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Case Reports
, 20 (9), 933-7

Neonatal Progeria: Increased Ratio of Progerin to Lamin A Leads to Progeria of the Newborn

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Case Reports

Neonatal Progeria: Increased Ratio of Progerin to Lamin A Leads to Progeria of the Newborn

Janine Reunert et al. Eur J Hum Genet.

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is an important model disease for premature ageing. Affected children appear healthy at birth, but develop the first symptoms during their first year of life. They die at an average age of 13 years, mostly because of myocardial infarction or stroke. Classical progeria is caused by the heterozygous point mutation c.1824C>T in the LMNA gene, which activates a cryptic splice site. The affected protein cannot be processed correctly to mature lamin A, but is modified into a farnesylated protein truncated by 50 amino acids (progerin). Three more variations in LMNA result in the same mutant protein, but different grades of disease severity. We describe a patient with the heterozygous LMNA mutation c.1821G>A, leading to neonatal progeria with death in the first year of life. Intracellular lamin A was downregulated in the patient's fibroblasts and the ratio of progerin to lamin A was increased when compared with HGPS. It is suggestive that the ratio of farnesylated protein to mature lamin A determines the disease severity in progeria.

Figures

Figure 1
Figure 1
Photograph and X-ray of patient N and his skin (a, b), X-ray of the truncated clavicula (c), photograph of the foot and hand (d, e).
Figure 2
Figure 2
Western blot analysis with a lamin A/C antibody in a healthy control (WT), a HGPS patient (HGPS) and patient N (N). The ratio of progerin to lamin A in patient N exceeded the ratio in classical HGPS.
Figure 3
Figure 3
LMNA expression analysis in healthy controls (WT), progeria patients (HGPS) and patient N (N). Expression of full-length lamin A relative to WT 1 (a) and the ratio of progerin to full-length lamin A relative to HGPS 1 (b) are shown.
Figure 4
Figure 4
A schematic model for lamin A and progerin splicing. Four mutations in LMNA leading to the usage of the identical cryptic splice site, resulting in a truncated, farnesylated protein. The mutation c.1821G>A leading to the neonatal progeroid phenotype in patient N is tagged in red.

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