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

J Clin Invest. 2016 Apr 1;126(4):1592-602. doi: 10.1172/JCI85908. Epub 2016 Mar 21.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alternative Splicing / drug effects*
  • Animals
  • Disease Models, Animal
  • Exons
  • Gene Knockdown Techniques
  • Humans
  • Lamin Type A / biosynthesis*
  • Lamin Type A / genetics
  • Mice
  • Mice, Transgenic
  • Mutation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Oligodeoxyribonucleotides, Antisense / genetics
  • Oligodeoxyribonucleotides, Antisense / pharmacology*
  • Progeria / drug therapy*
  • Progeria / genetics
  • Progeria / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Ribonucleoproteins / genetics
  • Ribonucleoproteins / metabolism
  • Serine-Arginine Splicing Factors


  • Lamin Type A
  • Lmna protein, mouse
  • Nuclear Proteins
  • Oligodeoxyribonucleotides, Antisense
  • RNA, Messenger
  • Ribonucleoproteins
  • SRSF2 protein, mouse
  • Serine-Arginine Splicing Factors