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Modulation of LMNA splicing as a strategy to treat prelamin A diseases
John M. Lee, … , Stephen G. Young, Loren G. Fong
John M. Lee, … , Stephen G. Young, Loren G. Fong
Published March 21, 2016
Citation Information: J Clin Invest. 2016;126(4):1592-1602. https://doi.org/10.1172/JCI85908.
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Research Article Aging Article has an altmetric score of 10

Modulation of LMNA splicing as a strategy to treat prelamin A diseases

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Abstract

The alternatively spliced products of LMNA, lamin C and prelamin A (the precursor to lamin A), are produced in similar amounts in most tissues and have largely redundant functions. This redundancy suggests that diseases, such as Hutchinson-Gilford progeria syndrome (HGPS), that are caused by prelamin A–specific mutations could be treated by shifting the output of LMNA more toward lamin C. Here, we investigated mechanisms that regulate LMNA mRNA alternative splicing and assessed the feasibility of reducing prelamin A expression in vivo. We identified an exon 11 antisense oligonucleotide (ASO) that increased lamin C production at the expense of prelamin A when transfected into mouse and human fibroblasts. The same ASO also reduced the expression of progerin, the mutant prelamin A protein in HGPS, in fibroblasts derived from patients with HGPS. Mechanistic studies revealed that the exon 11 sequences contain binding sites for serine/arginine-rich splicing factor 2 (SRSF2), and SRSF2 knockdown lowered lamin A production in cells and in murine tissues. Moreover, administration of the exon 11 ASO reduced lamin A expression in wild-type mice and progerin expression in an HGPS mouse model. Together, these studies identify ASO-mediated reduction of prelamin A as a potential strategy to treat prelamin A–specific diseases.

Authors

John M. Lee, Chika Nobumori, Yiping Tu, Catherine Choi, Shao H. Yang, Hea-Jin Jung, Timothy A. Vickers, Frank Rigo, C. Frank Bennett, Stephen G. Young, Loren G. Fong

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Figure 5

Lamin C/prelamin A splicing in mouse cells and tissues depends on SRSF2 expression.

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Lamin C/prelamin A splicing in mouse cells and tissues depends on SRSF2 ...
(A) Inactivating Srsf2 in mouse fibroblasts reduces prelamin A transcript levels and increases lamin C transcript levels without affecting total Lmna transcripts. A Srsf2fl/fl mouse fibroblast cell line was treated with adeno-Cre or adeno-LacZ. After 3 or 6 days, prelamin A and lamin C transcript levels were measured by qRT-PCR (mean ± SD). Srsf2 mRNA levels were reduced by >95% in the adeno-Cre–treated cells. (B) Western blots showing that Srsf2 inactivation in fibroblasts leads to reduced lamin A protein levels. Two Srsf2fl/fl fibroblast cell lines (cell lines 1 and 2) were treated with either adeno-Cre or adeno-LacZ. After 6 days, lamin A and lamin C levels were assessed by Western blotting. The bar graph shows changes in lamin expression (mean ± SEM) for 4 independent experiments. **P < 0.01, t test. (C) Western blots showing that an Srsf2 inactivation in the liver decreases lamin A levels and increases lamin C levels. Lamin A and lamin C protein levels were measured in isolated hepatocytes from Srsf2fl/fl mice (P23) expressing Cre in the liver (Srsf2fl/flAlb-Cre+). Actin levels were measured as a loading control. The bar graph shows the mean ± SEM for 3 mice per group. *P < 0.05.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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