A Franco-American team involving researchers from Inserm, Université Paris-Descartes and doctors grouped in the Institute Imagine the hospital Necker-Enfants Malades AP-HP and Rockefeller University New York discovered a genetic cause of Whipple’s disease, chronic intestinal pathology. By studying families with 4 members developed symptoms, the team found that the mutation of the gene causes IRF4 an impaired immune response to the bacteriaTropheryma whippleiAt the origin of the disease.This bacterium, common and experienced by many individuals, then causes in carriers of the mutation potentially fatal chronic infection without treatment. With this discovery, the first step towards a genetic explanation of the disease was done.

Chronic bacterial infection, Whipple’s disease occurs around the age of 50 and may result in clinical signs such as diarrhea, malabsorption, fever, weight loss, joint diseases, cardiovascular or central nervous system. In the absence or failure of antibiotic treatment, it can progress to death.

The disease is caused by Tropheryma whipplei , a bacterium that many of us encounter in our life (up to 50% of the members of some populations are carriers), but which affects a very small portion of individuals: only a subject on a million developing the symptoms of the disease.

The team led by Professor Jean-Laurent Casanova, laboratory director of Human Genetics of Infectious Diseases at the Institute. Imagine – Inserm, Paris Descartes University, AP-HP-member of Immunology, Hematology and Pediatric Rheumatology Hospital Necker Children AP-HP, Dr. Jacinta Bustamante, a research professor in the same laboratory and within the diagnostic center immune deficiencies at the Hospital Necker Children AP-HP, and Dr. Laurent Abel, co-director of the laboratory of human genetics of infectious diseases at Imagine , found that many families have multiple members affected by the disease, suggesting a genetic origin.

The researcher Antoine Guerin, first author of the scientific paper on this discovery, studied a French family with 5 healthy carriers and 4 members affected by the disease. These four patients are carriers of a mutation of the IRF4 gene, which codes for the production of a protein having a key role in immunity, and rendered non-functional by mutation. Dysfunction of this gene makes these patients vulnerable to infection with T. whipplei . The study also highlights the mode of transmission of the disease, hereditary, autosomal dominant: inherit a single mutated allele is enough to be reached.

With this study and the discovery of this mutation, the research team laid the foundation stone for a genetic understanding of the disease. Sequencing of a cohort of patients has not found other mutations in the same gene showing genetic heterogeneity of the disease. It remains to find and understand the mechanism immune deficiency caused by the mutation of the gene and to find other genetic mutations that may explain the vulnerability to disease.

This breakthrough helps explain why some patients exposed to the bacteria are sick or not, improve diagnosis, genetic counseling to families and the care of patients with the signs of the disease.

©Inserm/Féo, Claude

With the genome editing CRISPR-case.9 technique, researchers at INSERM, the hospital Necker Children-AP-HP, and Université Paris Descartes in the Institute Imagine managed to reactivate a gene that may improve the appearance of red blood cells of patients with hemoglobinopathies such as sickle cell anemia and beta-thalassemia. The teams Annarita Miccio, Inserm researcher, Prof. Marina Cavazzana AP-HP and Isabelle André-Schmutz, Inserm researcher show this new avenue of research and treatment of β -hémoglobinopathies in the journal Blood .

Millions of people are affected by severe forms of these diseases worldwide. They are characterized by an alteration in the expression of the gene encoding the β-globin: an essential component of hemoglobin . These changes can lead to a failure of expression of the β-globin gene, as in the case of β-thalassemia, or by an aggregation of hemoglobin into fibrils leading to the deformation of the red blood cells, in the case of sickle cell disease.

The laboratory Annarita Miccio, Inserm researcher, was particularly interested in the reactivation mechanisms of fetal hemoglobin . This hemoglobin is unusual act, instead of β-globin, other globin, γ-globin called, which is only expressed during fetal development.

