Autosomal-dominant Roquin-1 immunodeficiency and hyperinflammation

Genetic aberrations in pathways critical for cell development and growth can cause primary immunodeficiency with manifestations including susceptibility to infections, hyperinflammation, autoimmunity, and lymphoproliferation. Occasionally these conditions are caused by genetic variants that disrupt the regulation of an immune response by removing essential repressor activities. Roquin-1, encoded by ring finger and CCCH-type domains 1 (RC3H1), is a posttranscriptional repressor of multiple immune modulatory proteins. It plays a critical role in the control of immune responses through regulation of the posttranscriptional stability of selected messenger RNA.

We studied the mode of inheritance and molecular basis of a novel immunodeficiency disorder in an extended kindred.

Whole-exome sequencing was performed to identify the genetic change. Molecular and cellular techniques were utilized to assess the variant impact on immune function and RNA regulation.

We studied 3 individuals from an extended kindred presenting with a spectrum of infections, lymphoproliferation, and autoimmune manifestations. Whole-exome sequencing performed in patient 1 identified a novel heterozygous missense c.T674C (p.F225S) variant in the highly conserved ROQ domain sequence of RC3H1, encoding the RNA-binding protein Roquin-1. F225S Roquin-1 variant family segregation indicated an autosomal-dominant mode of inheritance. The patient's primary cells as well as F225S Roquin-1-transfected cells demonstrated a marked rise in ICOS1, IL6, and other proinflammatory Roquin target RNA, with increased message stability indicating lack of repressor Roquin-1 activity. The resultant aberrations in immunity included a selective antibody deficiency, expansion of CD8 memory and double-positive CD4⁺CD8⁺ T cells, skewed TCR repertoire, and enhanced IL-2 secretion and T-cell proliferation.

The RNA-binding protein Roquin-1 plays a critical role in the regulation of immune responses. A single heterozygous variant within the ROQ domain of Roquin-1 manifests as primary immunodeficiency, resulting in variable severity of infections, autoimmune features, and hyperinflammation.