Screen Readers Skip to Content

Progeria: Helping Young Patients with Old Hearts

Published: 2014-05-20 - Updated: 2022-06-24
Author: University of Maryland | Contact: umd.edu
Peer-Reviewed Publication: N/A

Synopsis: Racing the clock to help young patients with old hearts UMD study of prematurely aging children may help explain the effects of normal aging. Hutchinson-Gilford progeria syndrome, HGPS, progeria syndrome, is a sporadic genetic disorder where symptoms resembling aspects of aging are manifested at a very early age. Progeria is one of several progeroid syndromes. Researchers think that after losing so much smooth muscle tissues, the arteries are easily damaged by mechanical stresses such as blood pressure, making them vulnerable to failure in the form of coronary artery disease or strokes.

advertisements

Definition

Hutchinson-Gilford Progeria Syndrome (Progeria)
Hutchinson-Gilford Progeria Syndrome, also known as Progeria, is a specific type of progeroid syndrome. Progeroid syndromes are a group of diseases that causes individuals to age faster than usual, making them appear older. Children with progeria usually develop the first symptoms during their first few months. Affected children typically look normal at birth and early infancy but grow more slowly than other children and do not gain weight at the expected rate (failure to thrive). They develop a characteristic facial appearance, including prominent eyes, a thin nose with a beaked tip, thin lips, a small chin, and protruding ears. The earliest symptoms may include a failure to thrive and a localized scleroderma-like skin condition. Patients born with progeria typically live to mid-teens or early twenties.

Main Digest

Children with progeria, a rare disorder that causes premature aging, die in their teens of ailments that are common in octogenarians: heart failure and stroke. Kan Cao, an assistant professor of cell biology and molecular genetics, urgently wants to help find a cure. Cao and her colleagues have taken a big step in that direction, showing that a toxic protein destroys muscle cells inside the patients' arteries. The researchers suspect the damaged arteries are thus primed for failure.

This article is part our digest of 96 publications relating to Pediatric Health Concerns that include:

Hutchinson-Gilford progeria syndrome, HGPS, progeria syndrome, is a sporadic genetic disorder where symptoms resembling aspects of aging are manifested at a very early age. Progeria is one of several progeroid syndromes. The disorder has a meager incidence rate, occurring in an estimated 1 per 8 million live births. Those born with progeria typically live to their mid-teens or early twenties. It is a genetic condition that occurs as a new mutation and is rarely inherited, as patients usually do not live to reproduce. Although the term progeria applies strictly to all diseases characterized by premature aging symptoms and is often used, it is often applied specifically to Hutchinson-Gilford progeria syndrome (HGPS).

University of Maryland Asst. Prof. Kan Cao (front row, center left) and her research team met with progeria patients like Devin Scullion (front row center), age 16, at the Progeria Research Foundation International Workshop in April 2013. The fatal genetic disorder causes children to age prematurely and die of heart attacks or strokes. "It's a lot of motivation for us to work quickly," said Cao. Photo Credit: Courtesy of Kan Cao
University of Maryland Asst. Prof. Kan Cao (front row, center left) and her research team met with progeria patients like Devin Scullion (front row center), age 16, at the Progeria Research Foundation International Workshop in April 2013. The fatal genetic disorder causes children to age prematurely and die of heart attacks or strokes. "It's a lot of motivation for us to work quickly," said Cao. Photo Credit: Courtesy of Kan Cao

The researchers conducted their experiments on smooth muscle cells that they genetically engineered.

"This gives us a very good model for testing drugs to treat progeria," said Cao, senior author of a research article published in the May 19, 2014 online early edition of the Proceedings of the National Academy of Sciences. "And it may help us understand how cardiovascular disease develops in people aging normally."

Progeria is extremely rare - about 100 patients worldwide have been diagnosed - and always fatal at an early age. Patients typically die around age 13. The disorder is difficult to study because patients are so few, and their rapid decline mostly affects internal organs. That makes the effects hard to track without invasive testing, from which researchers want to spare the young patients.

Until now, researchers didn't know what mechanisms might be causing the patients' deaths. They knew a genetic mutation makes patients' cells produce progerin, a toxic form of a protein that, in healthy people, forms the skeletal structure of cell nuclei. In previous studies, Cao and others found that progerin builds up in the cells of older adults, suggesting that it is also linked to normal aging. But progerin's effects on smooth muscle cells were unknown before this study.

