Autosomal-dominant Roquin-1 immunodeficiency and hyperinflammation

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Primary immunodeficiency can arise from genetic defects in cell development and growth pathways.
• Roquin-1 (encoded by RC3H1) is a crucial posttranscriptional repressor regulating immune responses by controlling messenger RNA stability.

Purpose of the Study:

• Investigate the inheritance pattern and molecular basis of a novel immunodeficiency disorder within an extended family.
• Identify the specific genetic variant responsible for the observed immunodeficiency.

Main Methods:

• Whole-exome sequencing was employed to detect genetic alterations.
• Molecular and cellular assays were used to evaluate the variant's effect on immune function and RNA regulation.

Main Results:

• A novel heterozygous missense variant (p.F225S) in the ROQ domain of RC3H1 (Roquin-1) was identified in three affected individuals.
• This variant, inherited in an autosomal-dominant manner, impairs Roquin-1's repressor activity, leading to increased stability of proinflammatory RNAs (e.g., ICOS1, IL6).
• Immune dysregulation included selective antibody deficiency, expansion of CD8 memory and CD4+CD8+ T cells, skewed TCR repertoire, and enhanced T-cell responses.

Conclusions:

• The RNA-binding protein Roquin-1 is essential for regulating immune responses.
• A heterozygous variant in Roquin-1's ROQ domain causes primary immunodeficiency with variable clinical manifestations including infections, autoimmunity, and hyperinflammation.