Neonatal progeria: increased ratio of progerin to lamin A leads to progeria of the newborn

• Published in: European journal of human genetics : EJHG 2012-09, Vol.20 (9), p.933-937
• Main Authors: Reunert, Janine, Wentzell, Rüdiger, Walter, Michael, Jakubiczka, Sibylle, Zenker, Martin, Brune, Thomas, Rust, Stephan, Marquardt, Thorsten
• Format: Article
• Language: English
• Subjects: Age; Aging; Aging, Premature - genetics; Alternative Splicing; Amino acids; Birth; Cardiomyopathy; Cell cycle; Cerebral infarction; Children; Disease; Fatal Outcome; Fibroblasts; Fibroblasts - cytology; Fibroblasts - metabolism; Gene Expression; Genetics; Genotype; Heterozygote; Humans; Infant, Newborn; Infant, Newborn, Diseases - genetics; Intracellular; Lamin Type A - genetics; Lamin Type A - metabolism; Lamins; LMNA protein; Male; Muscular dystrophy; Mutation; Myocardial infarction; Neonates; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Patients; Phenotype; Point mutation; Progeria; Progeria - genetics; Protein Precursors - genetics; Protein Precursors - metabolism; Proteins; Severity of Illness Index; Stroke
• ISSN: 1018-4813; 1476-5438; 1476-5438
• DOI: 10.1038/ejhg.2012.36

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.