“CHildren with Inherited Platelet disorders Surveillance” (CHIPS) retrospective and prospective observational cohort ...

Genetics Of Aging Uncovered With Rare Disease Discovery

Small vessel disease (SVD) causes damage to small arteries and capillaries that reduces blood flow to sensitive organs like the eye, brain, and kidney and can be triggered by aging, high blood pressure, and genetic abnormalities. Retinal vasculopathy with cerebral leukoencephalopathy (RVCL) is an SVD caused by an inherited mutation in the TREX1 gene. It's rare, with fewer than 200 known cases worldwide. Symptoms develop between 35 and 55 and affect the liver, kidneys, eyes, and brain, leading to organ damage and failure and early death.

Scientists were aware of the link between the TREX1 gene and RVCL but not how the mutated gene caused small vessel damage. Now, a new study led by researchers from the Perelman School of Medicine at the University of Pennsylvania (Penn Medicine) and the Brain Research Institute at Niigata University, Japan, has shed light on the mutated gene's mechanism of action. And the findings may have repercussions beyond RVCL.

"It seems that accelerated DNA damage in RVCL causes the premature aging of certain cells, including the cells in the blood vessel wall," said Jonathan Miner, an associate professor of rheumatology at the Perelman School of Medicine and the study's corresponding author. "If this is the case, then targeting TREX1 could have very broad implications for the treatment of many human diseases linked to aging, including cardiovascular disease, autoimmune disorders, and cancer.

Many factors contribute to aging, one being DNA damage. DNA integrity is essential to the health of cells, tissues, and the entire organism. We can detect and repair DNA damage; this so-called 'DNA damage response' is commonly seen when our body attempts to fight off cancer. But if the damage response is prolonged and DNA damage goes unrepaired, it's thought to stop cells from growing and dividing and cause them to age prematurely. This is known as the 'DNA damage theory of aging.'

Examining RCVL models in animal and human cells, the researchers found that when both DNA strands were broken, mutation of the TREX1 gene interfered with the repair process, allowing DNA to be deleted and causing cells to stop dividing and prematurely age, which led to overall aging and organ damage.

Surprisingly, they also made a preliminary finding that RVCL patients had an increased odds ratio of breast cancer. The BRCA1 and BRCA2 genes play a critical role in DNA repair. Mutations of these genes are associated with an increased risk of breast cancer because they compromise this repair and cause the accumulation of DNA damage, increasing genome instability and cancer susceptibility. The finding that RVCL patients had high odds of developing breast cancer supports the hypothesis, the researchers say, that TREX1-caused DNA damage increases the risk of breast cancer.

The study's findings have provided insight into how RCVL might be treated, including lowering the levels of the TREX1 protein produced by the gene, correcting the mutation, or blocking the gene's DNA-damaging effects. However, the findings extend beyond RVCL because they contribute to the DNA damage theory of aging.

"One hope is that understanding the role of TREX1 in RVCL might help us uncover mechanisms that could link the TREX1 gene to a wide variety of human conditions that could also include normal aging," Miner said.

The study was published in the journal Nature Communications.

Source: Penn Medicine

African Ancestry Genes May Be Linked To Black Americans' Risk For Some Brain Disorders

A new study looks at the roles that African and European genetic ancestries can play in Black Americans' risk for some brain disorders. (TEK IMAGE/SCIENCE PHOTO LIBRARYGetty Images)

Black Americans are known to be at higher risk of some neurological disorders, and the reasons for this disparity remain unclear. Now, after examining the postmortem brains of 151 people, researchers in Baltimore have identified genes that may help explain why.

In those people, who all identified as Black or African American, the scientists analyzed the influence of two different ancestries: African and European.

They found that genes associated with African ancestry appear to affect certain brain cells in ways that could increase the risk of Alzheimer's disease and stroke.

But genes associated with European ancestry seem to influence other brain cells in ways that could increase the risk of Parkinson's disease, a disorder that is less common in Black Americans.

The study also probed whether genetic ancestry influenced neurons, which are critical to memory, movement, and thinking.

Neurons appear to play an important role in certain psychiatric disorders, including schizophrenia, which are diagnosed more frequently in Black Americans than their white counterparts.

Yet the researchers found no evidence that genetic ancestry influenced neurons. This could mean that societal factors, such as economic and psychological stress, exposure to traumatic events, and racial bias in diagnosis, account for the disparity — though the study did not include any direct measure of this possibility.

