Alt. symbols: CANDF2 | hCARD9

Approved name: caspase recruitment domain family member 9
Alt. names: caspase recruitment domain family, member 9

Location: 9q34.3: 136363956 - 136373681 (-)
Gene type: protein_coding, 11 transcripts.

Scores: LoFtool: 0.827000 | pLI: 0.00000000 | LOEUF: 1.126

HGNC: 16391

NCBI: 64170, RefSeq: NG_021197.1

Ensembl: ENSG00000187796.16

LRG_178 | Status: public

OMIM: 607212

Expression | ProteinAtlas

CARD9 transduces signals in myeloid cells downstream of C-type lectin receptors that detect pathogen-associated molecular patterns (PAMPs), such as fungal carbohydrates (PMID: 26961233, 33558980). As such, CARD9 is particularly important for defending the body against infections by fungi, particularly from the phylum Ascomycota (PMID: 29080677, 33558980), but also plays roles in regulating commensal gut microbiota (PMID: 33548172) and immune defense against other pathogens, such as bacteria, viruses and parasites, though there is more redundancy with other innate immune pathways for the latter. Upon activation, CARD9 homo-oligomerizes to form a nucleating helical template that recruits BCL10 via CARD-CARD interaction to promote polymerization of BCL10 and subsequent recruitment of MALT1. This leads to activation of NF-kB and p38/MAPK pathways, which stimulate the expression of genes encoding pro-inflammatory cytokines and chemokines (PMID: 11053425, 26488816, 31296852, 26961233, 33558980). CARD9 signaling in antigen-presenting cells links innate pathogen sensing to adaptive immune pathway activation, particularly by promoting the differentiation of IL-17-producing Th17 cells (PMID: 24231284). The IL-17 pathway creates inflammation, sending other cytokines and white blood cells to the infection site and promoting tissue repair. In addition, the IL-17 pathway promotes the production of peptides that control growth of Candida on the surface of mucous membranes and skin. In addition, the CARD9 protein is also important for recruiting neutrophils from the blood to protect the brain and other organs from fungal infection, because of their strong anti-fungal activity.

Biallelic nonsense, missense, frameshift and splice site mutations in CARD9 are associated with familial chronic mucocutaneous candidiasis (Candidiasis, familial, 2, autosomal recessive) [OMIM: 212050]. These individuals may not only develop yeast infections of the skin, nails, and mucous membranes, but also systemic fungal infections, a potentially life-threatening condition in which fungi invade the blood and vital organs, especially the brain. on immunophenotyping, these patients often show n ormal immunoglobulin levels and lymphocyte subsets, but significantly lower proportions of Th17 cells (PMID: 19864672) and/or reduced levels of IL-17 production as well as impaired neutrophil-killing capacity (PMID: 23335372). Additionally, heterozygous CARD9 variants c.1434+1G>C (rs141992399), p.E249K, p.R315H, and p.V385L (rs3124993) have been identified in individuals with susceptibility to pulmonary nontuberculous mycobacterial (PNTM) infection (PMID: 26038974). More recently, genome-wide association studies (GWAS) also identified heterozygous CARD9 variants as conferring either increased protection (rs141992399, rs200735402) or increased risk (rs10870077, rs4077515, rs10781499) towards the development of inflammatory bowel disease (IBD) (PMID: 24068945, 21983784). Individuals heterozygous for the S12N activating variant (rs4077515) show increased production of inflammatory cytokines, while heterozygosity for c.1434+1G>C (rs141992399) is thought to be IBD-protective via the generation of a shortened C-terminal tail that prevents CARD9 from binding TRIM62 for NF-?B activation, thus leading to a dominant negative inhibition of inflammatory cytokine production (PMID: 26488816). Of note, CARD9 S12N has recently also been reported as a risk factor for the development of allergic bronchopulmonary aspergillosis (ABPA) via the orchestration of dectin-1-mediated signaling for the induction of type 2 responses (PMID: 29777223). Goel et al. (2022) also recently identified a family with two siblings carrying homozygous CARD9 c.1434+1G>C variants with heterozygous asymptomatic parents. One sibling was asymptomatic at the the age of 5 years and the other presented with recurrent episodes of mucocutaneous candidiasis, and a CVID-like picture of upper respiratory infections, hypogammaglobulinemia, and low class-switched memory B cells. The authors went on to show that, in addition to its well-established myeloid functions, CARD9/Card9 is expressed in T and B cells and can affect specific T and B cell functions (i.e. Th1 commitment and plasmablast differentiation) in a manner dependent upon both gene dosage and mutational effect (PMID: 34791587). [Load More]