An encouraging progress report on the treatment of progeria and its implications for atherogenesis.

Abstract

There are no known human genetic syndromes that faithfully accelerate all of the common phenotypes associated with aging, but there are several striking disorders with multiple features (segmental progeroid syndromes). The suffix -oid is conceptually important, because it leaves open the possibility that the underlying mechanisms may differ to some extent from what is considered the usual pathogenesis. Two canonical examples are the Werner syndrome and the Hutchinson-Gilford Progeria Syndrome (HGPS). In both disorders, atherosclerosis is a particularly striking feature, causing the majority of deaths, usually via a myocardial infarction (although cancer is also a common cause of death in Werner syndrome, a later-onset disorder). Werner syndrome is an autosomal recessive disorder due to null mutations at a member of the RecQ family of DNA helicases and is associated with accelerated clonal senescence of somatic cells and genomic instability.1 HGPS is caused by a specific class of autosomal dominant mutations in lamin A, a component of the nuclear membrane. The causative mutations result in the synthesis of large amounts of an alternatively spliced toxic isoform known as progerin2–4; it is thus a gain-of-function mutation. Article see p 27 During the maturation of prelamin A, a farnesyl group is added to a cysteine residue at the C terminus and subsequently removed by a proteolytic enzyme, Zmpste24, to produce mature lamin A. In progerin, the proteolytic site for Zmpste24 is deleted because of a cryptic splice site generated by the mutation.2,3 A mouse model expressing the nonfarnesylated progerin exhibited near-normal phenotypes, …