Inherited TOP2B Mutation: Possible Confirmation of Mutational Hotspots in the TOPRIM Domain

Excerpt

B cell deficiencies as immunological phenotypes of human diseases have long been assigned to X-liked or autosomal recessive monogenic variants affecting the expression of the pre-B cell receptor (pre-BCR) or pre-BCR signaling [1]. The prototypical example is X-linked agammaglobulinemia (XLA), which is characterized by markedly reduced B cells and was first described by Bruton in 1952 [2]. Autosomal recessive etiologies of agammaglobulinemia include μ heavy chain deficiency (IGHM), λ5 deficiency (IGLL1), Igα deficiency (CD79A), Igβ deficiency (CD79B), BLNK deficiency (BLNK), p110δ deficiency (PIK3CD), p85 deficiency (PIK3R1), E47 transcription factor deficiency (TCF3), and SLC39A7 (ZIP7) deficiency (SLC39A7) [3]. Autosomal dominant etiology has also been reported, including E47 transcription factor (TCF3) mutation [3]. Most recently, heterozygous mutations were reported in TOP2B, which encodes a type II β DNA topoisomerase that regulates DNA topology and mitigates topological stress during DNA replication and gene transcription [4]. Only ten patients with TOP2B-mediated immunodeficiency have been published in the medical literature since 2001; all of them had dominant-negative mutations affecting TOPRIM, the DNA gating domain of TOP2B [4‐9]. Delays in diagnosis are common in this disease which results in remarkably associated morbidity. …