Most myopathic lamin variants aggregate: a functional genomics approach for assessing variants of uncertain significance

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 us...

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Autores principales:	Corey L. Anderson, Emma R. Langer, Timothy C. Routes, Seamus F. McWilliams, Igor Bereslavskyy, Timothy J. Kamp, Lee L. Eckhardt
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/cb36d873da8841c288bf1a7f3c726247
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spelling	oai:doaj.org-article:cb36d873da8841c288bf1a7f3c7262472021-12-05T12:26:31ZMost myopathic lamin variants aggregate: a functional genomics approach for assessing variants of uncertain significance10.1038/s41525-021-00265-x2056-7944https://doaj.org/article/cb36d873da8841c288bf1a7f3c7262472021-12-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00265-xhttps://doaj.org/toc/2056-7944Abstract 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.Corey L. AndersonEmma R. LangerTimothy C. RoutesSeamus F. McWilliamsIgor BereslavskyyTimothy J. KampLee L. EckhardtNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Genetics QH426-470
spellingShingle	Medicine R Genetics QH426-470 Corey L. Anderson Emma R. Langer Timothy C. Routes Seamus F. McWilliams Igor Bereslavskyy Timothy J. Kamp Lee L. Eckhardt Most myopathic lamin variants aggregate: a functional genomics approach for assessing variants of uncertain significance
description	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.
format	article
author	Corey L. Anderson Emma R. Langer Timothy C. Routes Seamus F. McWilliams Igor Bereslavskyy Timothy J. Kamp Lee L. Eckhardt
author_facet	Corey L. Anderson Emma R. Langer Timothy C. Routes Seamus F. McWilliams Igor Bereslavskyy Timothy J. Kamp Lee L. Eckhardt
author_sort	Corey L. Anderson
title	Most myopathic lamin variants aggregate: a functional genomics approach for assessing variants of uncertain significance
title_short	Most myopathic lamin variants aggregate: a functional genomics approach for assessing variants of uncertain significance
title_full	Most myopathic lamin variants aggregate: a functional genomics approach for assessing variants of uncertain significance
title_fullStr	Most myopathic lamin variants aggregate: a functional genomics approach for assessing variants of uncertain significance
title_full_unstemmed	Most myopathic lamin variants aggregate: a functional genomics approach for assessing variants of uncertain significance
title_sort	most myopathic lamin variants aggregate: a functional genomics approach for assessing variants of uncertain significance
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/cb36d873da8841c288bf1a7f3c726247
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Most myopathic lamin variants aggregate: a functional genomics approach for assessing variants of uncertain significance

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