The Kidney Foundation of Canada

Dr. Mathieu Lemaire 

Dr. Mathieu Lemaire

The Hospital for Sick Children, Ontario

Glomerular sialic acid deficiency as a novel cause of hemolytic-uremic syndrome

2017-2019:  $99,000  |  Biomedical Research Grants  |  Category: Kidney Biology

Investigating the pathophysiology of atypical hemolytic-uremic syndrome caused by DGKE deficiency

2017-2020:  $210,000  |  KRESCENT New Investigator Award  |  Category: Kidney Biology

2017-2018:  $25,000  |  KRESCENT Infrastructure Award  |  Category: Kidney Biology


Dr. Mathieu Lemaire finished his medical training at McGill University in 2004 and then moved to Toronto to learn Paediatrics and Nephrology at The Hospital for Sick Children. Then, he went to Yale University (New Haven, CT) to pursue a PhD in Investigative Medicine under the supervision of Dr Richard P. Lifton as a KRESCENT post-doctoral fellow.

The focus of his project was on the genetics of rare paediatric kidney diseases, with a particular focus on atypical hemolytic-uremic syndrome (aHUS). Dr. Lemaire returned to the University of Toronto in mid-2014 as Assistant Professor of Paediatrics: he joined the Division of Nephrology at The Hospital for Sick Children as Assistant Professor of Paediatrics, and the Cell Biology Program of the SickKids Research Institute as Scientist-Track Investigator. He is cross-appointed at the University of Toronto with the Institute of Medical Sciences and in the Biochemistry Department.

His main research interest is to do translational research that pertains to rare paediatric kidney diseases using genomic tools for gene discovery followed by careful functional dissection of candidate genes using cutting-edge microscopic, cell biology and biochemical methods.

The goal is to not only contribute to a better understanding of disease pathophysiology, but also aim to translate these findings into tangible changes in clinical care.

He played a central role in the identification of the first non-complement gene that causes a recessive form of aHUS, diacylglycerol kinase epsilon. His laboratory continues to work on teasing out the mechanisms by which DGKE deficiency causes thrombosis restricted to small blood vessels of the kidneys. His team continues to do gene discovery on a variety of rare paediatric kidney diseases using whole-exome sequencing: functional work is on the way for yet another novel gene that causes complement-independent aHUS.

Lay Summary

Glomerular sialic acid deficiency as a novel cause of hemolytic-uremic syndrome
Kidneys play a very important role in your body. Among other functions, they help filter wastes created by the body on a daily basis. To do that, enormous amounts of blood need to be brought to the kidneys every hour. The filter is called the glomerulus: it acts like a sieve in that it keeps all of the big molecules and cells in the blood (like noodles) and filters out all of the small molecules and water in the urine. Because of that, it is very important to keep the blood flowing smoothly to the kidneys. How the kidney blood vessels can do this remains a fascinating puzzle.

There are diseases in which the main problem is that blood flow in the kidney is abnormal or stops altogether because of blood clots. This may cause a lot of problems for the patient because the kidney is then unable to filter out the body wastes properly. Patients with severe infections caused by a bacteria called pneumococcus can develop blood clots in their kidneys. Most of these patients are children that will need dialysis while they are sick because their kidneys are not working at all. Many will also have kidney problems even after the infection is over. We do not know why blood clots are forming in their kidneys. We also do not know how to treat it: right now, all we can offer to patients is a “tincture of time” (we hope that the kidneys can repair themselves over time).

One hint that we have relates to an enzyme called sialidase that the bacteria release in the blood of patients. An enzyme is like a little engine that is able to do one thing very, very well. Sialidases have only one goal: to seek and remove a specific sugar, called sialic acid, found on proteins on the outside surface of cells. Proteins with sialic acids normally play important roles on cells: they can be used as a docking station by some blood cells whereas they may repel others. All patients who develop kidney disease during pneumococcus infection have a lot of sialidases in their blood (sialidases are never found in the blood of healthy people). The big problem: we do not know why having sialidase in the blood causes problems in the kidneys.

