Hypomorphic function and somatic reversion of DOCK8 cause combined immunodeficiency without hyper-IgE.

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Loss-of-function mutations in DOCK8 (dedicator of cytokinesis 8) are associated with hyper-IgE syndrome, characterized by recurrent infections, allergies, and elevated IgE.
• Phenotypic variability in DOCK8 deficiency is significant, but the underlying molecular mechanisms remain poorly understood.

Observation:

• A novel compound heterozygous mutation in DOCK8 was identified in a patient with primary combined immunodeficiency, presenting atypically compared to classical DOCK8 deficiency.
• This mutation led to a truncated DOCK8 protein with hypomorphic (reduced but not absent) function.
• Somatic reversion of the DOCK8 mutation was observed, predominantly in T cells.

Findings:

• The identified DOCK8 mutation results in a hypomorphic protein, unlike previously described null mutations.
• Somatic reversion in T cells partially restored DOCK8 function.
• The combination of hypomorphic DOCK8 function and somatic reversion explains the patient's milder and atypical clinical presentation.

Implications:

• This study expands the known spectrum of DOCK8-associated diseases and immunodeficiency phenotypes.
• Understanding the interplay between hypomorphic mutations and somatic reversion provides insights into disease variability.
• Further research into DOCK8 function and its role in immune cell development and function is warranted.