mutations

Dozens of COVID virus mutations arose in man with longest known case, research finds

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Dozens of COVID virus mutations arose in man with longest known case

An immune-compromised man with a year-and-a-half-long COVID infection served as a breeding ground for dozens of coronavirus mutations, a new study discovered.

Worse, several of the mutations were in the COVID spike protein, indicating that the virus had attempted to evolve around current vaccines, researchers report.

“This case underscores the risk of persistent SARS-CoV-2 infections in immunocompromised individuals, as unique SARS-CoV-2 viral variants may emerge,” said the research team led by Magda Vergouwe. She’s a doctoral candidate with Amsterdam University Medical Center in The Netherlands.

The patient in questioned endured the longest known COVID infection to date, fighting with the virus for 613 days before dying from the blood disease that had compromised his immune system, researchers said.

Immune-compromised patients who suffer persistent infections give the COVID virus an opportunity to adapt and evolve, the investigators explained.

For instance, the omicron variant is thought to have emerged in an immune-compromised patient initially infected with an earlier form of COVID, researchers said.

In this latest report, the man was admitted to Amsterdam University Medical Center in February 2022 with a COVID infection at age 72, after he’d already received multiple vaccinations.

He suffered from myelodysplastic and myeloproliferative overlap syndrome, a disease in which the bone marrow makes too many white blood cells, according to the U.S. National Cancer Institute.

Following a stem cell transplant, the man also had developed lymphoma, a cancer of the white blood cells, researchers said.

A drug he took for lymphoma, rituximab, depleted all the immune cells that normally produce antibodies for COVID, they added.

To clear his COVID, the man received a monoclonal antibody cocktail that ultimately proved ineffective.

In fact, gene sequencing showed that the coronavirus started mutating to evade the antibodies he’d received, a step that could have potentially undermined the effectiveness of the treatment in others, researchers said.

Gene sequencing of 27 nasal specimens taken from the man revealed more than 50 mutations in the COVID virus, including variants with changes in the spike protein targeted by vaccines.

“The prolonged infection has led to the emergence of a novel immune-evasive variant due to the extensive within-host evolution,” researchers said.

Such cases pose a “potential public health threat of possibly introducing viral escape variants into the community,” they added.

However, they noted that there had been no documented transmission of any COVID variants from the man into other people.

The researchers will present their findings at the European Society of Clinical Microbiology and Infectious Diseases meeting next week in Barcelona. Findings presented at medical meetings should be considered preliminary until published in a peer-reviewed journal.

Scientists Unveil Enzymes Driving Cancer Mutations

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DNA sequence with colored letters on black background containing mutation

Researchers at the University of California, Irvine (UCI), have uncovered the significant roles of two enzymes, APOBEC3A and APOBEC3B, in creating mutations within cancer genomes, opening up new avenues for developing targeted intervention strategies in cancer treatment.

Reporting in Nature Communications, the study highlights how these enzymes modify the DNA in tumor cells, leading to mutations associated with a worse prognosis for patients.

“It’s critical to understand how cancer cells accumulate mutations leading to hot spots that contribute to disease progression, drug resistance and metastasis,” said Rémi Buisson, the study’s corresponding author and an assistant professor of biological chemistry at UCI.

“Both APOBEC3A and APOBEC3B were known to generate mutations in many kinds of tumors, but until now we did not know how to identify the specific type caused by each. This finding will allow us to develop novel therapies to suppress mutation formation by directly targeting each enzyme accordingly.”

For their research, the team used a novel method to characterize the DNA sequences targeted by the enzymes, discovering that APOBEC3A and APOBEC3B do not recognize the same DNA sequences and structures within cancer genomes—a revelation that could lead to more personalized treatments.

The enzymes in question are known for their role in catalyzing the conversion of cytosine to uracil bases in the DNA—a process that can lead to harmful mutations in cells. Interestingly, in the experiments APOBEC3A showed a preference for single-stranded DNAs, especially those forming stem-loop secondary structures, while APOBEC3B selectively targeted distinct DNA stem-loop structures.

The study introduces “Oligo-seq,” an in vitro sequencing-based method that identifies specific sequence contexts that promote APOBEC3A and APOBEC3B activity. Using this method, the researchers were able to demonstrate that the base-conversion activity of these enzymes is highly influenced by the sequences surrounding the targeted base, as well as the structural features of APOBEC3B and APOBEC3A responsible for their substrate preferences.

The researchers believe, that the discovery that APOBEC3A and APOBEC3B generate distinct mutation landscapes in cancer genomes based on their unique substrate selectivity has vast implications, paving the way for developing novel therapies that could prevent these mutations from forming, potentially suppressing tumor evolution and improving patient outcomes.

“The next steps are to investigate whether mutations caused by these enzymes lead to various types of therapy resistance. It’s also critical to identify molecules that inhibit APOBEC3A and APOBEC3B to prevent mutations from forming,” Buisson explained, offering hope for more effective cancer therapies that can suppress mutation formation and, consequently, slow disease progression.

Omicron’s Mutations Impaired Vaccine Effectiveness, CDC Says

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Almost 40% of people hospitalized in the US with the Covid subvariant that circulated this spring were vaccinated and boosted, highlighting how new strains have mutated to more readily escape the immunity offered by current shots.

The findings from scientists at the US Centers for Disease Control and Prevention underscore the importance of having Covid shots that are better at targeting omicron subvariants. 

From the end of March through May, when the omicron BA.2 and BA.2.12.1 subvariants were dominant in the US, weekly hospitalization rates increased for all adults — with those over 65 hit the hardest. Even so, the total number of hospitalizations remained much lower than when the delta variant was rampant last fall. 

The overall number of hospitalizations is an important point, said Abraar Karan, an infectious disease doctor at Stanford University.

“When you look at who’s hospitalized, it’s much more likely that they will have been vaccinated because so many people are vaccinated now,” Karan said. “The real comparison is how many hospitalizations do we have now versus in the past when people were not vaccinated or not up-to-date with boosters.”

CDC scientists found that vaccines and boosters did a better job of keeping people with delta infections out of the hospital than those with later variants. Effectiveness decreased slightly with the BA.1 variant, then changed significantly with BA.2 — with a much greater share of hospitalized adults who had been vaccinated with at least one booster. 

Immunity from vaccines starts to wane within six months, so staying up-to-date with shots is key to being fully protected. Fewer than half of Americans have gotten a booster shot.

Adults with at least two booster shots fared better than other people when BA.2 was dominant. The majority of those admitted to the hospital also had at least one underlying condition. Unvaccinated adults were more than three times as likely to be hospitalized, but breakthrough infections still represented a significant number of the severe Covid cases, the data show.

US regulators have pushed Moderna Inc., Pfizer Inc. and BioNTech SE to expedite development of omicron-specific boosters for a September rollout. The drugmakers this week submitted early data to the US Food and Drug Administration seeking emergency clearance for updated shots that target the BA.4 and BA.5 virus strains. Scientists and vaccinemakers are already beginning to look toward next-generation shots that may provide longer-lasting protection against more variants. 

The new report’s findings also indicate that along with vaccination, other pharmaceutical and non-pharmaceutical measures should be used by those at highest risk of getting Covid. That includes easy access to therapeutics such as Pfizer’s antiviral drug Paxlovid and Gilead Sciences’ remdesivir, as well as AstraZeneca’s Evusheld for immunocompromised people. Scientists also note that wearing a mask can help guard the wearer from getting sick.  

Though the number of Covid deaths is the lowest it has been since last July, the US continues to see hundreds of deaths each day from Covid, CDC data show.

Many Paths to Failure

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Researchers find heart failure arises from mutations in numerous distinct genes

Microscopy shows cells in green and nuclei in blue

Microscope images of healthy heart tissue (left) and diseased heart tissue (right). Cell boundaries are stained in green, nuclei in blue, and heart muscle in gray. Images: Anissa Viveiros and Gavin Oudit/University of Alberta

Heart failure is a common and devastating disorder for which there is no cure. Many conditions that make it difficult for the heart to pump blood—such as dilated cardiomyopathy and arrhythmogenic cardiomyopathy—can lead to heart failure, but treatments for patients with heart failure do not take these distinct conditions into account.

Investigators from Harvard Medical School and Brigham and Women’s Hospital set out to identify molecules and pathways that may contribute to heart failure, with the aim of informing more effective and personalized treatments.

Using single nucleus RNA sequencing, or snRNAseq, to gain insight into the specific changes that occur in different cell types and cell states, the team made several surprising discoveries.

They found that while there are some shared genetic signatures, others are distinct, providing new candidate targets for therapy and predicting that personalized treatment could improve patient care. Results were published online August 4 in Science.

“Our findings hold enormous potential for rethinking how we treat heart failure and point to the importance of understanding its root causes and the mutations that lead to changes that may alter how the heart functions,” said co-senior author Christine Seidman, the Thomas W. Smith Professor of Medicine and professor of genetics in the Blavatnik Institute at HMS and director of the Cardiovascular Genetics Center at Brigham and Women’s.

