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

TitleDestabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease.
Publication TypeJournal Article
Year of Publication2016
Authorsvan der Crabben, SN, Hennus, MP, McGregor, GA, Ritter, DI, Nagamani, SCS, Wells, OS, Harakalova, M, Chinn, IK, Alt, A, Vondrova, L, Hochstenbach, R, van Montfrans, JM, Terheggen-Lagro, SW, van Lieshout, S, van Roosmalen, MJ, Renkens, I, Duran, K, Nijman, IJ, Kloosterman, WP, Hennekam, E, Orange, JS, van Hasselt, PM, Wheeler, DA, Palecek, JJ, Lehmann, AR, Oliver, AW, Pearl, LH, Plon, SE, Murray, JM, van Haaften, G
JournalJ Clin Invest
Volume126
Issue8
Pagination2881-92
Date Published2016 Aug 01
ISSN1558-8238
KeywordsAbnormalities, Multiple, Alleles, B-Lymphocytes, Cell Cycle Proteins, Cell Proliferation, Child, Child, Preschool, Chromosomal Proteins, Non-Histone, Chromosome Breakage, Chromosome Segregation, Chromosomes, DNA Damage, DNA Repair, DNA Replication, Family Health, Female, Fibroblasts, Homozygote, Humans, Infant, Intracellular Signaling Peptides and Proteins, Lung Diseases, Male, Meiosis, Mitosis, Mutation, Missense, Pedigree, Recombination, Genetic, Syndrome, T-Lymphocytes
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.

DOI10.1172/JCI82890
Alternate JournalJ Clin Invest
PubMed ID27427983
PubMed Central IDPMC4966312
Grant ListG0901011 / MRC_ / Medical Research Council / United Kingdom
K12 GM084897 / GM / NIGMS NIH HHS / United States
U54 HD083092 / HD / NICHD NIH HHS / United States
2013095 / DDCF / Doris Duke Charitable Foundation / United States
R01 CA138836 / CA / NCI NIH HHS / United States
G1001668 / MRC_ / Medical Research Council / United Kingdom
14532 / CRUK_ / Cancer Research UK / United Kingdom
G1100074 / MRC_ / Medical Research Council / United Kingdom

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