title: Neonatal progeria: increased ratio of progerin to lamin A leads to progeria of the newborn.
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.
authors.affiliation: Universitätsklinikum Münster, Klinik für Kinder- und Jugendmedizin - Allgemeine Pädiatrie, Münster, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Reunert
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Wentzell
authors.forename: Michael
authors.initials: M
authors.lastname: Walter
authors.forename: Sibylle
authors.initials: S
authors.lastname: Jakubiczka
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.forename: Thomas
authors.initials: T
authors.lastname: Brune
authors.forename: Stephan
authors.initials: S
authors.lastname: Rust
authors.forename: Thorsten
authors.initials: T
authors.lastname: Marquardt
mesh_terms: D019588:Aging, Premature / Q000235:genetics*; D017398:Alternative Splicing; D017809:Fatal Outcome; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000235:genetics*; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011371:Progeria / Q000235:genetics*; D011498:Protein Precursors / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A