“This is fundamental research, but it identifies targets that can be experimentally pursued to propel future therapeutics,” she said. “Our findings also point to the importance of genotyping. Not only does genotyping empower research but it can also lead to better, personalized treatment for patients.”

Team effort

black and white video of a beating heart
An echocardiogram shows abnormal heart structures and function—notably enlarged left atria and ventricle and reduced contraction in the ventricle—in a patient with dilated cardiomyopathy.

Seidman and Jonathan Seidman, the Henrietta B. and Frederick H. Bugher Foundation Professor of Genetics at HMS, collaborated with an international team.

To conduct their study, the Seidmans and colleagues analyzed samples from 18 control and 61 failing human hearts from patients with dilated cardiomyopathy, arrhythmogenic cardiomyopathy, or an unknown cardiomyopathy disease.

The human heart is composed of many different cell types, including cardiomyocytes (beating heart cells), fibroblasts (which help form connective tissue and contribute to scarring), and smooth muscle cells. The team used single nucleus RNA sequencing to look at the genetic readouts from individual cells and determine cellular and molecular changes in each distinct cell type.

From these data, the team identified 10 major cell types and 71 distinct transcriptional states.

They found that in the tissue from patients with dilated or arrhythmogenic cardiomyopathy, cardiomyocytes were depleted while endothelial and immune cells were increased. Overall, fibroblasts did not increase but showed altered activity.

Analyses of multiple hearts with mutations in certain disease genes—including TTN, PKP2, and LMNA—uncovered molecular and cellular differences as well as some shared responses.

The team also leveraged machine learning approaches to identify cell and genotype patterns in the data. This approach further confirmed that while some disease pathways converged, differences in genotype promoted distinct signals, even in advanced disease.

The authors note that future studies are needed to further define the molecular underpinnings of cardiomyopathies and heart failure across sex, age, and other demographics as well as across different areas of the heart. The team has made its datasets and platform freely available.

“We could not have done this work without sample donations from patients,” said Christine Seidman. “Our goal is to honor their contributions by accelerating research and making our work available so that others can continue to advance what we understand about disease, improve treatment, and work on strategies to prevent heart failure.”

Study shows more patients with ALS have genetic origin than previously thought

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DNA illustration.

Investigators Also Find That ALS Patients With Mutations in Multiple Genes Experience Earlier Disease Onset

Genetics may play a larger role in causing amyotrophic lateral sclerosis (ALS) than previously believed, potentially accounting for more than one-third of all cases, according to one of the most comprehensive genetic studies to date of patients who suffer from the condition.

The study, conducted by investigators at Cedars-Sinai and Washington University in St. Louis, also showed that patients with defects in two or more ALS-associated genes experience disease onset about 10 years earlier than patients with single-gene mutations.

“These findings shed new light on the genetic origins of ALS, especially in patients who had no prior family history of the disease,” said Robert H. Baloh, MD, PhD, director of neuromuscular medicine in the Department of Neurology and director of the ALS Program at Cedars-Sinai. Baloh is senior author of the study, published online in Annals of Neurology.

Typically, researchers classify 90 percent of ALS cases as “sporadic,” meaning they occur in patients without a family history of the disease. In their study, however, the researchers found a significant degree of genetic involvement in patients with no family history. Examining DNA from 391 individuals, they identified numerous new or very rare ALS gene mutations in such people. Added to the 10 percent of cases already known to be genetic because of family history, the study suggested that more than one-third of all ALS could be genetic in origin.

Baloh said the presence of the new and rare mutations, found among 17 genes already known to be associated with ALS, does not necessarily mean they all cause the disease. But they are considered likely suspects — especially in combination. ALS often is caused by well-known defects in single genes, but recent studies have suggested that some cases could be brought on by the simultaneous occurrence of two or more “lesser” genetic defects. In theory, each mutation alone might be tolerated without initiating disease, but in combination they exceed the threshold required for disease development.

This study strengthens that possibility: Fifteen patients — nine of whom had no previous family history of ALS — had mutations in two or more ALS-associated genes. The research also takes an important next step, showing that multiple genetic defects can influence the way disease manifests in individual patients. Those with mutations in two or more genes had onset about 10 years earlier than those with defects in only one gene.

Matthew B. Harms, MD, assistant professor of neurology at Washington University and co-corresponding author of the article, said that unknown factors still accounted for the majority of ALS cases.

