| Title: |
Most myopathic lamin variants aggregate: a functional genomics approach for assessing variants of uncertain significance |
| Authors: |
Corey L. Anderson, Emma R. Langer, Timothy C. Routes, Seamus F. McWilliams, Igor Bereslavskyy, Timothy J. Kamp, Lee L. Eckhardt |
| Source: |
npj Genomic Medicine, Vol 6, Iss 1, Pp 1-11 (2021) |
| Publisher Information: |
Nature Portfolio, 2021. |
| Publication Year: |
2021 |
| Collection: |
LCC:Medicine
LCC:Genetics |
| Subject Terms: |
Medicine, Genetics, QH426-470 |
| More Details: |
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. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
2056-7944 |
| Relation: |
https://doaj.org/toc/2056-7944 |
| DOI: |
10.1038/s41525-021-00265-x |
| Access URL: |
https://doaj.org/article/cb36d873da8841c288bf1a7f3c726247 |
| Accession Number: |
edsdoj.b36d873da8841c288bf1a7f3c726247 |
| Database: |
Directory of Open Access Journals |
