A Novel AICDA Splice-Site Mutation in Two Siblings with HIGM2 Permits Somatic Hypermutation but Abrogates Mutational...

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Hyper-IgM syndrome type 2 (HIGM2) is a primary immunodeficiency linked to mutations in AICDA, impacting B cell immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM).
• Autosomal-recessive AID deficiency (AR-AID) impairs both CSR and SHM, leading to enhanced germinal center (GC) reactions and autoimmunity.
• Autosomal-dominant AID deficiency (AD-AID) primarily affects CSR while partially impacting SHM, without the pronounced GC reactions seen in AR-AID.

Observation:

• A novel homozygous AICDA mutation (c.428-1G>T) was identified in two siblings with HIGM2.
• This mutation results in a truncated AID variant (AID-ΔE4a) lacking 10 amino acids from exon 4.
• Patients exhibited defective CSR and enhanced GC reactions, similar to AR-AID.

Findings:

• The AID-ΔE4a variant partially affected SHM, akin to AD-AID.
• Crucially, AID-ΔE4a demonstrated impaired targeting of mutational hotspots and distorted mutational patterns, unlike AD-AID.
• Qualitative defects in AID function and altered SHM patterns, rather than a global reduction in SHM, appear to drive the disease phenotype.

Implications:

• These findings suggest that qualitative alterations in somatic hypermutation, driven by specific AID defects, play a critical role in regulating germinal center reactions and peripheral B cell tolerance.
• Understanding these nuanced effects of AID mutations is crucial for diagnosing and potentially treating HIGM2 and related immunodeficiencies.
• The study highlights the complex relationship between AID function, SHM patterns, and the development of autoimmune manifestations in primary immunodeficiencies.