We recently discovered a new genetic disease where patients also develop blood clots in their kidneys. The interesting part of this story is that these patients have mutations in a gene called ST3GAL1 that also works with sialic acid in cells. In fact, its function is the exact opposite of sialidases: it is an enzyme that adds the very sialic acid to proteins that the sialidase likes to remove! Experiments done in our lab show that these mutations prevent this enzyme from working normally. The bacterial and genetic diseases may thus be mirror images of each other.

We propose to study the two diseases at the same time to try to figure out what may be the common thread between them. Indeed, this may help us understand why abnormal sialic acid biology causes so much problems for patients. We think there must be specific proteins with sialic acid normally on them that play an important role to prevent the formation of clots in the kidney blood vessels. A better understanding of these diseases is required if we want to develop specific treatments for these patients.

Investigating the pathophysiology of atypical hemolytic-uremic syndrome caused by DGKE deficiency
Blood vessels are like roads that can reach any cell of our body. We call the cells that line blood vessels "endothelial cells". Blood flows fast in normal blood vessels, but it is slow when there is damage. It forms a blood clot. This is similar to a “good traffic jam”: it helps repair injured blood vessels. The body must control the machines that help with repair to avoid “bad traffic jams”. Healthy blood vessels don't need blood clots.

In the lab, we study the function of endothelial cells in the kidneys. We work on a disease called "atypical hemolytic-uremic syndrome". For simplicity, we call it "aHUS". Patients with aHUS get kidney failure. Why? Blood clots form in the blood vessels of the kidneys. These clots prevent normal blood flow in kidneys. Blood flow is important to deliver food and oxygen to the kidneys.

We found that mutations in the gene DGKE can cause aHUS. Each cell in the body contains DNA, a code made of genes. Genes make proteins—the building blocks of cells. Mutations are changes in the DNA that cause abnormal function of a protein. For our patients, the mutations prevent DGKE from working well.

DGKE is an enzyme that work on fats. DGKE stands for "diacylglycerol kinase epsilon". Diacylglycerol is also called DAG. Enzymes are like machines that do specific tasks in cells. For example, a kinase adds a phosphorus group to its target. DGKE is a kinase that targets one type of fat named DAG. Cells use DAG as a signal to turn on specific functions. It is like a light switch. When DGKE modifies DAG, it turns off the signal in the cell. When DGKE can't work, it is as if the light switch is left on too long. When that happens, patients cannot prevents blood clotting in their kidneys. These patients develop kidney failure, and we have no treatment to offer.

We study endothelial cells that have no DGKE at all. We have found three clues that help guide this project. First, we found that when DGKE does not work, it affects the function of AKT, another protein that is like a light switch. In particular, AKT turns on another protein called eNOS. Second, we also found that the function of eNOS is abnormal in cells that have no DGKE. AKT and eNOS play a major role in making sure that blood vessels stay open and are not too sticky. We don't know how DGKE deficiency causes problems with AKT and eNOS, or how this affects blood vessels. Third, we also noticed that endothelial cells that have no DGKE protein have difficulties to function normally when exposed to blood flow. The endothelial cells are like flags that are not well attached to their pole when there is high wind: they fly away leaving blood vessels without a lining.

This project will tackle four different tasks to help us understand better DGKE function in endothelial cells.

1) Figure out how a deficiency in DGKE leads to abnormal AKT function in endothelial cells

2) Find out how abnormal eNOS function affects the function of blood vessels that have no DGKE protein

3) Determine how DGKE deficiency prevents endothelial cell to withstand normal blood flow

4) Study how DGKE mutations found in patients with aHUS affect the function and structure of DGKE enzymes

This research is important so we can start thinking about new treatment for this disease. Studies on the function and structure of DGKE could be helpful to diagnose patients with new mutations. It will also teach us a lot about how normal blood vessels prevent blood clot formation.