AICDA – Hyper-IgM syndrome type 2

Activation-induced cytidine deaminase (AID), encoded by the AICDA gene, catalyzes cytidine deamination initiating somatic hypermutation (SHM) and class switch recombination (CSR) in B cells. Biallelic loss-of-function variants in AICDA underlie autosomal recessive Hyper-IgM syndrome type 2 (Hyper-IgM syndrome type 2), characterized by recurrent infections and absent IgG/IgA ([PMID:23803409]).

Genetic evidence for AID deficiency includes case reports of two Brazilian sisters homozygous for c.43T>C (p.Phe15Leu), who display absent CSR and SHM in vivo and fail to rescue CSR in Aicda–/– murine B cells ([PMID:23803409]). A second family with a homozygous splice acceptor variant c.428-1G>T showed defective CSR with partial SHM preservation, mirroring other autosomal recessive patients ([PMID:35246784]).

An autosomal dominant form of HIGM2 is caused by heterozygous C-terminal truncating variants in exon 5 (e.g., c.568C>T (p.Arg190Ter) and L189X), which abolish CSR while variably affecting SHM, demonstrating dosage-sensitive functions of the nuclear export signal domain ([PMID:15893695]; [PMID:38363477]).

The spectrum of pathogenic AICDA variants comprises missense (n = 23), nonsense, frameshift, and splice-site changes across exons 2–5, with recurrent alleles in consanguineous populations (e.g., c.389A>C (p.His130Pro) in North African patients) ([PMID:26545377]).

Functional assays in cell lines and murine models show that missense mutants in catalytic (class I) or C-terminal regions exhibit diminished deaminase activity, impaired recruitment of repair factors, and failure of CSR/SHM, consistent with a loss-of-function mechanism (murine AID R112H, F vs L; CΔ10/15) ([PMID:23803409]).

No credible conflicting evidence has been reported. AID deficiency is a well-established cause of HIGM2 with robust segregation, biochemical, and in vivo rescue data supporting causality.

Key Take-home: Loss-of-function variants in AICDA cause Hyper-IgM syndrome type 2 by abolishing CSR and SHM, enabling precise molecular diagnosis and informing immunoglobulin replacement and gene therapy approaches.

References

• Clinical immunology (Orlando, Fla.) • 2013 • A novel activation-induced cytidine deaminase (AID) mutation in Brazilian patients with hyper-IgM type 2 syndrome. PMID:23803409
• Journal of clinical immunology • 2022 • A Novel AICDA Splice-Site Mutation in Two Siblings with HIGM2 Permits Somatic Hypermutation but Abrogates Mutational Targeting. PMID:35246784
• Clinical immunology (Orlando, Fla.) • 2005 • Analysis of class switch recombination and somatic hypermutation in patients affected with autosomal dominant hyper-IgM syndrome type 2. PMID:15893695
• Journal of clinical immunology • 2024 • A Novel Heterozygous Variant in AICDA Impairs Ig Class Switching and Somatic Hypermutation in Human B Cells and is Associated with Autosomal Dominant HIGM2 Syndrome. PMID:38363477
• Immunogenetics • 2016 • Novel and recurrent AID mutations underlie prevalent autosomal recessive form of HIGM in consanguineous patients. PMID:26545377

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