TY  - JOUR
A1  - Dirks, Johannes
A1  - Haase, Gabriele
A1  - Cantaert, Tineke
A1  - Frey, Lea
A1  - Klaas, Moritz
A1  - Rickert, Christian H.
A1  - Girschick, Hermann
A1  - Meffre, Eric
A1  - Morbach, Henner
T1  - A novel AICDA splice-site mutation in two siblings with HIGM2 permits somatic hypermutation but abrogates mutational targeting
JF  - Journal of Clinical Immunology
N2  - Hyper-IgM syndrome type 2 (HIGM2) is a B cell intrinsic primary immunodeficiency caused by mutations in AICDA encoding activation-induced cytidine deaminase (AID) which impair immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM). Whereas autosomal-recessive AID-deficiency (AR-AID) affects both CSR and SHM, the autosomal-dominant form (AD-AID) due to C-terminal heterozygous variants completely abolishes CSR but only partially affects SHM. AR-AID patients display enhanced germinal center (GC) reactions and autoimmune manifestations, which are not present in AD-AID, suggesting that SHM but not CSR regulates GC reactions and peripheral B cell tolerance. Herein, we describe two siblings with HIGM2 due to a novel homozygous AICDA mutation (c.428-1G > T) which disrupts the splice acceptor site of exon 4 and results in the sole expression of a truncated AID variant that lacks 10 highly conserved amino acids encoded by exon 4 (AID-ΔE4a). AID-ΔE4a patients suffered from defective CSR and enhanced GC reactions and were therefore indistinguishable from other AR-AID patients. However, the AID-ΔE4a variant only partially affected SHM as observed in AD-AID patients. In addition, AID-ΔE4a but not AD-AID patients revealed impaired targeting of mutational hotspot motives and distorted mutational patterns. Hence, qualitative defects in AID function and altered SHM rather than global decreased SHM activity may account for the disease phenotype in these patients.
KW  - hyper-IgM syndrome type 2 (HIGM2)
KW  - AICDA
KW  - AID-ΔE4a
KW  - AD-AID
KW  - mutational targeting
KW  - somatic hypermutation
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324253
VL  - 42
IS  - 4
ER  -