Variantes heterocigotas en DOCK2 que conducen a la susceptibilidad a enfermedades virales

Inborn errors of immunity (IEIs) are classically identified in infants and young children with severe or recurrent infections. However, hypomorphic variants with a partial loss of function can remain unrecognized until later in life and may underlie clinically significant susceptibility to infections in previously healthy individuals.

We investigated how three novel heterozygous variants in DOCK2 contribute to impaired anti-viral immunity, extending the understanding of DOCK2 deficiency beyond an autosomal recessive disease.

After identifying the first DOCK2 variant, we screened 1,109 exomes from three cohorts of patients with a history of at least one severe respiratory, bloodborne, or soft tissue infection. We assessed the biologic impact of each variant via functional and transcriptional assays of the patients' primary peripheral blood mononuclear cells and in cell-based overexpression systems.

Six individuals from three unrelated families, aged 3 months to 50 years, caried one of three heterozygous variants in DOCK2 and experienced severe infections with human papilloma virus, respiratory syncytial virus, or SARS-CoV-2. All variants reside within the DOCK2 domain that binds and stabilizes ELMO1. Each variant reduced DOCK2 protein expression, ELMO1 binding, and DOCK2 function, as shown by diminished Rac1 activation and selective defects in Toll-like receptor signaling. Weekly IFN-α therapy led to complete resolution of refractory warts in one patient, highlighting a potential therapeutic approach for DOCK2-associated immunodeficiency.

These findings expand the spectrum of DOCK2-related disease by showing that heterozygous pathogenic variants disrupting DOCK2-ELMO1 interactions impair protein stability and anti-viral immunity, revealing a previously unrecognized IEI affecting otherwise healthy individuals.