Hutchinson-Gilford Progeria Syndrome

Author: Brittany Shimanski

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare disease, associated with premature aging. It only affects 1 per 4-8 million live births across the world. It is common for people with HGPS to appear normal at birth, but then they commonly develop accelerated aging symptoms, including shortened stature, facial disproportion, thin skin, alopecia (hair loss), and osteoporosis (weak/brittle bones). Facial features of someone with HGPS may include prominent eyes, a thin nose with a beaked tip, thin lips, a small chin, and protruding ears. Though, intellectual development and development of motor skills and movement are not affected. HGPS patients are also more at risk to strokes and heart attacks. Death is common in the early teen years due to atherosclerosis (plaque buildup in the arteries).

Hutchinson-Gilford progeria syndrome was once thought to be an inherited disease from previous generations, but it is in fact not. HGPS is caused by a brand-new single gene mutation, only existent in a single generation. The mutation is on a gene called LMNA and on a piece of the gene called exon 11. The LMNA gene is the bodily code for lamins (specifically for lamin A), which are a network of fibers that help keep the nucleus of cells intact and of the correct shape. Lamins are also important replication of our DNA (helping the cell grow) and gene expression (making them important proteins for cellular function that the gene encodes).

This new specific mutation on exon 11 in the LMNA gene causes an abnormal cutting up of the genes. It causes a piece of the gene to be deleted that normally shouldn’t be. The precursor to lamin A is called prelamin A. Now, instead of the body making prelamin A, it makes a toxic product called progerin. Progerin can then not be properly processed and mature lamin A cannot be made. Many issues result from too much progerin in regards to cellular dysfunctions, such as irregular shaped nuclei, problems with DNA replication and DNA repair, problems with making the proteins that genes code for, and even cell death. The severity of symptoms of HGPS patients is related to the ratio of progerin to lamin A in cells.

Understanding why HGPS is associated with cell aging and death is still difficult for scientists as much mechanistic reasoning is unknown. It was found that progerin causes telomere loss (which protects the ends of chromosomes, containing genetic material, from deteriorating), which is known to be related to cellular aging. Various enzymes (proteins that help reactions occur) and their substrates (the molecules that bind to these enzymes) were found to be needed for the initiation of translating into proteins. Also, signaling pathways and cell division pathways related to premature aging were recognized and studied in relation to understanding cell aging in HGPS. All of this information has given scientists various ideas of how to treat HGPS patients and how to target specific parts of the disease. Different models to study this disease have been implemented, yet the understanding of HGPS and aging is still not completely clear.

There have been several different methods of developing drugs used to attempt to treat HGPS patients. The first type of drug researched is an inhibitor of farnesylation. Farnesylation is the addition of a chemical group onto the progerin during its attempted processing into what should be lamin A. Farnesylation inhibitors have been shown to control the toxicity of progerin and fix the shapes of nuclei, therefore reverting symptoms of HGPS. Another way to treat HGPS is to correct the abnormal cutting up of the gene, causing a piece to be deleted. One route is to use a small DNA molecule called an oligonucleotide that is targeted to the place of the incorrect cutting and corrects it. This resulted in reversal of symptoms by fixing various gene expressions. Another route is to change the cutting of the LMNA gene to making lamin C (just a different lamin encoded by LMNA) instead of lamin A, which can ideally decrease the levels of progerin, and fix nuclear shapes. A third way to treat HGPS is to fix the mechanism of DNA repair, so when DNA is damaged it can properly get fixed to prevent further cell damage. This was done by removing something called SUV39H1, allowing the proper cells to be degraded (the ones containing progerin), and saves the DNA repair mechanism. Though there are various methods of treating HGPS patients, no perfect treatment has been discovered. Though, as studies continue, more information about HGPS and the issues it causes in the body, specifically related to premature aging, will become known and hopefully a treatment will be implemented in the near future.

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