A homozygous CARD9 mutation in a family with susceptibility to fungal infections.
BACKGROUND
Chronic mucocutaneous candidiasis may be manifested as a primary immunodeficiency characterized by persistent or recurrent infections of the mucosa or the skin with candida species. Most cases are sporadic, but both autosomal dominant inheritance and autosomal recessive inheritance have been described.


METHODS
We performed genetic studies in 36 members of a large, consanguineous five-generation family, in which 4 members had recurrent fungal infections and an additional 3 members died during adolescence, 2 after invasive infection of the brain with candida species. All 36 family members were enrolled in the study, and 22 had blood samples taken for DNA analysis. Homozygosity mapping was used to locate the mutated gene. In the 4 affected family members (patients) and the 18 unaffected members we sequenced CARD9, the gene encoding the caspase recruitment domain-containing protein 9, carried out T-cell phenotyping, and performed functional studies, with the use of either leukocytes from the patients or a reconstituted murine model of the genetic defect.


RESULTS
We found linkage (lod score, 3.6) to a genomic interval on chromosome 9q, including CARD9. All four patients had a homozygous point mutation in CARD9, resulting in a premature termination codon (Q295X). Healthy family members had wild-type expression of the CARD9 protein; the four patients lacked wild-type expression, which was associated with low numbers of Th17 cells (helper T cells producing interleukin-17). Functional studies based on genetic reconstitution of myeloid cells from Card9(-/-) mice showed that the Q295X mutation impairs innate signaling from the antifungal pattern-recognition receptor dectin-1.


CONCLUSIONS
An autosomal recessive form of susceptibility to chronic mucocutaneous candidiasis is associated with homozygous mutations in CARD9.
Glocker
Erik-Oliver
EO
Department of Immunology and Molecular Pathology, Royal Free Hospital and University College London, London, United Kingdom.
Hennigs
Andre
A
Nabavi
Mohammad
M
Schäffer
Alejandro A
AA
Woellner
Cristina
C
Salzer
Ulrich
U
Pfeifer
Dietmar
D
Veelken
Hendrik
H
Warnatz
Klaus
K
Tahami
Fariba
F
Jamal
Sarah
S
Manguiat
Annabelle
A
Rezaei
Nima
N
Amirzargar
Ali Akbar
AA
Plebani
Alessandro
A
Hannesschläger
Nicole
N
Gross
Olaf
O
Ruland
Jürgen
J
Grimbacher
Bodo
B
D000293:Adolescent; D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics* / Q000378:metabolism; D002175:Candida; D002177:Candidiasis / Q000235:genetics / Q000276:immunology; D002178:Candidiasis, Chronic Mucocutaneous / Q000235:genetics*; D018389:Codon, Nonsense; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D008126:Lod Score; D008297:Male; D016921:Meningitis, Fungal / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D010375:Pedigree; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013601:T-Lymphocytes; D055815:Young Adult
D053468:CARD Signaling Adaptor Proteins; C505855:CARD9 protein, human; D018389:Codon, Nonsense; D012333:RNA, Messenger