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- Title
Most myopathic lamin variants aggregate: a functional genomics approach for assessing variants of uncertain significance.
- Authors
Anderson, Corey L.; Langer, Emma R.; Routes, Timothy C.; McWilliams, Seamus F.; Bereslavskyy, Igor; Kamp, Timothy J.; Eckhardt, Lee L.
- Abstract
Hundreds of LMNA variants have been associated with several distinct disease phenotypes. However, genotype–phenotype relationships remain largely undefined and the impact for most variants remains unknown. We performed a functional analysis for 178 variants across five structural domains using two different overexpression models. We found that lamin A aggregation is a major determinant for skeletal and cardiac laminopathies. An in vitro solubility assay shows that aggregation-prone variants in the immunoglobulin-like domain correlate with domain destabilization. Finally, we demonstrate that myopathic-associated LMNA variants show aggregation patterns in induced pluripotent stem cell derived-cardiomyocytes (iPSC-CMs) in contrast to non-myopathic LMNA variants. Our data-driven approach (1) reveals that striated muscle laminopathies are predominantly protein misfolding diseases, (2) demonstrates an iPSC-CM experimental platform for characterizing laminopathic variants in human cardiomyocytes, and (3) supports a functional assay to aid in assessing pathogenicity for myopathic variants of uncertain significance.
- Subjects
PLURIPOTENT stem cells; HEART cells; MICROBIAL virulence; SKELETAL muscle; CARDIAC patients
- Publication
NPJ Genomic Medicine, 2021, Vol 6, Issue 1, p1
- ISSN
2056-7944
- Publication type
Article
- DOI
10.1038/s41525-021-00265-x