The disease is caused by a de novo heterozygous dominant mutation in the LMNA gene (encoding nuclear A-type lamins), most frequently the single base substitution c.1824C>T (p.Gly608Gly) (“classic HGPS”, in ~90% of patients). This synonymous mutation activates an alternative splice donor site in LMNA exon 11, which produces an aberrant mRNA lacking 150 nucleotides (LMNAΔ150) that translates into a truncated version of prelamin A called progerin. The C-terminal end of progerin lacks the cleavage site for the endoprotease ZMPSTE24; therefore, progerin remains irreversibly farnesylated and methylated and exerts a dominant-negative damaging effect. Progerin accumulation causes multiple alterations in cells, including aberrant nuclear morphology, severe heterochromatin loss, mislocalization and loss of chromatin-associated proteins and DNA damage repair proteins, and telomere and mitochondrial dysfunction, among other alterations, which ultimately cause cell senescence and eventually cell death.
Hutchinson-Gilford progeria syndrome (HGPS) (OMIM 176670), also known as Progeria, is an ultrarare rare (prevalence 1 in 18-20 million) genetic pediatric disorder characterized by segmental severe premature aging and early death (average lifespan 14.5 years), and for which no cure exists.
The disease is caused by a de novo heterozygous dominant mutation in the LMNA gene (encoding nuclear A-type lamins), most frequently the single base substitution c.1824C>T (p.Gly608Gly) (“classic HGPS”, in ~90% of patients).
For reasons that remain unknown and unpredictable, HGPS progression shows high inter-individual variability (eg, lifespan in HGPS patients ranges from 6 to 20 years).
While previous studies have applied several high-throughput omics modalities in progerin-expressing animal models and human cells for the unbiased identification of disease biomarkers…
