Most myopathic lamin variants aggregate: a functional genomics approach for assessing variants of uncertain significance.
NPJ Genom Med
; 6(1): 103, 2021 Dec 03.
Article
in En
| MEDLINE
| ID: mdl-34862408
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
NPJ Genom Med
Year:
2021
Document type:
Article
Affiliation country:
United States
Country of publication:
United kingdom