IKZF1 Loss-of-Function Variant Causes Autoimmunity and Severe Familial Antiphospholipid Syndrome
To the Editor,
Ikaros is a transcription factor with key roles in lymphocyte development and homeostasis. It is encoded by the IKAROS family zinc finger protein 1 (IKZF1) gene, which contains highly conserved N-terminal and C-terminal zinc finger domains and is highly expressed in hematopoietic cells. The functions of Ikaros were first illustrated in different sets of IKZF1-deficient mice. In humans, IKZF1 loss-of-function (LOF) somatic variants are associated with leukemogenesis in B cell acute lymphoblastic leukemia (B-ALL) . More recently, different germline heterozygous variants, acting either by haploinsufficiency or by a dominant negative effect in IKZF1, were identified in autosomal dominant forms of common variable immunodeficiencies (CVID) or combined immunodeficiencies (CID) [2, 3, 4]. A series of families showed a progressive loss of B cells and hypogammaglobulinemia, but the absence of symptoms in several mutated patients suggests an incomplete penetrance. Additional...
We thank C. Bole and S. Hanein (Institut Imagine) for exome sequencing. We thank JL Pasquali and P Kieffer for clinical data. We thank S. Bahram for critical reading. We thank S Jung for her helpful comments.
A.S.K., A. G, and Y. D are supported by grants from the French Ministry of Health (PHRC IR 2011), from the Société Nationale Française de Médecine Interne (SNFMI), from the Hôpitaux Universitaires de Strasbourg (HUS), and from the EU-funded (ERDF) project INTERREG V “RARENET.” R.C. is supported by the Agence Nationale de la Recherche (ANR) (ANR-11-LABX-0070_TRANSPLANTEX), MSD Avenir, and the INTERREG V European regional development fund (European Union) program (project 3.2 TRIDIAG).
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Conflict of Interest
The authors declare that they have no competing interests.
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