The results, published in the journal Nature Neuroscience, are a first step toward "mitigating some of the increased risk that comes along with different ancestries," says Dr. Kafui Dzirasa, an investigator and professor of psychiatry at Duke University who was an advisor to the study, but not an author.

A community effort

Black Americans have been underrepresented in most genomic studies of neurological disorders.

As a result, scientists know relatively little about whether African ancestry affects a person's risk for these disorders, or their response to a particular treatment.

This dearth of research led to the creation, in 2019, of the African Ancestry Neuroscience Research Initiative, a collaboration involving African American community leaders, the Lieber Institute for Brain Development, Duke University and Morgan State University.

One of the early challenges for the initiative was to earn the trust of Baltimore's Black residents. That meant involving prominent African American educators, business people, and church leaders, including the Rev. Alvin Hathaway, Sr., who served as pastor of Union Baptist Church until 2021.

"You had to build relationships with families and communities such that when their loved ones passed away, they were willing to donate their brains to medical research," says Dzirasa, who advises the initiative.

The Baltimore team's study is the first to come out of the effort.

Because so much brain research has focused on people who identify as white, the team decided to look only at brains from people who identified themselves as Black or African American. Each brain was donated for research by a person's next of kin.

But a person's self-identified race allowed for a wide range of genetic ancestry.

As a result of centuries of intermixing — including the rape of enslaved women and girls before 1865 — the genomes of most Black individuals contain a combination of European and African ancestry.

"We leveraged the history of the U.S. To pinpoint how European ancestry vs. African ancestry affects gene expression in the brain," says Kynon Jade Benjamin, a researcher at the Lieber Institute and at Johns Hopkins University who led the work.

Genes vs. Environment

Gene expression describes how certain genes are turned on or off in a particular cell. That process can be influenced by a person's genes, experiences, and environment.

The study was designed to minimize the differences that could be attributed to two of those factors: experience and environment. As a result, they accounted for an estimated 15% of the differences in gene expression, while genetic ancestry accounted for more than 60%.

A person's ancestry was most likely to influence gene expression in immune cells and cells that form the walls of blood vessels, Benjamin says.

The blood vessel finding could be one reason that strokes caused by a blocked artery are 50% more common in African Americans than in their white counterparts.

And the two lineages' immune cell differences could help explain why African Americans are more likely to be living with Alzheimer's dementia, but less likely to get Parkinson's disease.

Both of those disorders have been linked to an overreaction by the brain's immune cells, which results in inflammation. And those immune responses are more likely when certain genes are switched on, or "upregulated," Benjamin says.

"For Parkinson's, we saw an upregulation in European ancestry," he says. "When we looked at stroke and Alzheimer's, we saw an upregulation in the genes associated with African ancestry."

African Americans 70 and older are about twice as likely as their white counterparts to be living with Alzheimer's. But they are just half as likely to be diagnosed with Parkinson's.

"We see these health disparities, which we know are partly to do with environment," Benjamin says, "but there's also a huge genetic component."

Neurons and psychiatric disorders

The study did not offer much insight into why Black Americans are about 20% more likely than white Americans to experience serious mental health problems, including schizophrenia and depression.

These disorders are thought to involve neurons, the cells that generate electrical impulses and are known as the brain's gray matter. But the study found that ancestry had no effect on gene expression in these cells.

That could mean that a person's environment and experience, rather than their genes, play a key role when it comes to mental illness.

But Dzirasa, who has spent his career studying genes and mental illness, thinks there may be a different explanation.

In adult brains, immune cells respond to injury or infection, he says. But earlier in life, "those same brain cell types may be giving rise to psychiatric disorders."

For example, immune cells called microglia "can prevent too many brain cells from being connected with each other by sort of trimming [the connections] away," Dzirasa says. "They're almost like a gardener trimming down bonsai trees to the right shape."

Disturbances in that process, called synaptic pruning, have been linked to schizophrenia and autism spectrum disorder, Dzirasa says.

A path to precision medicine

Even though the study used self-identified race as a starting point, it also shows why racial categories are a poor indicator of a person's genetic background, Benjamin says.

A look at the overall European ancestry of each person in the study found a range from zero to more than 60 percent.

That means doctors need to look beyond race when assessing a Black person's risk for a disease like cystic fibrosis, which is most common in people of Northern European ancestry, Benjamin says.

"If a patient comes in with some particular kind of symptoms, don't rule it out just because someone is African American," he says. "At that particular gene, they could be European."

