Display options
Cite
Lindholm ME, Jimenez-Morales D, Zhu H, et al. Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms. Circ Genom Precis Med. 2021;CIRCGEN121003419doi: 10.1161/CIRCGEN.121.003419.
Lindholm, M. E., Jimenez-Morales, D., Zhu, H., Seo, K., Amar, D., Zhao, C., Raja, A., Madhvani, R., Abramowitz, S., Espenel, C., Sutton, S., Caleshu, C., Berry, G. J., Motonaga, K. S., Dunn, K., Platt, J., Ashley, E. A., & Wheeler, M. T. (2021). Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms. Circulation. Genomic and precision medicine, CIRCGEN121003419. https://doi.org/10.1161/CIRCGEN.121.003419
Lindholm, Malene E, et al. "Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms." Circulation. Genomic and precision medicine vol. (2021): CIRCGEN121003419. doi: https://doi.org/10.1161/CIRCGEN.121.003419
Lindholm ME, Jimenez-Morales D, Zhu H, Seo K, Amar D, Zhao C, Raja A, Madhvani R, Abramowitz S, Espenel C, Sutton S, Caleshu C, Berry GJ, Motonaga KS, Dunn K, Platt J, Ashley EA, Wheeler MT. Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms. Circ Genom Precis Med. 2021 Nov 22;CIRCGEN121003419. doi: 10.1161/CIRCGEN.121.003419. Epub 2021 Nov 22. PMID: 34802252.
Copy Download .nbib Format: NLM
Share it on

Circ Genom Precis Med. 2021 Nov 22;CIRCGEN121003419. doi: 10.1161/CIRCGEN.121.003419. Epub 2021 Nov 22.

Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms.

Circulation. Genomic and precision medicine

Malene E Lindholm, David Jimenez-Morales, Han Zhu, Kinya Seo, David Amar, Chunli Zhao, Archana Raja, Roshni Madhvani, Sarah Abramowitz, Cedric Espenel, Shirley Sutton, Colleen Caleshu, Gerald J Berry, Kara S Motonaga, Kyla Dunn, Julia Platt, Euan A Ashley, Matthew T Wheeler

Affiliations

  1. Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine. (M.E.L., D.J.-M., H.Z., K.S., D.A., C.Z., A.R., R.M., S.A., S.S., C.C., J.P., E.A.A., M.T.W.).
  2. Cell Sciences Imaging Facility, Stanford University School of Medicine. (C.E.).
  3. GeneMatters, San Francisco, CA (C.C.).
  4. Department of Pathology, Stanford University School of Medicine. (G.J.B.).
  5. Center for Inherited Cardiovascular Diseases, Stanford University School of Medicine. (K.S.M., K.D., J.P., E.A.A., M.T.W.).
  6. Division of Pediatric Cardiology, Department of Pediatrics, Stanford University School of Medicine. (K.S.M., K.D.).

PMID: 34802252 DOI: 10.1161/CIRCGEN.121.003419

Abstract

BACKGROUND: ACTN2 (alpha-actinin 2) anchors actin within cardiac sarcomeres. The mechanisms linking

METHODS: Patients harboring ACTN2 protein-truncating variants were identified using a custom mutation pipeline. In patient-derived iPSC-cardiomyocytes, we investigated transcriptional profiles using RNA sequencing, contractile properties using video-based edge detection, and cellular hypertrophy using immunohistochemistry. Structural changes were analyzed through electron microscopy. For mechanistic studies, we used coimmunoprecipitation for ACTN2, followed by mass-spectrometry to investigate protein-protein interaction, and protein tagging followed by confocal microscopy to investigate introduction of truncated ACTN2 into the sarcomeres.

RESULTS: Patient-derived iPSC-cardiomyocytes were hypertrophic, displayed sarcomeric structural disarray, impaired contractility, and aberrant Ca

CONCLUSIONS: Together, these data advance our understanding of the role of ACTN2 in the human heart and establish recessive inheritance of

Keywords: actinin cardiomyopathy; hypertrophy; mass spectrometry; mutation; sarcomere

Publication Types

Grant support