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A novel X-linked recessive form of Mendelian susceptibility to mycobaterial disease
  1. Jacinta Bustamante1,
  2. Capucine Picard1,2,
  3. Claire Fieschi1,3,
  4. Orchidée Filipe-Santos1,
  5. Jacqueline Feinberg1,
  6. Christian Perronne4,
  7. Ariane Chapgier1,
  8. Ludovic de Beaucoudrey1,
  9. Guillaume Vogt1,
  10. Damien Sanlaville5,
  11. Arnaud Lemainque6,
  12. Jean-François Emile7,
  13. Laurent Abel1,
  14. Jean-Laurent Casanova1,8
  1. 1Laboratoire de Génétique Humaine des Maladies Infectieuses INSERM Unité 550, Faculté Necker, Paris, France
  2. 2Centre d’Etude des Déficits Immunitaires, Hôpital Necker, Paris, France
  3. 3Département d’Immunologie Clinique, Hôpital Saint Louis, Paris, France
  4. 4Unité de Maladies Infectieuses et Tropicales, Hôpital Raymond Poincaré, Garches, France
  5. 5Service de Cytogénétique, Laboratoire de Cytogénétique, Hôpital Necker, Paris, France
  6. 6Centre National de Génotypage, Evry, France
  7. 7Service d’Anatomie Pathologique, Hôpital Universitaire Ambroise Paré, Boulogne, France
  8. 8Unité d’Immunologie et d’Hématologie Pédiatriques, Hôpital Necker-Enfants Malades AP-HP, Paris, France
  1. Correspondence to:
 J-L Casanova Laboratory of Human Genetics of Infectious Diseases
 University of Paris René Descartes-INSERM U550, Necker Medical School, 156 rue de Vaugirard, 75015 Paris, France;casanova{at}


Background: Mendelian susceptibility to mycobacterial disease (MSMD) is associated with infection caused by weakly virulent mycobacteria in otherwise healthy people. Causal germline mutations in five autosomal genes (IFNGR1, IFNGR2, STAT1, IL12RB1, IL12B) and one X-linked (NEMO) gene have been described. The gene products are physiologically related, as they are involved in interleukin 12/23-dependent, interferon γ-mediated immunity. However, no genetic aetiology has yet been identified for about half the patients with MSMD.

Methods: A large kindred was studied, including four male maternal relatives with recurrent mycobacterial disease, suggesting X-linked recessive inheritance. Three patients had recurrent disease caused by the bacille Calmette–Guérin vaccine, and the fourth had recurrent tuberculosis. The infections showed tropism for the peripheral lymph nodes.

Results: Known autosomal and X-linked genetic aetiologies of MSMD were excluded through genetic and immunological investigations. Genetic linkage analysis of the X-chromosome identified two candidate regions, on Xp11.4–Xp21.2 and Xq25–Xq26.3, with a maximum LOD score of 2.

Conclusion: A new X-linked recessive form of MSMD is reported, paving the way for the identification of a new MSMD-causing gene.

  • BCG, bacille Calmette–Guérin
  • EBV, Epstein–Barr virus
  • IFN, interferon
  • LOD, logarithm of odds
  • LZD, leucine zipper domain
  • MSMD, Mendelian susceptibility to mycobacterial disease
  • NEMO, nuclear factor-κB essential modulator
  • PBMC, peripheral blood mononuclear cells
  • Stat 1, signal transducer and activator of transcription 1
  • XR-MSMD, X-linked recessive MSMD

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  • CP and CF contributed equally to this paper. J-LC is an international scholar of the Howard Hughes Medical Institute.

    Funding: JB was supported by Fondation Schlumberger and INSERM. This work was supported by Fondation BNP-Paribas, Foundation Schlumberger, Institut Universitaire de France and EU grant QLK2-CT-2002-00846.

  • Competing interests: None.