Most patients suffering from β-hemoglobinopathies have a non-altered form of the gene encoding this protein. Its reactivation in patients with thalassemia and sickle cell would replace β-globin mutated γ-globin. This change would result in a significant improvement in the observed state of red blood cells for these diseases and thus associated symptoms (pain associated with vaso-occlusive crises in sickle-cell anemia or correction of anemia in both diseases).

The results show that certain genetic sequences responsible for blocking the expression of globine- γcan be modified, including a DNA sequence which inhibits the production of globin γ after fetal development. Its removal, using “genetic scissors” CRISPR / case.9, reactive synthesis globine- γ at levels sufficient to be considered in the future treatment protocol.

This study also improves the state of knowledge on the expression regulation mechanism to β globin γ during our development.

It also contributes to developing curative therapeutic protocols for these diseases with the majority of current treatments remain symptomatic and very heavy for patients.

A team of researchers led by Maria-Christina Zennaro, Inserm research Director at the Paris Cardiovascular Research Center (Inserm/ Paris-Descartes University), in collaboration with German colleagues[1], has identified a new gene implicated in hypertension. This study has been published in Nature Genetics.

These new findings highlight the role of genetic predisposition in the onset of common diseases and the importance of the French Plan for Genomic Medicine 2025. A plan in which one objective is to enable access to genetic screening, even for common diseases, in order to provide personalized medical care.

Hypertension is a major cardiovascular risk factor which affects up to 25% of the population. In around 10% of cases, it is due to dysfunction of the adrenal gland, which produces too much aldosterone – a hormone that regulates blood pressure. This is known as primary aldosteronism. Patients with this condition have hypertension that is often severe and resistant to standard treatments. They are also at greater risk of experiencing cardiovascular events, notably myocardial infarction or stroke.

To elucidate the causes of this disease, Maria-Christina Zennaro and Fabio Fernandes-Rosa, Inserm researchers in Paris, analyzed the exomes (the part of the genome that codes for proteins) of patients affected by primary aldosteronism before the age of 20. By doing so, they identified a mutation in a previously unknown gene – CLCN2 – which codes for a chloride channel, whose presence and effects in the adrenal gland were at that point unknown. 

Autonomous aldosterone production

Thanks to their partnership with a German team, the researchers studied the mechanisms by which this mutation could induce autonomous aldosterone production and trigger hypertension. They discovered that the mutation led to a permanent opening in the chloride channel.

In an animal model, the researchers showed that this channel was indeed expressed in the area of the adrenal glands that produces aldosterone.

This study reveals a previously unknown role of a chloride channel in the production of aldosterone. It opens up entirely new prospects for the pathogenesis and management of hypertension.

[1] From the Leibniz Institute for Molecular Pharmacology (FMP) and the Max Delbrück Center for Molecular Medicine (MDC) in Berlin.

Scientists have found that certain compounds, produced by microbes in the guts of mice, could be used to show which animals are at greater risk of becoming obese, or developing health conditions such as diabetes or cardiovascular disease.

The group, led by scientists at Imperial College London and INSERM UMRS 1138 in Paris, tested the urine of mice for a number of these microbial compounds, finding that certain key chemical signatures could accurately predict how the animals would respond to a high-fat diet before they received it.

High-fat diets are a major driver of obesity and related health conditions, such as diabetes and cardiovascular disease. However, evidence from previous studies suggests different people eating the same high-fat diet may have different outcomes, making it hard to define a one-size-fits-all ‘healthy diet’.

Previous research has shown that the hundreds of species of bacteria and other microbes which inhabit our gut work with our own cells to carry out a number of roles, and that this microbial garden can be shaped by what we eat or medicines we take, such as antibiotics.

In the latest study, published in Cell Reports, researchers used genetically similar mice to highlight the role that gut bacteria played in how the body responds to changes in diet and the impacts on health.

Before animals switched diets, their urine was screened for compounds produced by their gut bacteria using magnetic resonance spectroscopy, giving the mice a profile of chemical signatures, generated by metabolites from their microbiomes.

