Abstract
Hutchinson-Gilford progeria syndrome (HGPS) and restrictive dermopathy (RD) are two rare
genetic disorders that affect children. Complications from cardiovascular disease, including
atherosclerosis, are the most common cause of death in HGPS, which occurs at around 13
years of age. RD patients seldom live beyond their first few weeks of life, with their
characteristically tight skin causing death by restricting respiration.
These diseases are caused by mutations that cause the accumulation of prelamin A, or one of
its truncated forms, prelamin AΔ50 (progerin). The majority of HGPS cases are due to a de
novo single point mutation in exon 11 of the LMNA gene, c.1824C>T (p.G608G). This gene
encodes the A-type lamins, which are major proteins of the inner nuclear lamina. Most cases
of RD are caused by loss of function mutations in the lamin A processing zmpste24 enzyme.
Inducible and tissue specific mouse models were used to examine the mechanistic effects of
progerin. The mouse models carried an artificial minigene which encoded lamin A with the
the most common HGPS mutation. This minigene was targeted to the skin in Papers I and II
by means of the keratin 5 (K5) promoter, and to the cardiovascular system in Paper III by
means of the sm22α promoter.
In Paper I, the effects of progerin were examined with a focus on postnatal skin. Our results
showed a reduced population of keratinocytes with stem cell properties. This was associated
with downregulation of P63 (an epidermal stem cell maintenance protein) in the HGPS mice,
an effect also found with increased ageing in HGPS patients cells.
In Paper II, to test the hypothesis that the more severe symptoms in RD, as compared with
HGPS, are due to the higher levels of farnesylated lamin A produced in RD, the LMNA c.
1824C>T, p.G608G was expressed in embryonic skin causing early postnatal death, as in the
human condition. This was accompanied by increased inflammation, prolonged expression
of the lamin B receptor gene, and arrested skin development.
In Paper III a model was designed to examine the effects of progerin in the cardiovascular
system. However the expression of the reverse sm22α transactivator was barely detectable in
arteries, and this low level of expression was not sufficient to induce expression of the target
human lamin A gene.
This thesis offers novel findings about the intricate molecular disease mechanisms underlying
HGPS and RD.
