in humans.^[15]

Alpha-7 integrin is highly expressed in striated muscle, namely skeletal and cardiac muscle, and functions as the major laminin-binding integrin.^[16] It was later shown that alpha-7 integrin is also highly expressed in smooth muscle.^[17] The two major splice variants of alpha-7 integrin appear to have developmentally regulated expression; alpha-7A integrin is expressed solely in skeletal muscle, however alpha-7B integrin is expressed more loosely in striated muscle as well as the vasculature.^[18]

Function

The function of alpha-7 integrin, as is the case for most integrins is to mediate cell membrane interactions with extracellular matrix.^[19]

The alpha-7/beta-1 integrin complex clearly plays a role in the development of striated muscle and smooth muscle. Alpha-7/beta-1 integrin promotes the adhesion and motility of myoblasts, and is likely important in the recruitment of myogenic precursors during muscle differentiation.^[20] It was shown however that beta-1D integrin appears at embryonic day 11 and alpha-7 integrin does not appear until embryonic day 17; thus, beta-1D associates with alternate alpha subunits (alpha-5, alpha-6A) prior to alpha-7.^[21] In human skeletal muscle, alpha-7 integrin is also developmentally regulated, being first detected at age 2.^[8]

In adult striated muscle cells, alpha-7 integrin (complexed to beta-1 integrin) is localized to Z-discs and costamere structures, bound to the four and one half LIM domain proteins, FHL1 and FHL2.^[10][22][23] It has been demonstrated that alpha-7 integrin can be mono-ADP-ribosylated on the cell surface in skeletal muscle cells;^[24] however, the functional significance of this modification has not been investigated.

Insights into the function of alpha-7 integrin have come from studies employing mouse transgenesis. A mouse expressing a null allele of the ITGA7 gene are viable, suggesting that alpha-7 integrin is not essential for normal myogenesis; however, these mice develop a phenotype that resembles muscular dystrophy. In soleus muscle, there was a significant disruption of myotendinous junctions, variation in the size of fibers, centrally located nuclei, necrosis, phagocytosis, and elevated serum levels of creatine kinase.^[25] It has also been proposed that alpha-7 integrin and gamma-sarcoglycan have overlapping functions in skeletal muscle. In support of this, a double knockout of gamma-sarcoglycan and alpha-7 integrin produced a phenotype that was far worse than either knockout alone. Mice died within 1 month of birth and had severe muscle degeneration, suggesting that the roles of these proteins may overlap to maintain the stability of the sarcolemma.^[26] Moreover, the double knockout of dystrophin and alpha-7 integrin produced a Duchenne muscular dystrophy-like phenotype, and demonstrated that alterations in alpha-7 integrin affect the pathological changes observed in dystrophin deficiencies.^[27] In support of this notion, AAV overexpression of ITGA7 in skeletal muscle of Duchenne muscular dystrophy (DMD) mice showed a significant protective effect against adverse functional parameters associated with DMD, combined with a reversal of these negative features, suggesting that alpha-7 integrin may be a potential therapeutic candidate to treat Duchenne muscular dystrophy.^[28]

Studies employing mutant alpha-7 integrin constructs have shown that the cytoplasmic tail of alpha-7B integrin is essential for regulation of lamellipodia formation and regulation of cell mobility regulation via laminin-1/E8 and p130(CAS)/Crk complex formation.^[29]

Clinical Significance

Mutations in ITGA7 have been found in patients with unclassified congenital myopathy.^[30] Additionally, in patients with severe congenital fiber type disproportion and left ventricular non-compaction cardiomyopathy, a missense mutation, Glu882Lys, was identified in ITGA7 along with a missense mutation in MYH7B, both novel disease genes having a synergistic effect on disease severity.^[31]

Alpha-7B integrin expression has been shown to be significantly decreased at sarcolemmal membranes in patients with laminin alpha2 chain-deficient congenital muscular dystrophy. Additionally, in Duchenne muscular dystrophy and Becker muscular dystrophy, the expression of alpha-7B integrin was enhanced.^[8]

Interactions

ITGA7 has been shown to interact with:

• Merosin^[32]
• ITGB1^[33][34]
• FHL2^[35] and
• FHL3.^[35]

See also

• Congenital muscular dystrophy

References

Further reading

External links

• ITGA7 Info with links in the Cell Migration Gateway