Guillaume Dorval, between research and clinic

Why this double degree of doctor-researcher? What does it bring you in your daily practice?

As a clinician, I am called to monitor young patients with kidney diseases. Some of them suffer from a disease called nephrotic syndrome, which is completely resistant to immunosuppressive therapies in 10% of cases. For most, these patients slowly develop chronic renal failure and go into a kidney transplant program in the shorter or longer term. Trying to find the genetic origin of their disease helps to both propose a diagnosis, but also to try to understand the mechanisms leading to a mutation in a gene on occurrence of the clinical expression of the disease (genetic nephrotic syndrome in this case). It is the progress in this understanding of diseases which, one day, will possibly help to put forward a conservative treatment adapted to each patient.

During my internship, I therefore carried out a Master 2 in Genetics within Corinne Antignac’s team, a pioneer in the genetics of nephrotic syndromes, as she was the first to show the genetic origin of a steroid-resistant nephrotic syndrome in 2001. After this Master 2, I decided to continue my research work in the laboratory. First, I left to train in animal models of kidney diseases, more specifically in zebrafish. For that, I had the opportunity to work in Prof. Iain Drummond’s laboratory at MGH in Boston (USA), who is a leading expert in the study of kidney diseases in zebrafish.

How do you go from one world to the other?

Within Imagine, it is common: many doctors are also researchers and vice versa. In basic science, I think it is crucial to be able to dedicate 100% of the time to research. The difficulty is to find funding that allows you to only dedicate yourself to research for a given period. Working in an Imagine laboratory allowed me to benefit from the Health-Science (MD-PhD) program supported by the Bettencourt-Schueller Foundation: its aim is to support young doctors or pharmacists in their research projects, in the context of a science thesis. Fortunately, this funding was perfectly consistent with the project in Boston.

How did you decide the direction of your research?

On returning from Boston, Corinne Antignac spoke to me about this family that I knew already as they are monitored in the Nephrology department at Necker. A genetic origin was strongly suspected for the disease of this family. This still has to be proved. Analysis of the exome (Ed.: part of the genome made up of exons, meaning the parts of the genes that are expressed to synthesize proteins) in the index case of this family helped to highlight a mutation presenting higher pathogenicity scores in gene TBC1D8B. Thanks to a European data sharing program, we have been able to identify another patient, in Bristol in the UK, who had a similar disease and was a carrier of another mutation in the same gene.

It is then that we began functional studies, both in vivo and in vitro, to prove the cause and effect relationship between mutations in this gene and the disease diagnosed in patients. We were able to highlight a similar phenotype in zebrafish with an invalidation of this specific gene: this model is therefore lacking in the protein, known as TBC1D8B, encoded by the mutated gene in patients. In a cellular model, we showed that the TBC1D8B protein interacted with a family of ‘Rab’ proteins that regulates the intracellular vesicular traffic. More specifically, the alteration of TBC1D8B prevents the inactivation of Rab11b causing a failure of the vesicular recycling process at the cell membrane. What is particularly interesting is that it is a cellular mechanism for which the alterations had never been described in nephrotic syndrome, therefore paving the way for new discoveries. These advances are the subject of a publication in the American Journal of Human Genetics and are at the heart of my science thesis.

Already, this gene will be added to the panel of genes analyzed in patients with steroid-resistant nephrotic syndrome. Some patients will see their diagnosis clarified and in families with a deleterious variant of this gene, genetic counseling may be offered so as to identify if other family members are likely to pass on the variant. This is already the first victory.