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

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posted on 2023-06-09, 01:14 authored by Saskia N van der Crabben, Marije P Hennus, Grant McGregor, Deborah I Ritter, Sandesh C S Nagamani, Owen Wells, Magdalena Harakalova, Ivan K Chinn, Aaron Alt, Lucie Vondrova, Ron Hochstenbach, Joris M van Montfrans, Suzanne W Terheggen-Lagro, Stef van Lieshout, Markus J van Roosmalen, Ivo Renkens, Karen Duran, Isaac J Nijman, Wigard P Kloosterman, Eric Hennekam, Jordan S Orange, Peter M van Hasselt, David A Wheeler, Jan J Palecek, Alan LehmannAlan Lehmann, Antony OliverAntony Oliver, Laurence PearlLaurence Pearl, Sharon E Plon, Jo Murray, Gijs van Haaften
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.

Funding

Structure of the Smc5-6 DNA repair and chromosome maintenance protein complex; G0256; MRC-MEDICAL RESEARCH COUNCIL; G1001668

Smc5/6 and replication fork stability; G0179; MRC-MEDICAL RESEARCH COUNCIL; G0901011

History

Publication status

  • Published

File Version

  • Published version

Journal

Journal of Clinical Investigation

ISSN

0021-9738

Publisher

American Society for Clinical Investigation

Issue

8

Volume

126

Page range

2881-2892

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2016-05-13

First Open Access (FOA) Date

2016-08-15

First Compliant Deposit (FCD) Date

2016-05-13

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