Progeria 101
What does HGPS stand for?
Hutchinson-Gilford Progeria Syndrome
Which gene is mutated in classic HGPS?
LMNA
The nucleus
What is the term for a stable state in which a cell stops dividing but remain alive?
Cellular senescence
Which drug used to treat HGPS is also called Zokinvy?
Lonafarnib
Progeria usually begins showing signs at which life stage
Early childhood, age ~ 1
What is the abnormal lamin A protein associated with progeria called?
Progerin
What visible change often occurs in the nuclei of progeria cells?
They become irregularly shaped, often developing bulges called nuclear blebs.
Progerin is found only in people with HGPS. T/F
False, low levels have also been detected in cells from people without HGPS
Lonafarnib inhibits which enzyme?
Farnesyltransferase, which adds farnesyl groups to proteins
"Children with progeria also experience accelerated intellectual decline". T/F
No. Not every aspect of aging is accelerated, intellectual ability is preserved
Progeria is autosomal dominant. How many altered copies of LMNA are sufficient to cause classic HGPS?
One altered copy
Progerin interferes with which sliding-clamp protein involved in DNA replication?
PCNA
Persistent DNA damage in progeria connects to which hallmark of aging?
Genomic instability
Does lonafarnib correct the LMNA mutation?
No. It targets protein modification rather than correcting the DNA sequence
Which body system develops the most life-threatening complications in progeria?
The cardiovascular system, specifically the arteries
The classic HGPS mutation activates a cryptic splice site. Which process does this disrupt?
RNA splicing, causing part of the lamin A coding sequence to be removed from the RNA
What lipid modification remain attached to progerin because it cannot undergo normal final processing?
A farnesyl group
Persistent DNA damage activates p53, which increases p21. What happens to cell division?
Cell-cycle progression is inhibited; persistent stress can lead to senescence
An experimental therapy blocks the abnormal splice site in LMNA RNA. What should happen to progerin production?
It should decrease because less progerin-producing RNA is formed
Name three physical features commonly associated with progeria
Any of: slowed growth, hair loss, loss of subcutaneous fat, tight skin, or joint stiffness
How can the classic HGPS mutation cause disease even though its codon still specifies the same amino acid?
Changes RNA splicing because of a cryptic splice site. The resulting RNA encodes a protein missing 50 amino acids, producing progerin
Why does progerin retain its farnesyl group?
Its missing segment includes the site needed for final cleavage by ZMPSTE24, so the farnesylated tail is not removed normally
Why is progeria described as a model of some aspects of aging rather than a perfect model of normal aging?
It reproduces selected aging-related changes, but its specific genetic cause and pattern of affected tissues do not represent all normal aging processes.
How does DNA base editing target the cause of HGPS differently from lonafarnib?
Base editing aims to correct the DNA mutation; lonafarnib inhibits farnesyltransferase without correcting the mutation