Progeria pathophysiology

It is thought that Hutchinson-Gilford progeria is the result due to mutation in LMNA gene.

• It is understood that Hutchinson-Gilford progeria is the result due to mutation in LMNA gene.^[1]

Genes involved in the pathogenesis of Hutchinson-Gilford progeria syndrome (HGPS) include:^[2]

LMNA Gene

Classic Hutchinson-Gilford progeria syndrome

• The location of the Hutchinson-Gilford progeria syndrome (HGPS) gene was at chromosome 1q.^[3][4]
• A single nucleotide substitution in the lamin A/C gene LMNA(c.1824C>T [p.Gly608Gly]) results in classic HGPS.^[5][6][7]
• The mutation does not change the position of glycine at 608 in protein chain.
• De novo dominant mutation in the LMNA gene causes classic HGPS.
• A single de novo dominant mutation at C to T pathogenic variant which is located at exon 11, C1824T of the LMNA gene results in activation of a cryptic splice donor site.^[8]
• Now at cryptic splice donor site there is formation of a messenger RNA with a 150-nucleotide internal deletion near the C-terminus of the chain.
• The resultant of the mutation leads to formation of short lamin A protein which is called progerin.
• Progerin has a 50-amino acid internal deletion along with CAAX box farnesylation site due to de novo dominant mutation.
• Now the progerin which has 50-amino acid misses the cleave site, due to internal deletion which results in continuous farnesylation which in turn results in progerin anchored to the nuclear envelope.^[9]
• This continuous farnesylation thought be the cause of the disease and results in following changes:
  • Nuclear blebbing
  • Disorganized heterochromatin
  • Dysregulated gene transcription
• This whole unexpected sequences in the cell leads to genomic instability and may leads to premature aging and disease in Hutchinson-Gilford progeria syndrome.^[10]
• And it is also thought that in Hutchinson-Gilford progeria syndrome telomere length is decreased gradually.^[11]

• The cause of atypical progeria syndromes is almost similar to Classic Hutchinson-Gilford progeria syndrome except the mutations are mostly occurs in intron 11 of the LMNA gene where as in Classic Hutchinson-Gilford progeria the mutations occurs in c.1824C>T [p.Gly608Gly].^[12][13]

Template:WH Template:WS