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Mystery Solved: Children’s Neurological Disease Traced to a Single Error in One Gene

06/08/2017

Scientists find that affected children’s cells are flooded with ribosomal RNA and are poisoned by it, the first time that an excess of ribosomal RNA has been linked to a disease in humans

In a new study published today in The American Journal of Human Genetics, a multinational team of researchers describes, for the first time, the biological basis of a severe neurological disorder in children.

The extremely rare disorder is characterized by developmental regression and neurodegeneration. At first the children lead normal lives and seem identical to their age-matched peers. However, beginning at around 3 to 6 years of age, they present with neurological deterioration, gradually losing motor, cognitive and speech functions. Although the condition progresses slowly, most patients are completely dependent on their caretakers by 15-20 years of age.

Researchers from the Hadassah Medical Center and the Hebrew University of Jerusalem’s Faculty of Medicine, working with colleagues from the Pennsylvania State University College of Medicine and a multinational  research team, have now identified and studied 7 children — from Canada, France, Israel, Russia and the United States — who suffer from the disorder.

The researchers found in all patients the same spontaneously occurring, non-inherited genetic change in a gene (named “UBTF”) responsible for ribosomal RNA formation.  Because of this small change, the patients’ cells are flooded with ribosomal RNA and are poisoned by it. (Ribosomes are responsible for the translation and production of cell proteins; themselves, they are made up of ribosomal proteins and of ribosomal RNA in a precise ratio).

The researchers found an identical error in the same gene in all the patients tested, representing a difference of one letter among the roughly 3 billion letters that make up human DNA. By finding the identical change in children who suffer from the identical clinical disease, the researchers determined that the altered gene is indeed the cause of the disease.

Prof. Orly Elpeleg, head of the Department of Genetics at Hadassah Medical Center in Jerusalem and a professor of Pediatrics at the Hebrew University’s Faculty of Medicine, led the multinational research. Prof. Elpeleg credits the discovery to deep sequencing technology that Hadassah and the Hebrew University were among the first to introduce into clinical practice in the world, and the first in Israel.

Prof. Elpeleg initially encountered the disease in a young girl who came to Hadassah: "Five years ago, I saw a patient who was healthy until the age of 3, and then experienced a disturbance in her walking and motor function, speech and cognition. Around that time, we had introduced the deep-sequencing technology for clinical use at Hadassah, which enabled us to read all the coding genetic material of a person within a couple of days, in order to identify genetic defects.” Since 2010, Hadassah has assembled the largest genetic mapping database in Israel, of about 2400 patients.

"Searching for similar genetic defects in this database, we found a 9-year-old boy who had been treated at Hadassah and now lives in Russia. The boy had been healthy until the age of 5, and then displayed neurological deterioration just like the girl I had diagnosed. Dr. Simon Edvardson, a pediatric neurologist at Hadassah, flew to Russia, examined the boy, took genetic samples from him and from his parents and confirmed that his illness was identical to that of the Israeli girl. We then knew we had identified a new disease that was not recognized in the medical literature," said Prof. Elpeleg.

Comparing their data in a program called Gene Matcher, the researchers found several more children around the world who shared an identical genetic defect and the same course of disease.

In order to understand the mechanism of the newly identified disease, the researchers collaborated with Dr. George-Lucian Moldovan at the Pennsylvania State University College of Medicine, in the United States. Dr. Moldovan confirmed the disease mechanism: in the children's cells, there is an excess RNA of the ribosome, which probably causes brain cells to be flooded and poisoned.

“Our study links neuronal degeneration in childhood with altered rDNA chromatin status and rRNA metabolism. It is the first time that an excess of ribosomal RNA has been linked to a genetic disease in humans,” said Prof. Elpeleg.

While there is currently no cure for genetic diseases of this kind, the identification of the exact mutation may allow for the planning of therapies designed to silence the mutant gene. "Science may not be able to repair the gene, but now that our findings are published, it may be possible to make early identification of the disease and in the future find ways to prevent such a serious deterioration," said Prof. Elpeleg.

The research was supported by the National Institutes of Health and the Trudy Mandel Louis Charitable Trust.

Citation: Edvardson et al., Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood, The American Journal of Human Genetics (2017), August 3, 2017, doi: 10.1016/j.ajhg.2017.07.002 http://dx.doi.org/10.1016/j.ajhg.2017.07.002

Photo for Download:  http://media.huji.ac.il/new/photos/hu170803_elpeleg2.jpg - Prof. Orly Elpeleg, head of the Department of Genetics at the Hadassah Medical Center and a professor at the Hebrew University’s Faculty of Medicine. (Photo credit: Hebrew University)

Mystery Solved: Children’s Neurological Disease Traced to a Single Error in One Gene
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How stress controls hemoglobin levels in blood

04/04/2017

“Even at the cellular level, stress and the ability to mount a stress response are essential to our survival”

Our ability to breathe oxygen is critical to our survival. This process is mediated by the hemoglobin in our blood, which carries oxygen. Since air contains less oxygen on high mountains, the body is under pressure to make hemoglobin rapidly -- a stressful time. But what role does cellular stress play in the production of hemoglobin?