Studies in mice with a genetically engineered form of progeria found the animals lost most of the smooth muscle cells in their large arteries. This muscle type, involved in the involuntary movement, is in the lining of many internal organs, including blood vessels.

Cao's team couldn't obtain human smooth muscle cells from progeria patients for their study because the process would be too invasive, so they used induced pluripotent stem cells - adult cells reprogrammed to behave like embryonic stem cells and develop into a variety of cell types.

In a first for a progeria study, the researchers induced skin cells from progeria patients and normal adults to develop into smooth muscle cells, then compared cell-reproduction and decay in healthy cells with those same processes in cells containing the progeria mutation. Both sets of smooth muscle cells began multiplying, but after two weeks, the progeria cells leveled off, as many cells were reproducing. The researchers discovered that the progeria cells accumulated toxic progerin and had abnormally low levels of PARP-1, a protein that is important in repairing cell damage.

Cells constantly repair damage to their DNA, Cao explained, and they have several ways to get the job done. When one strand in the DNA double helix breaks, cells usually use the unbroken strand as a template to make a perfect copy. PARP-1 is supposed to sense the break and start this repair process. In the study's normal smooth muscle cells, that's what happened.

But sometimes a cell splices two broken DNA strands together. If the right two strands reconnect, the cells resume normal reproduction, splitting to form two new daughter cells in mitosis. But those cells can't successfully split if the repair isn't right.

Seen through a microscope, these color-enhanced skin cells from progeria patients have been induced to become smooth muscle cells, some with abnormalities such as double nuclei. Picture Credit: Haoyue Zhang
Seen through a microscope, these color-enhanced skin cells from progeria patients have been induced to become smooth muscle cells, some with abnormalities such as double nuclei. Picture Credit: Haoyue Zhang

In this study, the smooth muscle cells created from progeria patient skin cells with high levels of progerin and low levels of PARP-1 did not use the more accurate repair method. Instead, they spliced together segments of DNA that happened to be nearby and usually got the sequence wrong.

After the faulty repairs, these cells could not split their contents evenly during mitosis. Some cells kept trying to divide and eventually died trying, in a phenomenon called "mitotic catastrophe." Others failed to divide and ended up as one cell with two nuclei.

Researchers think that after losing so much smooth muscle tissues, the arteries are easily damaged by mechanical stresses such as blood pressure, making them vulnerable to failure in the form of coronary artery disease or strokes. They'll test that in the next phase of their research and will try to determine why progeria cells do not use the best pathway for repairing DNA damage. They also plan to use the smooth muscle cells derived from human-induced pluripotent stem cells to test new treatments for progeria.

Cao, who has developed friendships with some progeria patients, took her research team, which includes three UMD undergraduate students, to a 2013 Progeria Research Foundation workshop where they met progeria patients.

"The students began thinking, 'My research is so important for the families.' It's a lot of motivation for them," Cao said, "and a lot of pressure for all of us to work quickly."

This research was supported by the National Institute on Aging (NIA) of the National Institutes of Health (NIH) under Award No. R00AG029761. The content of this article does not necessarily reflect the views of the NIH.

The research paper "Mechanisms controlling the smooth muscle cell death in progeria via down-regulation of Poly (ADP-ribose) polymerase 1," by Haoyue Zhang, Zheng-Mei Xiong, and Kan Cao, was published online May 19, 2014, in Early Edition of the Proceedings of the National Academy of Sciences.

Primary Information Source(s):

Progeria: Helping Young Patients with Old Hearts | University of Maryland (umd.edu). Disabled World makes no warranties or representations in connection therewith. Content may have been edited for style, clarity or length.

Post to Twitter Add to Facebook

Disabled World is an independent disability community established in 2004 to provide disability news and information to people with disabilities, seniors, their family and/or carers. See our homepage for informative news, reviews, sports, stories and how-tos. You can also connect with us on Twitter and Facebook or learn more about Disabled World on our about us page.

advertisements

Disabled World provides general information only. The materials presented are never meant to substitute for professional medical care by a qualified practitioner, nor should they be construed as such. Financial support is derived from advertisements or referral programs, where indicated. Any 3rd party offering or advertising does not constitute an endorsement.


Cite This Page (APA): University of Maryland. (2014, May 20). Progeria: Helping Young Patients with Old Hearts. Disabled World. Retrieved August 10, 2022 from www.disabled-world.com/health/pediatric/progeria.php

Permalink: <a href="https://www.disabled-world.com/health/pediatric/progeria.php">Progeria: Helping Young Patients with Old Hearts</a>