Martin, Carol-Anne ORCID: 0000-0001-5914-2757, Sarlos, Kata, Logan, Clare V., Thakur, Roshan Singh, Parry, David A., Bizard, Anna H., Leitch, Andrea, Cleal, Louise, Ali, Nadia Shaukat, Al-Owain, Mohammed A., Allen, William, Altmueller, Janine, Aza-Carmona, Miriam, Barakat, Bushra A. Y., Barraza-Garcia, Jimena, Begtrup, Amber, Bogliolo, Massimo ORCID: 0000-0001-8240-7784, Cho, Megan T., Cruz-Rojo, Jaime, Dhahrabi, Hassan Ali Mundi, Elcioglu, Nursel H., Gorman, Grainne S., Jobling, Rebekah, Kesterton, Ian, Kishita, Yoshihito ORCID: 0000-0003-4978-1680, Kohda, Masakazu, Stabej, Polona Le Quesne, Malallah, Asam Jassim, Nuernberg, Peter, Ohtake, Akira, Okazaki, Yasushi, Pujol, Roser, Ramirez, Maria Jose, Revah-Politi, Anya, Shimura, Masaru, Stevens, Paul, Taylor, Robert W., Turner, Lesley, Williams, Hywel ORCID: 0000-0001-7758-0312, Wilson, Carolyn, Yigit, Goekhan, Zahavich, Laura, Alkuraya, Fowzan S., Surralles, Jordi, Iglesais, Alejandro, Murayama, Kei, Wollnik, Bernd, Dattani, Mehul, Heath, Karen E., Hickson, Ian D. and Jackson, Andrew P. (2018). Mutations in TOP3A Cause a Bloom Syndrome-like Disorder. Am. J. Hum. Genet., 103 (2). S. 221 - 232. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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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 (TopIII alpha), 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 TopIII alpha, 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 TopIII alpha 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Martin, Carol-AnneUNSPECIFIEDorcid.org/0000-0001-5914-2757UNSPECIFIED
Sarlos, KataUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Logan, Clare V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thakur, Roshan SinghUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parry, David A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bizard, Anna H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leitch, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cleal, LouiseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ali, Nadia ShaukatUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Al-Owain, Mohammed A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Allen, WilliamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aza-Carmona, MiriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barakat, Bushra A. Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barraza-Garcia, JimenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Begtrup, AmberUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bogliolo, MassimoUNSPECIFIEDorcid.org/0000-0001-8240-7784UNSPECIFIED
Cho, Megan T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cruz-Rojo, JaimeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dhahrabi, Hassan Ali MundiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Elcioglu, Nursel H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gorman, Grainne S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jobling, RebekahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kesterton, IanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kishita, YoshihitoUNSPECIFIEDorcid.org/0000-0003-4978-1680UNSPECIFIED
Kohda, MasakazuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stabej, Polona Le QuesneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Malallah, Asam JassimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ohtake, AkiraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Okazaki, YasushiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pujol, RoserUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramirez, Maria JoseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Revah-Politi, AnyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shimura, MasaruUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stevens, PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Taylor, Robert W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Turner, LesleyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Williams, HywelUNSPECIFIEDorcid.org/0000-0001-7758-0312UNSPECIFIED
Wilson, CarolynUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yigit, GoekhanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zahavich, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alkuraya, Fowzan S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Surralles, JordiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iglesais, AlejandroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Murayama, KeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wollnik, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dattani, MehulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heath, Karen E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hickson, Ian D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jackson, Andrew P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-176731
DOI: 10.1016/j.ajhg.2018.07.001
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 103
Number: 2
Page Range: S. 221 - 232
Date: 2018
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TOPOISOMERASE-III-ALPHA; SYNDROME GENE-PRODUCT; SYNDROME PROTEIN; CHROMOSOME SEGREGATION; ESSENTIAL COMPONENT; GROWTH FAILURE; HELICASE; BLM; RECOMBINATION; DECATENATIONMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17673

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