CARD9 Expression Pattern, Gene Dosage, and Immunodeficiency Phenotype Revisited.

Area of Science:

• Immunology
• Genetics

Background:

• CARD9 deficiency causes primary immunodeficiency, leading to fungal infections.
• A rare CARD9 variant (c.1434+1G>C) has been linked to protection from inflammatory bowel disease.

Purpose of the Study:

• Investigate the impact of homozygous CARD9 variants (c.1434+1G>C) in siblings.
• Analyze CARD9 gene dosage effects on immune cell function.

Main Methods:

• Studied two siblings with homozygous CARD9 variants and their heterozygous parents.
• Analyzed CARD9 transcript variants, protein expression, and CBM complex formation.
• Assessed immune cell functions (cytokine generation, MAPK activation, T/B cell differentiation) across different CARD9 gene dosage conditions.

Main Results:

• Homozygous CARD9 variants produced non-functional transcripts (CARD9Δex.11 and CARD9Δ18 nt.), impairing CBM complex formation.
• CARD9 expression was detected in human and mouse lymphocytes and monocytes.
• Gene dosage of CARD9 differentially impacted lymphocyte and monocyte functions, including cytokine production and B cell differentiation.

Conclusions:

• CARD9 exon 11 integrity is essential for CBM complex function.
• CARD9 expression influences T and B cell functions in a gene dosage-dependent manner.
• CARD9 gene dosage may contribute to the clinical presentation of CARD9 deficiency.