Press releases

The HOIL1 gene – the cause of a new rare disease

30 Oct 2012 | By Inserm (Newsroom) | Immunology, inflammation, infectiology and microbiology

The researcher Capucine Picard, working with the team from Inserm unit 980 “Human genetics and infections diseases”/Université Paris Descartes under the leadership of Jean-Laurent Casanova, along  with researchers from a CNRS/Institut Pasteur laboratory headed by Alain Israël have succeeded in identifying the part played by the HOIL1 gene in cases of paradoxal association of an immune deficiency with a chronic autoinflammatory deficiency and a muscular deficiency in 3 children from 2 different families. This study once more highlights the importance of genetics in the body’s response to infectious agents. These works were published on line in the review Nature Immunology, of 28.10.12.

The science of genetics of infectious diseases arose from the observation that there is a wide variability of resistance to diseases from one person to another; that the same pathology could be fatal to one person, while benign or asymptomatic in others. The study also demonstrated that the predisposition to an infection is due to genetic particularities that result in variations in the molecular mechanisms of the immune response.

The 3 children, 2 of whom were monitored at the Hôpital Necker sick children’s hospital, suffered simultaneously from 3 pathologies: invasive bacterial infections (pneumococcus or other), an autoinflammatory disease (inherited recurring fevers) and amylopectinosis (a muscular deficiency that can affect the cardiac muscles in particular). The fact that 2 siblings suffered from the same symptoms drew the researchers’ attention to the hereditary genetic cause of this disease.

The team then carried out in-depth genetic studies in an attempt to identify the genetic defect responsible for these 3 observed pathologies: mutations of the HOIL1 gene.

Incomplete expression of this gene causes a dysfunction of the immune system. However, what makes this pathology unique is the fact that the genetic defect does not express in the same way, depending on the type of cells involved in the immune response. On the one had, this mutant gene is responsible for an over-reaction of leucocytes, which explains the autoinflammatory disease. On the other hand and quite to the contrary, this same genetic defect inhibits a response from other cells, which explains the susceptibility of these children to bacterial infections.

The HOIL1 molecule, derived from the gene of the same name, is responsible for an instability of the LUBAC complex that plays an important part in transmitting the signal received by the immune system cells in case of infection. This suggests that the genetic defect on HOIL1 in humans is responsible for a knock-on defect in the LUBAC complex, and that the LUBAC complex controls the immune response differently depending on the cell types involved.

Previously, the LUBAC complex had only been studied in mice. This is the first time that this deficiency has been detected in a human. For the moment, only 3 patients inFranceand inItalyhave been identified with this HOIL-1 deficiency. The discovery of this new genetic defect may allow us to identify new patients in other regions of the world.

Researcher Contact
Capucine Picard Chargée de recherche Inserm Unité Inserm 980 "Génétique Humaine et maladies infectieuses" Hôpital Necker Enfants Malades 01 44 49 50 88 rf.mresni@dracip.enicupac 
Press Contact
Inserm rf.mresni@esserp 
Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency Bertrand Boisson1,18, Emmanuel Laplantine2,18, Carolina Prando1,18, Silvia Giliani3,18, Elisabeth Israelsson4,18, Zhaohui Xu5,18, Avinash Abhyankar1,18, Laura Israël6,7, Giraldina Trevejo-Nunez1, Dusan Bogunovic1, Alma-Martina Cepika5, Donna MacDuff8, Maya Chrabieh6,7, Marjorie Hubeau6,7, Fanny Bajolle9, Marianne Debré10, Evelina Mazzolari3, Donatella Vairo3, Fabrice Agou11, Herbert W Virgin8, Xavier Bossuyt12, Caroline Rambaud13, Fabio Facchetti14, Damien Bonnet7,9, Pierre Quartier7,10, Jean-Christophe Fournet7,15, Virginia Pascual5,18, Damien Chaussabel4,5,18, Luigi D Notarangelo16,18, Anne Puel6,7,18, Alain Israël2,18, Jean-Laurent Casanova1,6,7,10,18 & Capucine Picard6,7,10,17,18 1St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, New York, USA. 2Laboratory of Molecular Signaling and Cell Activation, Centre National de la Recherche Scientifique (CNRS), Unité de Recherche Associée (URA) 2582, Institut Pasteur, Paris, France. 3Laboratory of Genetic Disorders of Childhood and Pediatric Clinic, A. Nocivelli Institute for Molecular Medicine, Department of Pathology, Spedali Civili and Pediatric Clinic, University of Brescia, Brescia, Italy. 4Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA. 5Baylor Institute for Immunology Research and Baylor Research Institute, Dallas, Texas, USA. 6Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U980, Necker Medical School, Paris, France. 7Paris Descartes Université, Sorbonne Paris Cité, France. 8Washington University School of Medicine and Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Disease Research, Saint Louis, Missouri, USA. 9Reference Center for Complex Congenital Heart Defects, Assistance Publique Hôpitaux de Paris (AP-HP), Necker Enfants Malades Hospital, Paris, France. 10Pediatric Hematology-Immunology-Rheumatology Unit, AP-HP, Necker Enfants Malades Hospital, Paris, France. 11Institut Pasteur, Structural and Cellular Biochemistry Unit, CNRS, URA 2185, France. 12Experimental Laboratory Immunology, Department of Microbiology and Immunology, Biomedical Science Group, Catholic University of Leuven, Leuven, Belgium. 13Pathology Laboratory, AP-HP, Raymond Poincarré, Garches, France. 14Department of Pathology, Spedali Civili and University of Brescia, Brescia, Italy. 15Pathology Laboratory, AP-HP, Necker Enfants Malades Hospital, Paris, France. 16Division of Immunology and The Manton Center for Orphan Disease Research, Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 17Study Center for Primary Immunodeficiencies, AP-HP, Necker Enfants Malades Hospital, Paris, France. 18These authors contributed equally to this work. Correspondence should be addressed to J.-L.C. (ude.rellefekcor@avonasac.tnerual-naej) Nature Immunology, October 28, 2012 Doi : 10.1038/ni.2457