Mutations in the integrin α7 gene cause congenital myopathy

Hayashi, Yukiko; Chou, F. L.; Engvall, Eva; Ogawa, Megumu; Matsuda, Chie; Hirabayashi, Shinichi; Yokochi, Kenji; Ziober, Barry L.; Kramer, Randall H.; Kaufman, Stephen J.; Ozawa, Eijiro; Goto, Yu‐ichi; Nonaka, Ikuya; Tsukahara, Toshifumi; Wang, Jianzhou; Hoffman, Eric P.; Arahata, Kiichi

doi:10.1038/ng0598-94

Cited by 338 publications

(249 citation statements)

References 25 publications

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“…The ␣ 7 ␤ 1 -integrin is the predominant laminin-binding integrin in cardiac and skeletal muscle (7). Mutations in the ␣ 7 -integrin gene cause congenital myopathy in both humans and mice (8)(9)(10). Transgenic overexpression of the ␣ 7 -integrin in the skeletal muscle of severely dystrophic mice improves muscle pathology and increases lifespan (11).…”

mentioning

confidence: 99%

Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy

Rooney¹,

Gurpur²,

Burkin

2009

Proc. Natl. Acad. Sci. U.S.A.

114

109

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Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin results in reduced sarcolemmal integrity and increased susceptibility to muscle damage. The α 7 β 1 -integrin is a laminin-binding protein up-regulated in the skeletal muscle of DMD patients and in the mdx mouse model. Transgenic overexpression of the α 7 -integrin alleviates muscle disease in dystrophic mice, making this gene a target for pharmacological intervention. Studies suggest laminin may regulate α 7 -integrin expression. To test this hypothesis, mouse and human myoblasts were treated with laminin and assayed for α 7 -integrin expression. We show that laminin-111 (α 1 , β 1 , γ 1 ), which is expressed during embryonic development but absent in normal or dystrophic skeletal muscle, increased α 7 -integrin expression in mouse and DMD patient myoblasts. Injection of laminin-111 protein into the mdx mouse model of DMD increased expression of α 7 -integrin, stabilized the sarcolemma, restored serum creatine kinase to wild-type levels, and protected muscle from exercised-induced damage. These findings demonstrate that laminin-111 is a highly potent therapeutic agent for the mdx mouse model of DMD and represents a paradigm for the systemic delivery of extracellular matrix proteins as therapies for genetic diseases.

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mentioning

confidence: 99%

Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy

Rooney¹,

Gurpur²,

Burkin

2009

Proc. Natl. Acad. Sci. U.S.A.

114

109

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“…Mice carrying an inactivated integrin a7 gene (ITGA7) were shown to develop a mild, but progressive muscular dystrophy (Mayer et al 1997). Only Japanese patients so far have been identified with a primary integrin a7 deficiency and clinically classified as having congenital myopathy with a delayed motor milestone (Hayashi et al 1998). The integrin a7 deficiency was reported to be caused by splice mutations and deletions, leading to frameshifts, and/ or marked reduction of ITGA7 mRNA.…”

Section: Extracellular Matrix Proteins and Receptorsmentioning

confidence: 99%

The genetic and molecular basis of muscular dystrophy: roles of cell–matrix linkage in the pathogenesis

2006

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Muscular dystrophies are a heterogeneous group of genetic disorders. In addition to genetic information, a combination of various approaches such as the use of genetic animal models, muscle cell biology, and biochemistry has contributed to improving the understanding of the molecular basis of muscular dystrophy's etiology. Several lines of evidence confirm that the structural linkage between the muscle extracellular matrix and the cytoskeleton is crucial to prevent the progression of muscular dystrophy. The dystrophin-glycoprotein complex links the extracellular matrix to the cytoskeleton, and mutations in the component of this complex cause Duchenne-type or limb-girdle-type muscular dystrophy. Mutations in laminin or collagen VI, muscle matrix proteins, are known to cause a congenital type of muscular dystrophy. Moreover, it is not only the primary genetic defects in the structural or matrix proteins, but also the primary mutations of enzymes involved in the protein glycosylation pathway that are now recognized to disrupt the matrix-cell interaction in a certain group of muscular dystrophies. This group of diseases is caused by the secondary functional defects of dystroglycan, a transmembrane matrix receptor. This review considers recent advances in understanding the molecular pathogenesis of muscular dystrophies that can be caused by the disruption of the cell-matrix linkage.

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“…In vertebrates, it is α7β1D that is required for the maintenance of adult muscles. The α7β1 integrin is a laminin receptor and loss of either the α7 subunit or its ligand laminin 2/4 leads to congenital muscular dystrophy in human patients as well as in mice [96][97][98][99].…”

Section: Skeletal Musclementioning

confidence: 99%

Integrins in regulation of tissue development and function

Danen¹,

Sonnenberg²

2003

The Journal of Pathology

229

173

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Cell adhesion is indispensable for embryonic development and for proper tissue function. In metazoans, integrins are the major adhesion receptors that connect cells to components of the extracellular matrix. Integrins are implicated in assembly of extracellular matrices, cell adhesion and migration on extracellular matrices, and in vertebrates (in which the integrin family has expanded) they can also mediate cell-cell adhesion. Furthermore, integrinmediated adhesion can modulate many different signal transduction cascades and support cell survival, proliferation, and influence the expression of differentiation-related genes. In this review we briefly explain how integrins can affect so many different aspects of cell behavior and discuss evidence for roles of integrins in tissue development, function, and disease.

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Mutations in the integrin α7 gene cause congenital myopathy

Cited by 338 publications

References 25 publications

Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy

Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy

The genetic and molecular basis of muscular dystrophy: roles of cell–matrix linkage in the pathogenesis

Integrins in regulation of tissue development and function

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