Introduction
Microcephalic primordial dwarfism (MPD) is used to collectively describe a heterogeneous group of disorders characterized by significant in utero and postnatal growth retardation alongside marked microcephaly.1 Bloom syndrome (MIM: 210900) is also associated with prenatal growth restriction, short stature, and microcephaly. It is distinguished by an erythematous sun-sensitive facial rash that can become evident during childhood.2 A predisposition to the development of cancer in early adulthood is also seen, and both solid tumors and hematological malignancies are a major cause of early death.3 Additionally, a key cytogenetic feature of Bloom syndrome is an increased number of sister chromatid exchanges (SCEs).4 Notably, when molecular testing is inconclusive, a finding of elevated SCEs is currently utilized for diagnostic confirmation of Bloom syndrome (see GeneReviews in Web Resources).
In 1995, Bloom syndrome was shown to be caused by mutations in BLM (MIM: 604610), which encodes a RecQ family DNA helicase.5 Mutations in BLM are typically biallelic loss-of-function mutations.6 BLM forms the BTRR complex with topoisomerase III alpha (TopIIIα) and RecQ-mediated genome instability proteins 1 and 2 (RMI1 and RMI2, respectively). Together, these proteins process double Holliday junctions (dHJs) that arise as a result of homologous-recombination-mediated repair of double-stranded DNA (dsDNA) breaks during DNA synthesis.7, 8, 9, 10, 11, 12, 13 The process of dHJ dissolution requires two steps. First, the BTRR complex promotes the convergent branch migration of the dHJ to create a hemicatenane intermediate, and then this structure is decatenated by TopIIIα in concert with RMI1 and RMI2.14, 15 Dissolution of a dHJ by this mechanism can be completed without any potentially detrimental exchanges between genetic markers flanking the original site of homologous recombination. The alternative processing of dHJs by Holliday junction resolvases (SLX-MUS81 and GEN1 nucleases) can yield crossover events, and increased usage of this pathway has been proposed to explain the increase in SCEs in BLM-deficient cells.16 Crossover events between homologous chromosomes can lead to loss of heterozygosity (LOH),17 which can be detrimental to cell survival and contribute to increased cancer predisposition.18 Additionally, unresolved recombination intermediates can persist into mitosis, leading to chromosome bridges, and act as a source of genome instability.19
Here, we report the identification of pathogenic mutations in TOP3A (MIM: 601243) in ten individuals with Bloom syndrome-like phenotypic features and characterize the cellular consequences of these mutations.