In a paper in the high-impact journal Cell Research, published April 4, 2017, researchers at the Hebrew University of Jerusalem report the discovery of an entirely new mechanism through which globin genes are expressed. Discovery of this hitherto unknown property of the hemoglobin genes shows that stress is absolutely needed to allow for the production of hemoglobin.

To produce a globin protein molecule, the DNA of the globin gene is first transcribed into a long RNA molecule from which internal segments must be excised, or spliced out, to generate the RNA template for protein synthesis in the red cell.

Now, a team of molecular biologists led by Prof. Raymond Kaempfer in the Hebrew University’s Faculty of Medicine reports that for each of the adult and fetal globin genes, the splicing of its RNA is strictly controlled by an intracellular stress signal.

The signal, which has been known for a long time, involves an enzyme present in every cell of the body, called PKR, which remains silent unless it is activated by a specific RNA structure thought to occur only in RNA made by viruses.

What Kaempfer and collaborators have discovered is that the long RNAs transcribed from the globin genes each contain a short intrinsic RNA element that is capable of strongly activating PKR. Unless the PKR enzyme is activated in this manner, the long RNA cannot be spliced to form the mature RNA template for globin protein synthesis.

“Surprisingly, we have revealed an entirely new mechanism through which hemoglobin gene expression is regulated by stress. An intracellular signal, essential for coping with stress, is absolutely necessary to allow for hemoglobin production. That stress signal is activated by the hemoglobin gene itself. Although we have long known that this signal strongly inhibits protein synthesis in general, during hemoglobin gene expression it first plays its indispensable, positive role before being turned off promptly to allow for massive hemoglobin formation needed for breathing,” said Prof. Raymond Kaempfer, the Dr. Philip M. Marcus Professor of Molecular Biology and Cancer Research at the Hebrew University of Jerusalem.

Once activated, PKR will place a phosphate (a process known as phosphorylation) onto a key initiation factor needed for the synthesis of all proteins, called eIF2-alpha. That in turn leads to inactivation of eIF2-alpha, resulting in a block in protein synthesis. This process is essential for coping with stress.

Most unexpectedly, they discovered that once activated, PKR must phosphorylate eIF2-alpha, and that phosphorylated eIF2-alpha is essential to form the machinery needed to splice globin RNA. In the splicing process, removal of an internal RNA segment causes the mature RNA product to refold such that it no longer will activate PKR, now allowing for unimpeded synthesis on this RNA of the essential globin protein chains at maximal rates, allowing for effective oxygen breathing. In other words, the ability to activate PKR remains transient, serving solely to enable splicing.

Thus, the team has demonstrated a novel, positive role for PKR activation and eIF2-alpha phosphorylation in human globin RNA splicing, in contrast to the long-standing negative role of this intracellular stress response in protein synthesis.  

The realization that stress is not only important but also essential may have important implications for how we understand hemoglobin expression. “What this boils down to is that even at the cellular level, stress and the ability to mount a stress response are essential to our survival. We have long known this in relation to other biological processes, and now we see that it is at play even for the tiny molecules that carry oxygen in our blood,” said Prof. Kaempfer.

Kaempfer's lab is in the Department of Biochemistry and Molecular Biology at IMRIC, the Institute for Medical Research-Israel Canada, in the Hebrew University's Faculty of Medicine. IMRIC is one of the most innovative biomedical research organizations in Israel and worldwide, bringing together brilliant scientific minds to find solutions to the world's most serious medical problems through a multidisciplinary approach to biomedical research. More information at http://imric.org.

CITATION: PKR activation and eIF2-alpha phosphorylation mediate human globin mRNA splicing at spliceosome assembly. Lena Ilan, Farhat Osman, Lise Sarah Namer, Einav Eliahu, Smadar Cohen-Chalamish, Yitzhak Ben-Asouli, Yona Banai, Raymond Kaempfer. Cell Research, advance online publication on April 4, 2017. doi: doi:10.1038/cr.2017.39

FUNDING: This work was supported by grants from the Israel Science Foundation.             

How stress controls hemoglobin levels in blood
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New study shows circular RNA can encode for proteins

26/03/2017

Research shows RNA molecules until now considered "non-coding" can encode for proteins

Scientists in Israel and Germany have discovered a protein-encoding function for circular RNA, a kind of RNA molecule that is highly active in brain cells and could play an important role in neurodegenerative diseases.

