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.

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