Journal article
Activating the synthesis of progerin, the mutant prelamin A in Hutchinson-Gilford progeria syndrome, with antisense oligonucleotides
Human molecular genetics, Vol.18(13), pp.2462-2471
07/01/2009
DOI: 10.1093/hmg/ddp184
PMCID: PMC2694694
PMID: 19376814
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.
Details
- Title: Subtitle
- Activating the synthesis of progerin, the mutant prelamin A in Hutchinson-Gilford progeria syndrome, with antisense oligonucleotides
- Creators
- Loren G Fong - 1 Department of MedicineTimothy A Vickers - 3 Department of Antisense Research, ISIS Pharmaceuticals, Carlsbad, CA 92008, USAEmily A Farber - 1 Department of MedicineChristine Choi - 1 Department of MedicineUi Jeong Yun - 1 Department of MedicineYan Hu - 1 Department of MedicineShao H Yang - 1 Department of MedicineCatherine Coffinier - 1 Department of MedicineRoger Lee - David Geffen School of Medicine at UCLALiya Yin - University of California, Los AngelesBrandon S.J Davies - 1 Department of MedicineDouglas A Andres - 4 Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USAH. Peter Spielmann - 4 Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USAC. Frank Bennett - 3 Department of Antisense Research, ISIS Pharmaceuticals, Carlsbad, CA 92008, USAStephen G Young - 1 Department of Medicine
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.18(13), pp.2462-2471
- DOI
- 10.1093/hmg/ddp184
- PMID
- 19376814
- PMCID
- PMC2694694
- NLM abbreviation
- Hum Mol Genet
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Publisher
- Oxford University Press
- Language
- English
- Date published
- 07/01/2009
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9984024558802771
Metrics
25 Record Views