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.1824C4T 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.1821G4A, 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.

New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update

“…Indeed, double knock out Zmpste24 À/ À Lmna þ / À mice were phenotypically entirely normal, lacking all disease features, compared with Zmpste24 À/ À mice. 38,39 Finally, Moulson et al 34 and Reunert et al 40 found larger amounts of progerin in neonatal forms of progeria compared with several classic ones and, conversely, lower progerin accumulation was observed in mild progeria/atypical Werner syndromes. 41 RD samples are extremely rare, moreover primary RD fibroblasts are not easy to maintain in culture, because of their intrinsic pathology.…”

Truncated prelamin A expression in HGPS-like patients: a transcriptional study

“…11,[14][15][16]21,22 Using specific macros on ImageJ, we then analyzed the ratio of abnormal nuclei, based on DAPI staining in at least 100 cells, for patients 1 and 2, an HGPS patient and a healthy control. No differences were observed between patients' cells regarding the circularity (0.83 for HGPS, 0.78 for P1 and 0.80 for P2) but all patients presented a significantly higher level of circular nuclei in contrast to control cells (0.69% for control).…”

“…[8][9][10] Other LMNA-dominant mutations have been associated with the production of progerin or other deleted prelamin A isoforms (prelamin AΔ35 and prelamin AΔ90). [11][12][13][14][15][16] We enrolled eight patients, including two sibs and a parent of a family in which the disease segregated on an autosomal dominant basis, carrying four different LMNA mutations affecting prelamin A splicing. The aim of our study was to explore in detail the transcriptional prelamin A-/lamin C-expression patterns associated to the different mutations, in either lymphoblastoid or fibroblast cell lines of the patients.…”

Genetics of aging, progeria and lamin disorders

“…This study challenged the concept of only lamin A mutations to be responsible for causing HGPS. Another report revealed an additional heterozygous mutation in LMNA gene G1821A causing neonatal progeria [58]. These reports are thus suggestive of the existence of varied forms of point mutations in LMNA gene that can also result in progeroid phenotypes.…”