“This tells us that more research is needed to identify other genes that influence ALS risk, and that ultimately, individuals may have more than one gene contributing toward developing disease,” Harms said.

ALS is an incurable, virtually untreatable neurodegenerative disease that attacks motor neurons — nerve cells responsible for muscle function — in the brain and spinal cord. It causes progressive weakness and eventual failure of muscles throughout the body; patients typically survive three to five years after onset.

Investigators in this study used new-generation technology that quickly and efficiently determines the organizational structure of large numbers of genes. They expect this and similar research to usher in personalized medicine in ALS that will allow healthcare teams to analyze a patient’s entire genetic makeup and deliver gene-specific therapies to correct detected defects. Cedars-Sinai researchers recently conducted a disease-in-a-dish study with cells from patients with defects in a gene that commonly causes ALS. Using small segments of genetic material to target the defects, they showed that this type of gene therapy can improve neurons from patients with the disease.

These individualized-treatment studies recently received a $1.6-million boost from the ALS Association, which awarded the funds to the Cedars-Sinai Board of Governors Regenerative Medicine Institute as part of an initial distribution of money raised by the ALS Ice Bucket Challenge. With this funding, investigators will employ a specialized stem cell process to create motor neurons from a large number of patients with ALS.

ATRX mutation possible biomarker for rare neuroendocrine tumors

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A somatic mutation in the ATP-dependent helicase, or ATRX, gene — recently demonstrating potential as a molecular marker for aggressive brain tumors — could also serve as a biomarker for rare neuroendocrine tumors, according to research published in Nature Communications.

“We have identified, for the first time, somatic ATRX mutations in pheochromocytomas and paragangliomas,” Katherine Nathanson, MD, of the division of translational medicine and human genetics, department of medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, told Endocrine Today.

Kate Nathanson

Katherine Nathanson

Although typically benign, pheochromocytomas and paragangliomas (PCC/PGL) turn very aggressive on becoming malignant, according to a press release.

“In our data set, they appear to be associated with more aggressive disease, but other studies should be done for external validation,” Nathanson said.

Inherited mutated genes, including VHL and RET, have been linked to the tumors forming in the center of the adrenal glandor among the nerve ganglia, but little is known about the somatic genetic changes leading to tumorigenesis, according to the release.

“In the future, somatic ATRX mutations may be identified through tumor testing, and be a biomarker of aggressive disease in this tumor type,” Nathanson said.

Nathanson, with Lauren Fishbein, MD, PhD, of the division of endocrinology, diabetes and metabolism at the Perelman School of Medicine, and colleagues used whole-exome sequencing on a set of 21 germline DNA samples of sporadic or inherited PCC/PGL; these are the solid tumor type most frequently associated with an inherited susceptibility syndrome.

The researchers looked for markers of malignant potential by comparing benign and clinically aggressive tumors. Somatic ATRX mutations were seen in two of seven tumors associated with germline succinate dehydrogenase B (SDHB). The scientists also sequenced the ATRX coding region in a distinct set of 103 tumors samples to quantify the frequency of somatic ATRX mutations in PCC/PGL; 13% of tumors showed ATRX mutations.

The sample set of PCC/PGL with ATRX variants is not large enough to identify statistically significant associations, according to the researchers. But clinically aggressive features, inherited SDHx mutations and alternative lengthening of telomeres suggest an interaction between somatic and inherited genomes in solid cancers and warrant further research, they wrote.

“For pheochromocytomas and paragangliomas, currently there is no reliable marker of aggressive or potential malignant disease other than an inherited SDHB mutation,” Nathanson said. “However, further studies should be done to validate these findings before any clinical implementation.”

Studies involving larger sample sets of PCC/PGL, such as The Cancer Genome Atlas rare tumor project, will be helpful, she added. But other research specific to mutated ATRX also is necessary.

“Studies of aggressive and metastatic tumors are needed in particular to confirm whether ATRX mutations are a biomarker,” Nathanson said. “Additionally, functional studies of ATRX mutations in this disease type will be important to understand its biological role.”

Clinical practice guidelines released by the Endocrine Society in 2014 offer evidence-based guidance for the management of patients with PCC/PGL

“The Endocrine Society guidelines on PCC/PGL go a long way to recommend consideration of clinical genetic testing for all patients with these tumors,” Fishbein said in the press release. “It is especially important to identify SDHxmutation carriers who have higher incidence of multifocal disease and SDHB mutation carriers at higher risk of malignant disease.” – by Allegra Tiver