Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease

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Publikace nespadá pod Filozofickou fakultu, ale pod Středoevropský technologický institut. Oficiální stránka publikace je na webu muni.cz.
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VAN DER CRABBEN Saskia HENNUS Marije MCGREGOR Grant RITTER Deborah NAGAMANI Sandesh WELLS Owen HARAKALOVA Magdalena CHINN Ivan ALT Aaron VONDROVÁ Lucie HOCHSTENBACH Ron VAN MONTFRANS Joris TERHEGGEN-LAGRO Suzanne VAN LIESHOUT Stef VAN ROOSMALEN Markus RENKENS Ivo DURAN Karen NIJMAN Isaac KLOOSTERMAN Wigard HENNEKAM Eric ORANGE Jordan VAN HASSELT Peter WHEELER David PALEČEK Jan LEHMANN Alan OLIVER Antony William PEARL Laurence PLON Sharon MURRAY Johanne VAN HAAFTEN Gijs

Rok publikování 2016
Druh Článek v odborném periodiku
Časopis / Zdroj Journal of Clinical Investigation
Fakulta / Pracoviště MU

Středoevropský technologický institut

Citace
www https://www.jci.org/articles/view/82890
Doi http://dx.doi.org/10.1172/JCI82890
Obor Genetika a molekulární biologie
Klíčová slova STALLED REPLICATION FORKS; DOUBLE-STRAND BREAKS; HUMAN CELL STRAINS; DNA-REPAIR; HOMOLOGOUS RECOMBINATION; ATAXIA-TELANGIECTASIA; LIGASE ACTIVITY; GENE; PROTEINS; IDENTIFICATION
Popis The structural maintenance of chromosomes (SMC) family of proteins supports mitotic proliferation, meiosis, and DNA repair to control genomic stability. Impairments in chromosome maintenance are linked to rare chromosome breakage disorders. Here, we have identified a chromosome breakage syndrome associated with severe lung disease in early childhood. Four children from two unrelated kindreds died of severe pulmonary disease during infancy following viral pneumonia with evidence of combined T and B cell immunodeficiency. Whole exome sequencing revealed biallelic missense mutations in the NSMCE3 (also known as NDNL2) gene, which encodes a subunit of the SMC5/6 complex that is essential for DNA damage response and chromosome segregation. The NSMCE3 mutations disrupted interactions within the SMC5/6 complex, leading to destabilization of the complex. Patient cells showed chromosome rearrangements, micronuclei, sensitivity to replication stress and DNA damage, and defective homologous recombination. This work associates missense mutations in NSMCE3 with an autosomal recessive chromosome breakage syndrome that leads to defective T and B cell function and acute respiratory distress syndrome in early childhood.
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