IRF4 haploinsufficiency in a family with Whipple’s disease

• Published in: eLife Vol. 7
• Main Authors: Guérin, Antoine, Kerner, Gaspard, Marr, Nico, Markle, Janet G, Fenollar, Florence, Wong, Natalie, Boughorbel, Sabri, Avery, Danielle T, Ma, Cindy S, Bougarn, Salim, Bouaziz, Matthieu, Béziat, Vivien, Della Mina, Erika, Oleaga-Quintas, Carmen, Lazarov, Tomi, Worley, Lisa, Nguyen, Tina, Patin, Etienne, Deswarte, Caroline, Martinez-Barricarte, Rubén, Boucherit, Soraya, Ayral, Xavier, Edouard, Sophie, Boisson-Dupuis, Stéphanie, Rattina, Vimel, Bigio, Benedetta, Vogt, Guillaume, Geissmann, Frédéric, Quintana-Murci, Lluis, Chaussabel, Damien, Tangye, Stuart G, Raoult, Didier, Abel, Laurent, Bustamante, Jacinta, Casanova, Jean-Laurent
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 14.03.2018; eLife Sciences Publication; eLife Sciences Publications, Ltd
• Subjects: Age; Aged; Aged, 80 and over; Arthritis; Biopsy; Chronic illnesses; Cytokines; Feces; Female; Gene expression; Genetic Predisposition to Disease - genetics; Genetics; Haploinsufficiency; Haploinsufficiency - genetics; Heredity; Hospitals; Human health and pathology; Humans; Immunology; Immunology and Inflammation; Infections; Infectious diseases; Interferon regulatory factor 4; Interferon Regulatory Factors - genetics; IRF4; Laboratories; Leukocytes; Leukocytes - microbiology; Life Sciences; Lymphocytes; Male; Microbiology and Infectious Disease; Middle Aged; Mutation; Pedigree; Penetrance; primary immunodeficiency; Tropheryma - genetics; Tropheryma - pathogenicity; Tropheryma whipplei; Viral infections; Whipple Disease - genetics; Whipple Disease - microbiology; Whipple Disease - pathology; Whipple's disease; New York; Australia; France; United States > US; Paris France; haploinsufficiency; IRF4; infectious disease; inflammation; microbiology; primary immunodeficiency; human; immunology; Whipple's disease; haploinsufficiency 44
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.32340

Most humans are exposed to Tropheryma whipplei (Tw). Whipple’s disease (WD) strikes only a small minority of individuals infected with Tw (<0.01%), whereas asymptomatic chronic carriage is more common (<25%). We studied a multiplex kindred, containing four WD patients and five healthy Tw chronic carriers. We hypothesized that WD displays autosomal dominant (AD) inheritance, with age-dependent incomplete penetrance. We identified a single very rare non-synonymous mutation in the four patients: the private R98W variant of IRF4, a transcription factor involved in immunity. The five Tw carriers were younger, and also heterozygous for R98W. We found that R98W was loss-of-function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. We also found that only six of the other 153 known non-synonymous IRF4 variants were loss-of-function. Finally, we found that IRF4 had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance. In 1907, George Hoyt Whipple – an American pathologist working at Johns Hopkins University in Baltimore – described a new inflammatory disease that affects the intestine. Patients with this condition, now known as Whipple’s disease, experience diarrhea, weight loss, and abdominal and joint pain. The disease is rare; it affects about one in a million people, mostly those over the age of 50 who are of European descent. Later it was discovered that bacteria called Tropheryma whipplei cause Whipple’s disease and that antibiotics can cure it. These bacteria are widespread and yet only a small minority of individuals infected with T. whipplei goes on to develop Whipple’s disease. In some populations, over 50% of individuals have been infected with the bacteria at some point in their lives, but most will get rid of the infection. This raised the question: when exposed to the same microbe, why do some individuals develop a severe disease, while others remain unharmed? From the 1950s onwards, scientists identified a few families with multiple members who have developed Whipple’s disease. These observations suggested that human genes may play a role in determining whether a person infected with T. whipplei becomes ill. Rare genetic mutations that affect the immune system have also been linked to the development of life-threatening cases of influenza or tuberculosis. Now, Guérin et al. report that, in one French family, an extremely rare mutation in the gene that codes for a protein called IRF4 may contribute to the development of Whipple’s disease. This family had four members with Whipple’s disease, all of whom had one copy of the gene with this rare mutation and one normal copy of the gene. The IRF4 protein acts like a switch that turns on and off some genes involved in the body’s response to infection. In patients with this mutation, the IRF4 protein does not work as it should. Guérin et al. suggest that Whipple’s disease may be caused by specific genetic mutations affecting the immune system in subjects infected by T. whipplei. More studies are needed to see if other genetic mutations also contribute to other cases of Whipple’s disease. Such studies may help physicians to better understand why some people become sick after T. whipplei infections while others do not. They may also help physicians to diagnose the disease, and even lead to better treatments.