DS0410 -

Human genetic dissection of Mendelian susceptibility to mycobacterial disease – GENMSMD

Submission summary

Mendelian Susceptibility to Mycobacterial Diseases (MSMD) is a primary immunodeficiency characterized by severe disease caused by weakly virulent mycobacteria, such BCG vaccines and environmental mycobacteria, in otherwise healthy patients. Patients with MSMD are also vulnerable to tuberculosis. Other infections are rare, with the exception of non-typhoidal salmonellosis, found in about half the patients. First described clinically in the 1950s, the pathogenesis of MSMD remained unclear until 1996, when its first genetic etiology was deciphered in children with interferon-g receptor 1 (IFN-gR1) deficiency. Genetic dissection of MSMD has identified nine morbid genes, including seven autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, IRF8 and ISG15) and two X-linked (NEMO and CYBB) genes. The high level of allelic heterogeneity has led to the definition of up to 18 distinct disorders, with dominant and recessive traits at the same locus, complete and partial defects of the same protein, and defects due to a lack of protein or the production of a dysfunctional protein. Mutations in these genes affect the IFN-g pathway. However, the genetic etiology remains unknown in about half the MSMD patients. This project aims to identify and characterize new genetic defects, including new loci and new alleles, involved in IFN-g immunity or in other circuits. We will follow hypothesis-generating, genome-wide screening approaches. We will search for MSMD-causing genes by genome-wide linkage and whole exome/genome sequencing. To date, we have enrolled 295 patients and we intend to recruit, within the next three years, a total of 345 patients. We will search for and characterize the underling genetic defects using i) cutting-edge genome-wide strategies, including next-generation sequencing (NSG) technologies and ii) in dept-functional studies to validate the genetic mutations identified. Our preliminary data show very promising mutations in five novel MSMD-causing genes and we have some interesting data about the impact of the mutations. The clinical implications of the identification of novel genetic etiologies are considerable, as molecular genetic diagnosis and genetic counseling will be offered to the patients and their families. Our project is innovative, feasible, and supported by strong preliminary evidence. From a basic biological standpoint, this research will provide considerable insight into the mechanisms of human immunity to mycobacteria. Our results will also guide treatment with recombinant molecules, such as IFN-g, in addition to antibiotics and based on improvements in our understanding of this disease’s pathogenesis. This endeavor is unique in the fields of medicine, human genetics, immunology, and infectious disease. Finally, the genetic dissection of MSMD paves the way for the genetic dissection of severe tuberculosis in otherwise healthy children and young adults.

Project coordinator

Madame Jacinta Bustamante (Institut National de la Santé et de la Recherche Médicale (INSERM))

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


INSERM DR Paris 5 - U1163 - GHMI Institut National de la Santé et de la Recherche Médicale (INSERM)
AP-HP, Hôpital Necker - Service IHP AP-HP, Hôpital Necker - Service d'Immunologie et Hématologie Pédiatrique
Hôpital Foch - service de Pneumologie Hôpital Foch - service de Pneumologie
INSERM U1223 Institut National de la Santé et de la Recherche Médicale

Help of the ANR 488,160 euros
Beginning and duration of the scientific project: December 2016 - 48 Months

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