Several years ago, scientists discovered a new type of RNA molecule. Unlike all other known RNAs, this molecule forms a closed loop, and was therefore labeled circular RNA (circRNAs). Although circRNA molecules are abundant - in particular in the brain where they accumulate as we age - little is known about their function. In contrast to messenger RNAs (mRNAs), which are generated from genes and have the information to make proteins, circRNAs were previously thought to perform other duties in the cells.

Now, in an article published in the prestigious journal Molecular Cell, Prof. Sebastian Kadener and colleagues at the Hebrew University of Jerusalem, in collaboration with researchers of the Berlin Institute for Medical Systems Biology (BIMSB) at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Berlin, have demonstrated that circRNAs can encode for proteins.

This discovery reveals an unexplored layer of gene activity in a type of molecule not previously thought to produce proteins. It also reveals the existence of a new universe of proteins not yet characterized.

To determine whether circRNAs are translated, the researchers used Drosophila (fruit flies) and developed or adapted various techniques from molecular biology, computational biochemistry and neurobiology. They showed that specific circRNAs molecules are bound to ribosomes, the machinery that makes proteins, and they were able to find proteins produced from these molecules.

They also found that translated circRNAs are associated with specific places in the cells, in particular synapses, the junctions where electrical impulses pass from one nerve cell to another nerve or muscle cell. Indeed, the proteins produced from these circRNAs are present in synapses and are translated in response to specific signals, e.g. when the flies did not have access to food for 12 hours. This suggests that communication between neurons might involve unknown and uncharacterized mechanisms. Moreover, starvation and other pathways that induce the translation of circRNAs are also involved in aging, suggesting a strong link between circRNA translation and aging and a possible role for these molecules in neurodegenerative diseases.

As circRNAs are extremely stable, they potentially could be stored for a long time in compartments more distant to the cell’s body like axons of neuron cells. There, the RNA molecules could serve as a reservoir for proteins being produced at a given time.

According to Prof. Kadener, from the Biological Chemistry Department at the Hebrew University's Alexander Silberman Institute of Life Sciences, "By identifying the function of circRNAs, this research helps advance our understanding of molecular biology, and can be helpful in understanding aging or neurodegenerative diseases."

Prof. Nikolaus Rajewsky, of BIMSB/Max Delbrück Center for Molecular Medicine, added: “We think that translation of circRNAs is very interesting and that its prevalence and importance must be further investigated.”

Prof. Gil Ast, from the Department of Human Molecular Genetics & Biochemistry, at the Sackler Medical School at Tel Aviv University, who was not involved in the current study, said: "This study by Kadener and collaborators demonstrates that some circRNAs are translated. They show that the circRNAs translate mainly in the brain, likely in synapses. This is a very important, promising and timely discovery that gives an important hint of the function of these abundant yet uncharacterized RNAs. These findings are very important also due to the possible involvement of circRNAs in brain related diseases."

Among the circRNAs that Prof. Kadener showed to be translated is circMbl, which is generated from the muscleblind gene. Importantly, defects in muscleblind function are known to cause a severe degenerative disease called myotonic dystrophy. Characterized by progressive muscle wasting and weakness, this is the most common form of muscular dystrophy that begins in adulthood. Considered together, the role played by muscleblind in regulating circRNAs, combined with these molecules' abundance and translation in the brain, suggests that circRNAs might be involved in development of myotonic dystrophy.

Now, the researchers would like to explore how important circRNA translation is for normal brain function and whether circRNAs are involved in aging and age-related disorders. They would also like to analyze the mechanism of translation of circRNAs. This might teach us more generally about translation as a central process in the cell.

The research is published in Molecular Cell as “Translation of circRNAs”. Kadener’s group was supported by a Consolidator Grant from the European Research Council (ERC). The work was a collaborative effort between the Kadener group and several groups at the Max Delbrück Center for Molecular Medicine (MDC) in Berlin including the groups of Nikolaus Rajewsky, Marina Chekulaeva, Markus Landthaler and Gunnar Dittmar.

FUNDING: SK is funded by the ERC Consolidator Grant (ERC #647989). M.C., N.R. and L.R. are supported by the Einstein foundation grant “Single molecule RNA network”. ER was supported by the Berlin School of Integrative Oncology (GSC 1091). MJ received a fellowship from DFG (GRK#1772). CS is funded by BIF. N.R.P. is funded by a JBC fellowship. NR and CS is part of the SIGNGENE program between the MDC and HUJI.

CITATION: Pamudurti, Nagarjuna Reddy et al.: "Translation of circRNAs”. Molecular Cell, March 23, 2017. doi: 10.1016/j.molcel.2017.02.021.

PHOTO: http://media.huji.ac.il/new/photos/hu170223_circrna.jpg - Circular RNAs (circRNA) are produced in the cell nucleus after they are copied from the DNA and closed. This new research shows that some of them are translated and produce protein once they are exported from the nucleus.  (Image courtesy Sebastian Kadener)

New study shows circular RNA can encode for proteins
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