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

van der Crabben, Saskia N, Hennus, Marije P, McGregor, Grant, Ritter, Deborah I, Nagamani, Sandesh C S, Wells, Owen S, Harakalova, Magdalena, Chinn, Ivan K, Alt, Aaron, Vondrova, Lucie, Hochstenbach, Ron, van Montfrans, Joris M, Terheggen-Lagro, Suzanne W, van Lieshout, Stef, van Roosmalen, Markus J, Renkens, Ivo, Duran, Karen, Nijman, Isaac J, Kloosterman, Wigard P, Hennekam, Eric, Orange, Jordan S, van Hasselt, Peter M, Wheeler, David A, Palecek, Jan J, Lehmann, Alan R, Oliver, Antony W, Pearl, Laurence H, Plon, Sharon E, Murray, Johanne M and van Haaften, Gijs (2016) Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease. Journal of Clinical Investigation, 126 (8). pp. 2881-2892. ISSN 0021-9738

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Abstract

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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Depositing User: Gee Wheatley
Date Deposited: 13 May 2016 13:59
Last Modified: 17 Aug 2017 05:08
URI: http://sro.sussex.ac.uk/id/eprint/60994

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Project NameSussex Project NumberFunderFunder Ref
Smc5/6 and replication fork stabilityG0179MRC-MEDICAL RESEARCH COUNCILG0901011
Structure of the Smc5-6 DNA repair and chromosome maintenance protein complexG0256MRC-MEDICAL RESEARCH COUNCILG1001668