CARD9 Expression Pattern, Gene Dosage, and Immunodeficiency Phenotype Revisited.
J Clin Immunol
; 42(2): 336-349, 2022 02.
Article
em En
| MEDLINE
| ID: mdl-34791587
ABSTRACT
BACKGROUND:
CARD9 deficiency is an autosomal recessive primary immunodeficiency underlying increased susceptibility to fungal infection primarily presenting as invasive CNS Candida and/or cutaneous/invasive dermatophyte infections. More recently, a rare heterozygous dominant negative CARD9 variant c.1434 + 1G > C was reported to be protective from inflammatory bowel disease.OBJECTIVE:
We studied two siblings carrying homozygous CARD9 variants (c.1434 + 1G > C) and born to heterozygous asymptomatic parents. One sibling was asymptomatic and the other presented with candida esophagitis, upper respiratory infections, hypogammaglobulinemia, and low class-switched memory B cells. METHODS ANDRESULTS:
The CARD9 c.1434 + 1G > C variant generated two mutant transcripts confirmed by mRNA and protein expression an out-of-frame c.1358-1434 deletion/ ~ 55 kDa protein (CARD9Δex.11) and an in-frame c.1417-1434 deletion/ ~ 61 kDa protein (CARD9Δ18 nt.). Neither transcript was able to form a complete/functional CBM complex, which includes TRIM62. Based on the index patient's CVID-like phenotype, CARD9 expression was tested and detected in lymphocytes and monocytes from humans and mice. The functional impact of different CARD9 mutations and gene dosage conditions was evaluated in heterozygous and homozygous c.1434 + 1 G > C members of the index family, and in WT (two WT alleles), haploinsufficiency (one WT, one null allele), and null (two null alleles) individuals. CARD9 gene dosage impacted lymphocyte and monocyte functions including cytokine generation, MAPK activation, T-helper commitment, transcription, plasmablast differentiation, and immunoglobulin production in a differential manner.CONCLUSIONS:
CARD9 exon 11 integrity is critical to CBM complex function. CARD9 is expressed and affects particular T and B cell functions in a gene dosage-dependent manner, which in turn may contribute to the phenotype of CARD9 deficiency.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Candidíase Mucocutânea Crônica
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Clin Immunol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos