Activating the synthesis of progerin, the mutant prelamin A in Hutchinson-Gilford progeria syndrome, with antisense oligonucleotides

Loren G. Fong, Timothy A. Vickers, Emily A. Farber, Christine Choi, Ui Jeong Yun, Yan Hu, Shao H. Yang, Catherine Coffinier, Roger Lee, Liya Yin, Brandon S.J. Davies, Douglas A. Andres, H. Peter Spielmann, C. Frank Bennett, Stephen G. Young

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is caused by point mutations that increase utilization of an alternate splice donor site in exon 11 of LMNA (the gene encoding lamin C and prelamin A). The alternate splicing reduces transcripts for wild-type prelamin A and increases transcripts for a truncated prelamin A (progerin). Here, we show that antisense oligonucleotides (ASOs) against exon 11 sequences downstream from the exon 11 splice donor site promote alternate splicing in both wild-type and HGPS fibroblasts, increasing the synthesis of progerin. Indeed, wild-type fibroblasts transfected with these ASOs exhibit progerin levels similar to (or greater than) those in fibroblasts from HGPS patients. This progerin was farnesylated, as judged by metabolic labeling studies. The synthesis of progerin in wild-type fibroblasts was accompanied by the same nuclear shape and gene-expression perturbations observed in HGPS fibroblasts. An ASO corresponding to the 5′ portion of intron 11 also promoted alternate splicing. In contrast, an ASO against exon 11 sequences 5′ to the alternate splice site reduced alternate splicing in HGPS cells and modestly lowered progerin levels. Thus, different ASOs can be used to increase or decrease 'HGPS splicing'. ASOs represent a new and powerful tool for recreating HGPS pathophysiology in wild-type cells.

Original languageEnglish
Pages (from-to)2462-2471
Number of pages10
JournalHuman Molecular Genetics
Volume18
Issue number13
DOIs
StatePublished - 2009

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Grants AR050200, HL76839, HL86683, GM66152, a March of Dimes grant 6-FY2007-1012, and an Ellison Medical Foundation Senior Scholar Award. Funding to pay the Open Access charge was provided by the National Institutes of Health.

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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