Alt. symbols: TOPIIB | top2beta

Approved name: DNA topoisomerase II beta
Alt. names: topoisomerase (DNA) II beta 180kDa

Location: 3p24.2: 25597978 - 25664909 (-)
Gene type: protein_coding, 26 transcripts.

Scores: LoFtool: 0.820000 | pLI: 0.99731109 | LOEUF: 0.247

HGNC: 11990

NCBI: 7155, RefSeq: NG_052961.1

Ensembl: ENSG00000077097.17

LRG_ | Status: none

OMIM: 126431

Expression | ProteinAtlas

TOP2B encodes a topoisomerase that can relax both negative and positive supercoils. It decatenates DNA by binding to 2 double-stranded DNA (dsDNA) molecules, generating a double-stranded break in one of the strands, passing the intact strand through the broken strand, and re-ligating the broken strand. Signal-dependent activation of gene transcription by nuclear receptors and other classes of DNA binding transcription factors has been found to rely on such TOP2B-dependent, transient, site-specific dsDNA break formation. Moreover, its enzymatic activity appears to be important for the expression of long genes in neuronal lineages, consistent with the murine loss-of-function (LOF) phenotype.

Monoallelic mutations in TOP2B have been associated with an autosomal dominant primary immunodeficiency with specifically impaired B-cell development and function. Edery et al. (2001) first reported a 3-generation family with 4 affected family members presenting with B cell immunodeficiency, distal limbs abnormalities, genitourinary malformations, and mildly dysmorphic features but normal growth and intelligence (PMID: 11476068), followed by the identification of a second family by Tischkowitz e t al. (2004) (PMID: 15521984). In parallel, Hoffman et al. (2001), reported a 6 year old girl with isolated humoral immunodeficiency, microcephaly, postnatal growth and developmental delays, and unique craniofacial, limb and genitourinary dysmoprhisms. Her immunophenotype was notable for recurrent sinopulmonary infections, pneumococcal bacteremia, with hypogammaglobulinemia and absent B cells on labs (PMID: 11152140). A number of additional patients with similar features were subsequently reported by Hugle et al. (2010) (PMID: 21204224). Thus, this condition came to be called either BILU (B cell Immunodeficiency, Limb anomalies, and Urogenital malformations) or Hoffman syndrome [MIM: 609296]. However, it was not until Broderick et al. (2019) that an underlying molecular etiology was suggested. These authors reported the identification of 2 heterozygous missense and and 1 in-frame deletion mutation affecting the TOPRIM, or DNA gating, domain of TOP2B (PMID: 31409799). As for the previously reported patients, affected individuals showed recurrent bacterial infections, severe hypogammaglobulinemia, and absent CD19+ B cells with normal T-cell responses to mitogens. Using functional studies in yeast and mice, the authors showed that the mutations exerted a dominant negative effect on enzyme function, leading to defects in B-cell development and activation in response to antigen stimulation. This association was subsequently expanded by Papapietro et al. (2020) and Erdos et al. (2021), all noting dominant negative mutations (A485P, S483L, E587del, G633S) in the TOPRIM domain thus far (PMID: 32128574, 33459963). Additionally, Lam et al. (2017) reported the finding of a de novo heterozygous variant (c.187C>T; p.H58Y) in the ATPase domain for a 15 yo girl with developmental delay, intellectual disability, hypotonia, microcephaly and autistic features (PMID: 28343847). Unfortunately, no infectious history or immunophenotyping was performed or provided. This same variant (c.187C>T; p.H63Y in their report) was subsequently identified by Hiraide et al. (2020) in a 7-year-old girl with hypotonia, stereotypic hand movements, epilepsy, global developmental delay, and autism spectrum disorder (PMID: 31953910) – they noted no episodes of recurrent infections. Finally, Xia et al. (2019) reported autosomal dominant segregation of a C-terminal domain variant (D1613H) in a Chinese family with 3-generations of sensorineural hearing loss (PMID: 31198993). This, along with 2 other variants K1435del and L721F, were also identified in patients with sporadic hearing loss. Using zebrafish studies, the authors proposed a model by which TOP2B LOF resulted in decreased cell proliferation via PI3K?Akt signaling inhibition, leading to hearing loss. [Load More]