Inherited human ezrin deficiency impairs adaptive immunity

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Inborn errors of immunity (IEI) are genetic disorders increasing susceptibility to infections, autoimmunity, and cancer.
• The genetic basis for many IEI cases remains unidentified, necessitating further research.

Purpose of the Study:

• To identify the genetic cause of an inborn error of immunity in a patient with unknown etiology.
• To elucidate the functional consequences of the identified genetic mutation on immune cell function.

Main Methods:

• Whole-exome sequencing was employed to identify genetic variants.
• Mass cytometry and flow cytometry were used for multidimensional immunophenotyping.
• Functional assays assessed the impact of the mutation on protein phosphorylation and calcium signaling.

Main Results:

• A homozygous missense mutation (A129T) in the ezrin (EZR) gene was identified.
• The A129T mutation resulted in a complete loss of ezrin function due to abolished phosphorylation and decreased calcium signaling.
• Immunophenotyping revealed hypogammaglobulinemia and reduced frequencies of various immune cell populations, including B cells, T cells (CD4+, CD8+, MAIT, γδ T), and naive CD4+ T cells.

Conclusions:

• Autosomal-recessive ezrin deficiency is a newly identified genetic cause of severe B-cell deficiency.
• Ezrin deficiency profoundly impacts both cellular and humoral immunity.
• This finding expands the spectrum of known inborn errors of immunity.