The team found that once the mice were switched to the same high-fat diet, they had a range of outcomes, with some animals gaining more weight than others, or becoming less tolerant to glucose – one of the early warning signs of diabetes.

Analysis revealed that key chemical signatures in their urine were predictive of some outcomes, such as changes in behaviour, weight gain and tolerance to glucose. One compound in particular, trimethylamine-N-oxide (TMAO), was shown to be predictive of glucose tolerance.

“We know that our environment and genetics can influence our risk of obesity and disease, but the effects of these communities of bacteria living inside us are less well understood,” said Dr Marc-Emmanuel Dumas, from the Department of Surgery & Cancer at Imperial, who led the research. “By using a group of mice with the same genetic makeup, we were able to zoom in on the variability in animals switched to a high-fat diet.”

“This study shows that value of a diet is determined not only by your genes, but also the genes of your gut microbes. This work has implications in lots of different areas, which is why it’s so exciting.” Senior investigator on the study, Dr Dominique Gauguier, from INSERM-Paris and a visiting professor at Imperial, said: “Our results illustrate the strong capacity of an organism’s gut microbiome to drive the adaptation to environmental challenges regardless of genetic variation and underline the need of deeper physiological and molecular phenotyping of individuals in large scale genetic studies.”

The findings will be explored further as part of an ongoing large clinical trial of 2,000 patients, where details of their lifestyle, diet, medication and other factors, as well as their microbiomes being characterised. Pulling together all of these data, and building on previous findings, they will be able to reveal how people react to different diets, and how their microbiomes influence the outcome.

According to the researchers, the hope is that in future, a patient’s profile could be generated from urine and blood samples and used to predict which diet they will respond to best.

“Our findings reveal that measuring metabolites in urine before the diet switch, we can predict which animals will get fat and become intolerant to glucose and which ones won’t,” added Dr Gauguier. “These findings open up really strong perspectives into designing personalised diets and harnessing our gut bacteria to promote health.”

In a study published today in the journal EMBO Molecular Medicine1, the team led by Prof. Nicolas Lévy identifies the mechanism associated with the accumulation of progerin, a toxic protein produced in the course of ageing, and demonstrates the therapeutic potential of a new drug – MG132 – to treat progeria, a rare syndrome involving premature and accelerated ageing. Nicolas Lévy and his team have demonstrated the ability of this drug to considerably reduce progerin production and simultaneously degrade it. This drug, along with other compounds from the same family, is undergoing evaluation for the treatment of other rare diseases, as well as more common diseases including certain types of cancer.

This work, supported by Inserm, Aix-Marseille University, the A*Midex foundation and AFM-Téléthon, paves the way to a therapeutic trial and the development of compounds to reduce the effects of accelerated and physiological ageing.

 Hutchinson Gilford progeria syndrome (HGPS) is an extremely rare and severe genetic disease that causes precocious and accelerated ageing in children. Although it spares the brain functions, it progressively leads to ageing in the vast majority of the organs, with particularly dramatic consequences being observed in the skin, adipose tissue, cardiovascular system and bones. Constantly fatal, death usually occurs around the age of 13 years. This disease, which affects 1 birth per 10–20 million worldwide, is caused by a mutation in the LMNA gene taht leads to the production  and  accumulation  of  a toxic protein, progerin, in cells nuclei. Progerin causes serious cellular dysfunctions (defects in DNA breaks repair, failure of cell proliferation    and    differentiation, etc…). Progeria is thus a unique model for understanding major mechanisms involved in natural ageing. Since 2003, Nicolas Lévy and his team have identified the gene and mechanism inducing progeria and other premature ageing diseases, developed therapeutic approaches, and conducted the first European trial in 12 children affected with the disease.

