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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.

journal_name

Am J Hum Genet

journal_title

American journal of human genetics

authors

Martin CA,Sarlós K,Logan CV,Thakur RS,Parry DA,Bizard AH,Leitch A,Cleal L,Ali NS,Al-Owain MA,Allen W,Altmüller J,Aza-Carmona M,Barakat BAY,Barraza-García J,Begtrup A,Bogliolo M,Cho MT,Cruz-Rojo J,Dhahrabi HAM,Elci

doi

10.1016/j.ajhg.2018.07.001

subject

Has Abstract

pub_date

2018-08-02 00:00:00

pages

221-231

issue

2

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(18)30228-3

journal_volume

103

pub_type

杂志文章

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