Altered splicing in prelamin A-associated premature aging phenotypes

Prog Mol Subcell Biol. 2006:44:199-232. doi: 10.1007/978-3-540-34449-0_9.

Abstract

Hutchinson-Gilford progeria (HGPS), a rare and severe developmental disorder characterized by features recalling premature aging, and restrictive dermopathy (RD), a neonatal lethal genodermatosis, have recently been identified as being primary or secondary "laminopathies." These are heterogeneous disorders due to altered function of lamins A/C or related proteins. In physiological conditions, mature lamin A is obtained through a series of post-translational processing steps performed on a protein precursor, prelamin A. The major pathophysiological mechanism involved in progeria is an aberrant splicing of pre-mRNAs issued from the LMNA gene, due to a de novo heterozygous point mutation, leading to the production and accumulation of truncated lamin A precursors. Aberrant splicing of prelamin A pre-mRNAs causing the production of more extensively truncated precursors is involved in the allelic disease restrictive dermopathy. Other restrictive dermopathy cases are due to the inactivation of a key enzyme involved in the maturation of lamin A precursors (ZMPSTE24). In functional terms, all these conditions share the same pathophysiological basis: intranuclear accumulation of lamin A precursors, which cannot be fully processed (due to primary or secondary events) and exert toxic, dominant negative effects on nuclear homeostasis. Most other laminopathies are due to autosomal dominant LMNA point mutations inferred to cause single amino acid substitutions. In any case, the impact of these mutations on pre-mRNA splicing has rarely been assessed. These disorders affect different tissues and organs, mainly including bone, skin, striated muscles, adipose tissue, vessels, and peripheral nerves in isolated or combined fashions, giving rise to syndromes whose severity ranges from mild to perinatally lethal. In this chapter we review the structure and functions of lamins A/C in physiological and pathological conditions, describe their known or putative roles, namely, in the pathogenesis of HGPS and RD in relation to existing animal models, and envisage possible targeted therapeutic strategies on the basis of recent research results.

Publication types

  • Review

MeSH terms

  • Aging, Premature / genetics*
  • Aging, Premature / pathology
  • Alternative Splicing*
  • Animals
  • Humans
  • Lamin Type A / genetics*
  • Phenotype*
  • Progeria / genetics
  • Progeria / pathology

Substances

  • Lamin Type A