Progerin

Source: Wikipedia, the free encyclopedia.

Progerin (UniProt# P02545-6) is a truncated version of 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 globular shape.[4] Progerin activates genes that regulate stem cell differentiation via the Notch signaling pathway.[5] Progerin increases the frequency of unrepaired double-strand breaks in DNA following exposure to ionizing radiation.[6] Also, overexpression of progerin is correlated with an increase in non-homologous end joining relative to homologous recombination among those DNA double-strand breaks that are repaired.[7] Furthermore, the fraction of homologous recombination events occurring by gene conversion is increased. These findings suggest that the normal untruncated nuclear lamina has an important role in the proper repair of DNA double-strand breaks.[6]

Point Mutation

c.1824 C>T (GGC -> GGT, p.Gly608Gly) is the single point nucleotide polymorphism that occurs in most patients with progeria. The mutation occurs in the region G608 in exon 11 causing the sporadic mutation resulting in the amino acid glycine GGC to an alternative version of glycine GGT known as Gly608Gly. This single nucleotide C -> T polymorphism encodes for exon 11 to delete the 50 essential amino acid groups in the maturation of Lamin A.[8] This deletion is then what causes the mutation of premature Lamin A to become the defective protein Progerin.

Premature Aging

The defective gene in HGPS Progerin has effects on accelerated aging effects due to the conformational stress Progerin has on the

DNA damage along the cellular membrane causing stress which activates the protein p53
resulting in premature cellular senescence causing the rapid aging effects you see in HGPS.

Lonafarnib

Researchers are exploring

pharmacological therapy against the negative effects of Progerin on nuclear morphology in HGPS. lonafarnib, so far is currently the only FDA approved treatment for HGPS.[10]

Other Information

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".[5][11]

References

  1. PMID 16461887
    .
  2. S2CID 4420150
    .
  3. PMID 20301300
    , retrieved 2022-04-26
  4. ^ "Anti-cancer Drugs May Hold Promise For Premature Aging Disorder". ScienceDaily. Retrieved 2022-04-26.
  5. ^
    PMID 18311132
    .
  6. ^
    PMID 27350809
    .
  7. PMID 33010688
    .
  8. PMID 30691039
    .
  9. PMID 33316938
    .
  10. PMID 33590450
    .
  11. PMID 18366013
    .
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