Mutations in TOP3A Cause a Bloom Syndrome-like Disorder

Abstract

Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and increased cancer predisposition. Diagnostically, a hallmark feature is the presence of increased sister chromatid exchanges (SCEs) on cytogenetic testing. Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly. TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination. We also identify a homozygous truncating variant in RMI1, which encodes another component of the BTRR complex, in two individuals with microcephalic dwarfism. The TOP3A mutations substantially reduce cellular levels of TopIIIα, and consequently subjects' cells demonstrate elevated rates of SCE. Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome. Clinical features of mitochondrial dysfunction are evident in several individuals with biallelic TOP3A mutations, consistent with the recently reported additional function of TopIIIα in mitochondrial DNA decatenation. In summary, our findings establish TOP3A mutations as an additional cause of prenatal-onset short stature with increased cytogenetic SCEs and implicate the decatenation activity of the BTRR complex in their pathogenesis.

Systematic detection of brain protein-coding genes under positive selection during primate evolution and their roles in cognition

“…Some proteins linked to brain morphology disorders also displayed a divergence specifically in the hominin lineage: TTLL6, DYNC2LI1, and TOP3A respectively implicated in Joubert syndrome, ciliopathy, and microcephaly. TOP3A is particularly interesting since it is strongly conserved in Pan troglodytes and two hominin specific variants (RNA NM_004618, R831Q and E959G) are located in the vicinity of pathogenic mutations causing microcephaly 43 .…”

A humanized yeast phenomic model of deoxycytidine kinase to predict genetic buffering of nucleoside analog cytotoxicity

“…Human TOP3A was also UES for cytarabine in lung tissue (Fig 5C; 2-0.16-1 ). TOP3A is underexpressed in ovarian cancer, and mutations in TOP3A are associated with increased risk for acute myeloid leukemia, myelodysplastic syndromes, suggesting potential cancer vulnerabilities if somatic, but can also occur in the germline, which would lead to enhanced host toxicity [90-92].…”

Predominant cellular mitochondrial dysfunction in the TOP3A gene caused Bloom syndrome-like disorder

“…3.2 TOP3A loss moderately affects sister chromatid exchange and cell proliferation but not UV sensitivity Cells derived from TOP3A de ciency individuals were reported with elevated sister chromatid exchanges (SCEs), which is a typical characteristic of Bloom-like syndrome [15]. To investigate whether the affected patients in this study carry the similar cytological phenotype, fresh blood samples collected from the sister and an age-matched control were assayed microscopically for SCE events.…”

“…Cells derived from BLM-de cient individuals show more SCEs and genome instability [13,14]. Recently, individuals with balletic mutations in RMI1, RMI2, or TOP3A, had been described as Bloom syndrome-like disorder [15,16]. In total, 11 individuals with TOP3A de ciency-induced Bloom syndrome-like disorder caused by 8 different TOP3A mutations had been reported.…”