Progerin
Progerin is a truncated version of the lamin A protein involved in the pathology of Hutchinson–Gilford progeria syndrome. Progerin is most often generated by a single nucleotide polymorphism in the gene that codes for Lamin A. This mutation activates a cryptic splice site and gives rise to a form of lamin A with a deletion of 50 amino acids near the C-terminus. Approximately
80% of all Hutchinson–Gilford progeria syndrome cases are heterozygous for this deleterious single nucleotide polymorphism within exon 11 of the LMNA gene.
Lamin A constitutes a major structural component of the lamina, a scaffold of proteins found inside the nuclear membrane of a cell; progerin does not properly integrate into the lamina, which disrupts the scaffold structure and leads to significant disfigurement of the nucleus, characterized by a lobular shape. Progerin activates genes that regulate stem cell differentiation via the Notch signaling pathway.
Progerin increases the frequency of unrepaired double-strand breaks in DNA following exposure to ionizing radiation. This finding suggests that the nuclear lamina has an important role in the repair of DNA double-strand breaks.
Researchers are exploring lonafarnib as a potential pharmacological therapy against the negative effects of progerin on nuclear morphology in HGPS.
Recently, rapamycin has been shown to prevent progerin aggregates in cells and hence delay premature aging.
Progerin, which has been linked to normal aging, is produced in healthy individuals via "sporadic use of the cryptic splice site".
