Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic...

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Caspase activation and recruitment domain 11 (CARD11) is a key scaffold protein in lymphocyte signaling.
• Germline CARD11 mutations are linked to primary immune disorders like SCID, B-cell expansion, and atopic disease.
• Whole-exome sequencing has increased the identification of CARD11 mutations.

Purpose of the Study:

• To investigate the molecular functions of diverse CARD11 variants.
• To define the spectrum of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles.

Main Methods:

• Utilized cell transfections and primary T-cell assays.
• Evaluated the signaling and functional impact of CARD11 variants.

Main Results:

• Identified novel heterozygous CARD11 mutations presenting with diverse immunologic phenotypes beyond atopy.
• Observed phenotypes resembling STAT3, DOCK8, CVID, neutropenia, and IPEX-like syndromes.
• Pathogenic variants demonstrated dominant negative activity, primarily within CARD and coiled-coil domains.

Conclusions:

• CARD11 mutations are associated with a broader spectrum of human immune disorders than previously recognized.
• Functional validation is essential for rare gene variants, even when found in unexpected clinical presentations.