The study also shows "clearly and scientifically" why genetic research needs to be more diverse, Dzirasa says.

Finding genes that protect someone with a particular ancestry from a disease like Parkinson's could help scientists figure out how to protect all people.

Race is a social construct, not a biological one, Dzirasa says. Even so, he still notes race when glancing at a patient's chart because it does indicate something about their life experience and disease risk.

But he looks forward to an emerging approach, known as precision medicine, that doesn't look at race.

"The more optimal future is one in which we understand each person's individual genomic architecture, and then prescribe medicines based on this," Dzirasa says.

Transcript:

AILSA CHANG, HOST:

Brain disorders like Alzheimer's disease and stroke are more common in Black Americans than in white Americans. At the same time, Parkinson's disease is less common. NPR's Jon Hamilton reports on a new genetic analysis that could help explain why.

JON HAMILTON, BYLINE: Black Americans have been underrepresented in most genetic studies. So a team of researchers in Baltimore did one that included only individuals who identified as Black or African American. Kynon Jade Benjamin is a scientist at the Lieber Institute for Brain Development at Johns Hopkins University. He says the team wanted to answer a question about brain disorders.

KYNON JADE BENJAMIN: Can we tease apart anything that might be influenced by our ancestry – our genetic ancestry?

HAMILTON: To find out, the team studied cadaver brain tissue from 151 people whose next-of-kin agreed to the research. Most Black Americans have a mix of African and European genetic ancestry. Benjamin says that allowed the team to see how each of these two ancestries affected the brain.

BENJAMIN: We leverage the history of the U.S. To pinpoint, in just a Black population, how European ancestry versus African ancestry affects gene expression in the brain.

HAMILTON: Gene expression describes which genes are turned on or off in a cell. And Benjamin says a person's ancestry was most likely to influence the gene expression in immune cells.

BENJAMIN: Even though we're looking in the brain, we're seeing immune – an immune response as the things that are – seemed to be affected by genetic ancestry.

HAMILTON: Ancestry also affected gene expression in cells that line blood vessels, which might explain differences in the risk for stroke. But it did not affect neurons, the brain cells thought to play a key role in psychiatric disorders like schizophrenia. So at least in this study, ancestry did not explain why schizophrenia is diagnosed more frequently in Black Americans than white Americans. The finding with immune cells could help explain why Black Americans are more vulnerable to Alzheimer's, while their white counterparts are more likely to get Parkinson's. Benjamin says in those disorders, certain genes are more likely to be switched on or upregulated.

BENJAMIN: For, like, Parkinson's, we saw an upregulation in European ancestry. While when we looked at stroke and Alzheimer's, we saw that upregulation in the genes associated with African ancestry.

HAMILTON: Overall, inherited differences explained about 60% of the changes in gene expression. Environmental factors such as nutrition and mental stress appeared to explain another 15%. Benjamin says the study, published in the journal Nature Neuroscience, suggests that doctors need to look beyond race when assessing a person's risk for a specific disease.

BENJAMIN: If a patient comes with some kind of particular symptoms, don't rule it out just because somebody is African American 'cause at that particular gene, they could be European.

HAMILTON: The study also shows why genetic research needs to be more diverse. Dr. Kafui Dzirasa is a researcher and psychiatrist at Duke University.

KAFUI DZIRASA: This study is really important because it demonstrates, clearly, scientifically, the imperative for advancing science in a way that works for everybody.

HAMILTON: Dzirasa says understanding how ancestry can protect someone from a disease could lead to new and better treatments. He says race is a social construct, not a biological one, so it's a highly imperfect way of assessing someone's ancestry. Even so, he still notes how his patients identify, for now.

DZIRASA: The more optimal future is one in which we understand each person's individual genomic architecture and then prescribe medicines based on this.

HAMILTON: Which is the goal of an emerging approach known as precision medicine. Jon Hamilton, NPR News.

(SOUNDBITE OF KENDRICK LAMAR SONG, "SING ABOUT ME, I'M DYING OF THIRST")

Mutated TREX1 Gene Linked To Catastrophic DNA Damage And Deadly Rare Disease

TREX1 is a gene that is supposed to direct the maintenance of the entire body's DNA, but new research shows that when people are born with mutated TREX1, it causes catastrophic damage to the DNA over time, resulting in a deadly rare disease called retinal vasculopathy with cerebral leukoencephalopathy (RVCL). Published in Nature Communications, the research was led by teams at the Perelman School of Medicine at the University of Pennsylvania and the Brain Research Institute at Niigata University in Japan.

