| Autor: |
Corey L. Anderson, Emma R. Langer, Timothy C. Routes, Seamus F. McWilliams, Igor Bereslavskyy, Timothy J. Kamp, Lee L. Eckhardt |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
npj Genomic Medicine, Vol 6, Iss 1, Pp 1-11 (2021) |
| Druh dokumentu: |
article |
| ISSN: |
2056-7944 |
| DOI: |
10.1038/s41525-021-00265-x |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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