In the study published today, Nicolas Lévy’s team – UMR_S910, Aix-Marseille University/Inserm – has identified the mechanism whereby progerin accumulates without being degraded, and has identified a family of drugs that not only allow a tremendous reduction in its initial production, but also the simultaneous elimination of the remaining produced progerin. This study, using cells from children affected with progeria as well as a mouse model developed within this same team£, paves the way for a clinical trial for  progeria and other severe diseases of accelerated ageing. It will also be exploited in order to define the potential of each drug identified in the family, with respect to rare genetic diseases, cancers and natural ageing. For Dr Karim Harhouri, first author of the study, “These 5 years of work have enabled us to discover the real mechanism whereby progerin accumulates without being degraded, and a class of drugs that had not been exploited before, with a seemingly major therapeutic potential.”

“This work is part of the main thrust of our research in the area of rare genetic diseases, continuously aimed at translating knowledge of fundamental mechanisms into the most efficient possible treatments for our patients. This could not have been achieved without the convergence of talents, human skills and expertises to reach a common ambition, that of expanding effective treatments for our patients while reducing the access time; this is the philosophy we should be adopting, that of integrated research on care-related problems, and which we are upholding with the creation of the GIPTIS Institute*,” explains Nicolas Lévy, principal investigator, senior author of the study and proponent of the GIPTIS Institute*, which should open its doore in Marseille in 2020.

This work is the subject of a joint patent application – WO2016/113357 – holded by Aix- Marseille University, Inserm, AFM-Téléthon, CNRS and the ProGeLife** biotech company.

*GIPTIS : Genetics Institute for Patients, Therapies, Innovation and Science (www.giptis.com)

** www.progelife.com

©F Alpy/IGBMC

Cholesterol plays a central role in many living processes. In a new study, a team led by Catherine-Laure Tomasetto, Inserm research director at the Institute of Genetics and Molecular and Cellular Biology (Inserm/CNRS/Université de Strasbourg) reveals the role played by the STARD3 protein in the distribution of cholesterol within cells. A little like molecular velcro, this protein has the capacity to form membrane contacts between two cell organelles, enabling it to transport cholesterol from one organelle to another.

This research has been published in the EMBO Journal

Cholesterol is a component of biological membranes and essential for human cell functioning. A cell has two ways of obtaining cholesterol: by capturing it in the blood and internalizing it using endosomes, or by producing it in the endoplasmic reticulum, a network covering the inside of the cell that synthesizes most lipids. Once captured or synthesized, cholesterol is redistributed throughout the cell’s membranes via mechanisms that have not all been elucidated.

Since cholesterol is not water-soluble, its movements within the cell are very limited. To ensure its transport, the cells have specialized transporters. Catherine-Laure Tomasetto’s team is interested in one of them, protein STARD3, the role of which had remained quite a mystery until now. In this new study, the researchers unraveled some of that mystery. STARD3 is anchored to the endosomes, cell organelles that ensure communication between the outside and the inside of cells. Within the cell, STARD3 attaches to VAP, a protein that is itself fixed to the endoplasmic reticulum. This association creates close appositions between the endosome and the endoplasmic reticulum that are known as membrane contact sites. At these sites, the membranes of the two organelles are very close (less than 30 nm), thus facilitating communication and exchange. In this study, the researchers demonstrated that these membrane contact sites between the endosomes and the endoplasmic reticulum form a type of bridge, enabling STARD3 to transfer cholesterol from the membrane of the endoplasmic reticulum to that of the endosome, thereby rerouting some of the cholesterol that was intended for the plasma membrane.

These results therefore identify a new pathway that regulates cholesterol flow within cells. Understanding how cells balance the two available cholesterol sources will probably help us better understand the mechanisms of certain neurodegenerative or cardiovascular disorders presenting alterations in cholesterol distribution.

This study was funded by the French National Cancer Institute (INCA), the French foundation for medical research (FRM), the French League against cancer, the Ara Parseghian Medical Research Foundation, and the Vaincre les Maladies Lysosomales (overcoming lysosomal diseases) association.

The formation of a membrane contact site for the transport of cholesterol

Image credit: F Alpy/IGBMC