Integrin alpha 7 Mutations Are Associated With Adult-Onset Cardiac Dysfunction in Humans and Mice

BackgroundIntegrin alpha 7 beta 1 is a major laminin receptor in skeletal and cardiac muscle. In skeletal muscle, integrin alpha 7 beta 1 plays an important role during muscle development and has been described as an important modifier of skeletal muscle diseases. The integrin alpha 7 beta 1 is also highly expressed in the heart, but its precise role in cardiac function is unknown. Mutations in the integrin alpha 7 gene (ITGA7) have been reported in children with congenital myopathy. Methods and ResultsIn this study, we described skeletal and cardiac muscle pathology in Itga7(-/-) mice and 5 patients from 2 unrelated families with ITGA7 mutations. Proband in family 1 presented a homozygous c.806_818del [p.S269fs] variant, and proband in family 2 was identified with 2 intron variants in the ITGA7 gene. The complete absence of the integrin alpha 7 protein in muscle supports the ITGA7 mutations are pathogenic. We performed electrocardiography, echocardiography, or cardiac magnetic resonance imaging, and histological biopsy analyses in patients with ITGA7 deficiency and Itga7(-/-) mice. The patients exhibited cardiac dysrhythmia and dysfunction from the third decade of life and late-onset respiratory insufficiency, but with relatively mild limb muscle involvement. Mice demonstrated corresponding abnormalities in cardiac conduction and contraction as well as diaphragm muscle fibrosis. ConclusionsOur data suggest that loss of integrin alpha 7 causes a novel form of adult-onset cardiac dysfunction indicating a critical role for the integrin alpha 7 beta 1 in normal cardiac function and highlights the need for long-term cardiac monitoring in patients with ITGA7-related congenital myopathy.