While it was already known that a mutation in TREX1 was behind RVCL, the mechanism by which it did its damage was not known. In discovering that TREX1 speeds up the typical process of DNA damage-;a process some theorize is tied to every animal's aging process-;the researchers may not have only discovered the weapon TREX1 uses on RVCL patients, but also offered insight beyond this rare disease population.

It seems that accelerated DNA damage in RVCL causes the premature aging of certain cells, including the cells in the blood vessel wall. If this is the case, then targeting TREX1 could have very broad implications for the treatment of many human diseases linked to aging, including cardiovascular diseases, autoimmune disorders, and cancer."

Jonathan Miner, MD, PhD, study's lead author, associate professor of Rheumatology at the Perelman School of Medicine

RVCL impacts about 200 people worldwide and is often misdiagnosed as lupus, multiple sclerosis, or cancer. The disease causes the breakdown of small blood vessels in the body, which can affect many organs, including the brain, eyes, kidneys, liver, and bones. Patients with the condition typically do not begin to have symptoms-;such as memory loss, partial loss of vision, and small strokes-;until their 40s or 50s. Eventually, the breakdowns can cause organ damage and failure, including brain atrophy and blindness. There is no cure or treatment, and many patients die within five to ten years of symptoms beginning.

"We're hopeful that our work will put us on the path toward improving the lives of patients with RVCL," said the other lead author of this study Taisuke Kato, PhD, an associate professor of Molecular Neuroscience at Niigata University. "With our discoveries, we feel we will be much better equipped to address what is happening within their bodies."

Studying RVCL models in animal and human cells, Miner and his colleagues explored their hypothesis that the TREX1 mutation, which shortens the gene, was causing instability within cells and damage that appears similar to breakdowns seen in radiation injuries.

They found that the mutation was interfering with a DNA repair process, which occurs when there is a break in both strands of DNA. This interruption of the process allowed DNA to be deleted, and cells prematurely aged and stopped dividing, which leads to overall premature aging and organ damage.

In addition to uncovering RVCL's primary mechanism of damage, the researchers also found that the TREX1 mutation also displayed a cell-level vulnerability that mirrors those seen in people with mutations to the BRCA1 and BRCA2 genes, which cause breast cancer. Sure enough, the authors found similar elevated rates of risk of breast cancer in patients with TREX1 mutations as in patients with mutations in the BRCA1 and BRCA2 genes.

But on top of that, the TREX1 mutation's effect on DNA damage also makes people with it more susceptible to damage from chemotherapy, the team found.

"I do worry that certain treatments may have accelerated the progression of disease in some patients," Miner said. "In many cases, chemotherapy was prescribed as a way of treating suspected 'autoimmunity' since certain chemotherapeutic agents can also be used to treat patients with systemic lupus. This was frequently employed in the treatment of RVCL in the past, and even recently by some, and we are concerned that this would actually make the disease worse."

The study's findings provide a clearer picture for the types of treatments and medicines that could be pursued for people with RVCL. They could involve lowering levels of TREX1 in the body, correcting the mutation, or just blocking the gene's DNA-damaging effects.

"Until those therapies are developed, we are working to figure out whether certain mediations already FDA-approved for the treatment of other diseases might be repurposed for RVCL or potentially impact TREX1 levels in the body overall," Miner said. "TREX1 levels increase with age in multiple tissues in all humans-;even in healthy individuals without RVCL-;and we need to understand the processes linked to this."

To that end, the study's findings extend well beyond the population of patients with RVCL because of what it may add to the DNA damage theory of aging.

"One hope is that understanding the role of TREX1 in RVCL might help us uncover mechanisms that could link the TREX1 gene to a wide variety of human conditions that could also include normal aging," Miner said.

This study was funded by the National Institutes of Health (K08AR070918, R01AI143982, R01NS131480, T32 GM007170), the Rheumatology Research Foundation, the Colton Center for Autoimmunity, the Clayco Foundation, the Penn RVCL Sisters Fund, the Japan Agency for Medical Research and Development (22ek0109424h0003), the Japan Society for the Promotion of Science (22H00466), and the Japan MHLW for Research on Intractable Disease (JP21FC1007).

Source:

Journal reference:

Chauvin, S. D., et al. (2024). Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans. Nature Communications. Doi.Org/10.1038/s41467-024-49066-7.

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