A Novel AICDA Splice-Site Mutation in Two Siblings with HIGM2 Permits Somatic Hypermutation but Abrogates Mutational Targeting
© 2022. The Author(s)..
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.
| Errataetall: |
CommentIn: J Clin Immunol. 2022 May;42(4):713-715. - PMID 35332417 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:42 |
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| Enthalten in: |
Journal of clinical immunology - 42(2022), 4 vom: 05. Mai, Seite 771-782 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Dirks, Johannes [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.06.2022 Date Revised 18.08.2022 published: Print-Electronic CommentIn: J Clin Immunol. 2022 May;42(4):713-715. - PMID 35332417 Citation Status MEDLINE |
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| doi: |
10.1007/s10875-022-01233-5 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM337778655 |
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| 100 | 1 | |a Dirks, Johannes |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A Novel AICDA Splice-Site Mutation in Two Siblings with HIGM2 Permits Somatic Hypermutation but Abrogates Mutational Targeting |
| 264 | 1 | |c 2022 | |
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| 500 | |a CommentIn: J Clin Immunol. 2022 May;42(4):713-715. - PMID 35332417 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. The Author(s). | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Case Reports | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a AD-AID | |
| 650 | 4 | |a AICDA | |
| 650 | 4 | |a AID-ΔE4a | |
| 650 | 4 | |a Hyper-IgM syndrome type 2 | |
| 650 | 4 | |a Mutational targeting | |
| 650 | 4 | |a Somatic hypermutation | |
| 650 | 7 | |a AICDA (activation-induced cytidine deaminase) |2 NLM | |
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| 650 | 7 | |a Cytidine Deaminase |2 NLM | |
| 650 | 7 | |a EC 3.5.4.5 |2 NLM | |
| 700 | 1 | |a Haase, Gabriele |e verfasserin |4 aut | |
| 700 | 1 | |a Cantaert, Tineke |e verfasserin |4 aut | |
| 700 | 1 | |a Frey, Lea |e verfasserin |4 aut | |
| 700 | 1 | |a Klaas, Moritz |e verfasserin |4 aut | |
| 700 | 1 | |a Rickert, Christian H |e verfasserin |4 aut | |
| 700 | 1 | |a Girschick, Hermann |e verfasserin |4 aut | |
| 700 | 1 | |a Meffre, Eric |e verfasserin |4 aut | |
| 700 | 1 | |a Morbach, Henner |e verfasserin |4 aut | |
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