Integrin α7 Mutations Are Associated With Adult‐Onset Cardiac Dysfunction in Humans and Mice

• Published in: Journal of the American Heart Association Vol. 11; no. 23; p. e026494
• Main Authors: Bugiardini, Enrico, Nunes, Andreia M., Oliveira‐Santos, Ariany, Dagda, Marisela, Fontelonga, Tatiana M., Barraza‐Flores, Pamela, Pittman, Alan M., Morrow, Jasper M., Parton, Matthew, Houlden, Henry, Elliott, Perry M., Syrris, Petros, Maas, Roderick P., Akhtar, Mohammed M., Küsters, Benno, Raaphorst, Joost, Schouten, Meyke, Kamsteeg, Erik‐Jan, van Engelen, Baziel, Hanna, Michael G., Phadke, Rahul, Lopes, Luis R., Matthews, Emma, Burkin, Dean J.
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 06.12.2022; Wiley
• Subjects: Adult; Animals; cardiomyopathy; Child; congenital muscular dystrophy; congenital myopathy; Family; Heart Diseases; Humans; integrin α7; Mice; Muscular Diseases; Original Research; congenital muscular dystrophy; integrin α7; cardiomyopathy; congenital myopathy
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.122.026494

Background Integrin α7β1 is a major laminin receptor in skeletal and cardiac muscle. In skeletal muscle, integrin α7β1 plays an important role during muscle development and has been described as an important modifier of skeletal muscle diseases. The integrin α7β1 is also highly expressed in the heart, but its precise role in cardiac function is unknown. Mutations in the integrin α7 gene ( ) have been reported in children with congenital myopathy. Methods and Results In this study, we described skeletal and cardiac muscle pathology in mice and 5 patients from 2 unrelated families with 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 gene. The complete absence of the integrin α7 protein in muscle supports the mutations are pathogenic. We performed electrocardiography, echocardiography, or cardiac magnetic resonance imaging, and histological biopsy analyses in patients with deficiency and 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. Conclusions Our data suggest that loss of integrin α7 causes a novel form of adult-onset cardiac dysfunction indicating a critical role for the integrin α7β1 in normal cardiac function and highlights the need for long-term cardiac monitoring in patients with -related congenital myopathy.