Mutations in TOP3A Cause a Bloom Syndrome-like Disorder

GOSgene

doi:10.1016/j.ajhg.2018.07.001

Mutations in TOP3A Cause a Bloom Syndrome-like Disorder

GOSgene

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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.

Original language	English
Journal	American Journal of Human Genetics
Volume	103
Issue number	2
Pages (from-to)	221-231
Number of pages	11
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2018.07.001
Publication status	Published - 2018

Keywords

BLM
Bloom syndrome
double Holliday junction dissolution
genomic instability
RecQ helicases
topoisomerase III

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10.1016/j.ajhg.2018.07.001Licence: CC BY-NC-ND

Mutations in TOP3A Cause a Bloom Syndrome-like DisorderFinal published version, 1.24 MBLicence: CC BY-NC-ND

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@article{a0dd5707f4d74019b6327e58154f9f10,

title = "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{\textquoteright} 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.",

keywords = "BLM, Bloom syndrome, double Holliday junction dissolution, genomic instability, RecQ helicases, topoisomerase III",

author = "Martin, {Carol Anne} and Kata Sarl{\'o}s and Logan, {Clare V.} and Thakur, {Roshan Singh} and Parry, {David A.} and Bizard, {Anna H.} and Andrea Leitch and Louise Cleal and Ali, {Nadia Shaukat} and Al-Owain, {Mohammed A.} and William Allen and Janine Altm{\"u}ller and Miriam Aza-Carmona and Barakat, {Bushra A.Y.} and Jimena Barraza-Garc{\'i}a and Amber Begtrup and Massimo Bogliolo and Cho, {Megan T.} and Jaime Cruz-Rojo and Dhahrabi, {Hassan Ali Mundi} and Elcioglu, {Nursel H.} and Gorman, {Gr{\'a}inne S.} and Rebekah Jobling and Ian Kesterton and Yoshihito Kishita and Masakazu Kohda and {Le Quesne Stabej}, Polona and Malallah, {Asam Jassim} and Peter N{\"u}rnberg and Akira Ohtake and Yasushi Okazaki and Roser Pujol and Ramirez, {Maria Jos{\'e}} and Anya Revah-Politi and Masaru Shimura and Paul Stevens and Taylor, {Robert W.} and Lesley Turner and Hywel Williams and Carolyn Wilson and G{\"o}khan Yigit and Laura Zahavich and Alkuraya, {Fowzan S.} and Jordi Surralles and Alejandro Iglesias and Kei Murayama and Bernd Wollnik and Mehul Dattani and Heath, {Karen E.} and Hickson, {Ian D.} and GOSgene",

year = "2018",

doi = "10.1016/j.ajhg.2018.07.001",

language = "English",

volume = "103",

pages = "221--231",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "2",

}

TY - JOUR

T1 - Mutations in TOP3A Cause a Bloom Syndrome-like Disorder

AU - Martin, Carol Anne

AU - Sarlós, Kata

AU - Logan, Clare V.

AU - Thakur, Roshan Singh

AU - Parry, David A.

AU - Bizard, Anna H.

AU - Leitch, Andrea

AU - Cleal, Louise

AU - Ali, Nadia Shaukat

AU - Al-Owain, Mohammed A.

AU - Allen, William

AU - Altmüller, Janine

AU - Aza-Carmona, Miriam

AU - Barakat, Bushra A.Y.

AU - Barraza-García, Jimena

AU - Begtrup, Amber

AU - Bogliolo, Massimo

AU - Cho, Megan T.

AU - Cruz-Rojo, Jaime

AU - Dhahrabi, Hassan Ali Mundi

AU - Elcioglu, Nursel H.

AU - Gorman, Gráinne S.

AU - Jobling, Rebekah

AU - Kesterton, Ian

AU - Kishita, Yoshihito

AU - Kohda, Masakazu

AU - Le Quesne Stabej, Polona

AU - Malallah, Asam Jassim

AU - Nürnberg, Peter

AU - Ohtake, Akira

AU - Okazaki, Yasushi

AU - Pujol, Roser

AU - Ramirez, Maria José

AU - Revah-Politi, Anya

AU - Shimura, Masaru

AU - Stevens, Paul

AU - Taylor, Robert W.

AU - Turner, Lesley

AU - Williams, Hywel

AU - Wilson, Carolyn

AU - Yigit, Gökhan

AU - Zahavich, Laura

AU - Alkuraya, Fowzan S.

AU - Surralles, Jordi

AU - Iglesias, Alejandro

AU - Murayama, Kei

AU - Wollnik, Bernd

AU - Dattani, Mehul

AU - Heath, Karen E.

AU - Hickson, Ian D.

AU - GOSgene

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - BLM

KW - Bloom syndrome

KW - double Holliday junction dissolution

KW - genomic instability

KW - RecQ helicases

KW - topoisomerase III

U2 - 10.1016/j.ajhg.2018.07.001

DO - 10.1016/j.ajhg.2018.07.001

M3 - Journal article

C2 - 30057030

AN - SCOPUS:85052988354

SN - 0002-9297

VL - 103

SP - 221

EP - 231

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 2

ER -

Mutations in TOP3A Cause a Bloom Syndrome-like Disorder

Abstract

Keywords

UN SDGs

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