A novel X-linked recessive form of Mendelian susceptibility to mycobaterial disease.
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 gamma-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.


CONCLUSIONS
A new X-linked recessive form of MSMD is reported, paving the way for the identification of a new MSMD-causing gene.
Bustamante
Jacinta
J
Laboratoire de Génétique Humaine des Maladies Infectieuses INSERM Unité 550, Faculté Necker, Paris, France.
Picard
Capucine
C
Fieschi
Claire
C
Filipe-Santos
Orchidée
O
Feinberg
Jacqueline
J
Perronne
Christian
C
Chapgier
Ariane
A
de Beaucoudrey
Ludovic
L
Vogt
Guillaume
G
Sanlaville
Damien
D
Lemainque
Arnaud
A
Emile
Jean-François
JF
Abel
Laurent
L
Casanova
Jean-Laurent
JL
D000328:Adult; D001500:BCG Vaccine / Q000627:therapeutic use; D002874:Chromosome Mapping; D041321:Chromosomes, Human, X; D005260:Female; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006099:Granuloma / Q000235:genetics / Q000473:pathology; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008206:Lymphatic Diseases / Q000235:genetics / Q000473:pathology; D008297:Male; D009164:Mycobacterium Infections / Q000235:genetics*; D010375:Pedigree; D012008:Recurrence; D014376:Tuberculosis / Q000235:genetics* / Q000517:prevention & control
D001500:BCG Vaccine