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A nonsense mutation of human XRCC4 is associated with adult-onset progressive encephalocardiomyopathy

We studied two monozygotic twins, born to first cousins, affected by a multisystem disease. At birth, they both presented with bilateral cryptorchidism and malformations. Since early adulthood, they developed a slowly progressive neurological syndrome, with cerebellar and pyramidal signs, cognitive...

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Autores principales: Bee, Leonardo, Nasca, Alessia, Zanolini, Alice, Cendron, Filippo, d'Adamo, Pio, Costa, Rodolfo, Lamperti, Costanza, Celotti, Lucia, Ghezzi, Daniele, Zeviani, Massimo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520657/
https://www.ncbi.nlm.nih.gov/pubmed/25872942
http://dx.doi.org/10.15252/emmm.201404803
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author Bee, Leonardo
Nasca, Alessia
Zanolini, Alice
Cendron, Filippo
d'Adamo, Pio
Costa, Rodolfo
Lamperti, Costanza
Celotti, Lucia
Ghezzi, Daniele
Zeviani, Massimo
author_facet Bee, Leonardo
Nasca, Alessia
Zanolini, Alice
Cendron, Filippo
d'Adamo, Pio
Costa, Rodolfo
Lamperti, Costanza
Celotti, Lucia
Ghezzi, Daniele
Zeviani, Massimo
author_sort Bee, Leonardo
collection PubMed
description We studied two monozygotic twins, born to first cousins, affected by a multisystem disease. At birth, they both presented with bilateral cryptorchidism and malformations. Since early adulthood, they developed a slowly progressive neurological syndrome, with cerebellar and pyramidal signs, cognitive impairment, and depression. Dilating cardiomyopathy is also present in both. By whole-exome sequencing, we found a homozygous nucleotide change in XRCC4 (c.673C>T), predicted to introduce a premature stop codon (p.R225*). XRCC4 transcript levels were profoundly reduced, and the protein was undetectable in patients' skin fibroblasts. XRCC4 plays an important role in non-homologous end joining of DNA double-strand breaks (DSB), a system that is involved in repairing DNA damage from, for example, ionizing radiations. Gamma-irradiated mutant cells demonstrated reduction, but not abolition, of DSB repair. In contrast with embryonic lethality of the Xrcc4 KO mouse, nonsense mutations in human XRCC4 have recently been associated with primordial dwarfism and, in our cases, with adult-onset neurological impairment, suggesting an important role for DNA repair in the brain. Surprisingly, neither immunodeficiency nor predisposition to malignancy was reported in these patients.
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spelling pubmed-45206572015-08-05 A nonsense mutation of human XRCC4 is associated with adult-onset progressive encephalocardiomyopathy Bee, Leonardo Nasca, Alessia Zanolini, Alice Cendron, Filippo d'Adamo, Pio Costa, Rodolfo Lamperti, Costanza Celotti, Lucia Ghezzi, Daniele Zeviani, Massimo EMBO Mol Med Research Articles We studied two monozygotic twins, born to first cousins, affected by a multisystem disease. At birth, they both presented with bilateral cryptorchidism and malformations. Since early adulthood, they developed a slowly progressive neurological syndrome, with cerebellar and pyramidal signs, cognitive impairment, and depression. Dilating cardiomyopathy is also present in both. By whole-exome sequencing, we found a homozygous nucleotide change in XRCC4 (c.673C>T), predicted to introduce a premature stop codon (p.R225*). XRCC4 transcript levels were profoundly reduced, and the protein was undetectable in patients' skin fibroblasts. XRCC4 plays an important role in non-homologous end joining of DNA double-strand breaks (DSB), a system that is involved in repairing DNA damage from, for example, ionizing radiations. Gamma-irradiated mutant cells demonstrated reduction, but not abolition, of DSB repair. In contrast with embryonic lethality of the Xrcc4 KO mouse, nonsense mutations in human XRCC4 have recently been associated with primordial dwarfism and, in our cases, with adult-onset neurological impairment, suggesting an important role for DNA repair in the brain. Surprisingly, neither immunodeficiency nor predisposition to malignancy was reported in these patients. John Wiley & Sons, Ltd 2015-07 2015-04-14 /pmc/articles/PMC4520657/ /pubmed/25872942 http://dx.doi.org/10.15252/emmm.201404803 Text en © 2015 The Authors. Published under the terms of the CC BY 4.0 license http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Bee, Leonardo
Nasca, Alessia
Zanolini, Alice
Cendron, Filippo
d'Adamo, Pio
Costa, Rodolfo
Lamperti, Costanza
Celotti, Lucia
Ghezzi, Daniele
Zeviani, Massimo
A nonsense mutation of human XRCC4 is associated with adult-onset progressive encephalocardiomyopathy
title A nonsense mutation of human XRCC4 is associated with adult-onset progressive encephalocardiomyopathy
title_full A nonsense mutation of human XRCC4 is associated with adult-onset progressive encephalocardiomyopathy
title_fullStr A nonsense mutation of human XRCC4 is associated with adult-onset progressive encephalocardiomyopathy
title_full_unstemmed A nonsense mutation of human XRCC4 is associated with adult-onset progressive encephalocardiomyopathy
title_short A nonsense mutation of human XRCC4 is associated with adult-onset progressive encephalocardiomyopathy
title_sort nonsense mutation of human xrcc4 is associated with adult-onset progressive encephalocardiomyopathy
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520657/
https://www.ncbi.nlm.nih.gov/pubmed/25872942
http://dx.doi.org/10.15252/emmm.201404803
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