title: Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease.
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.
authors.forename: Saskia N
authors.initials: SN
authors.lastname: van der Crabben
authors.forename: Marije P
authors.initials: MP
authors.lastname: Hennus
authors.forename: Grant A
authors.initials: GA
authors.lastname: McGregor
authors.forename: Deborah I
authors.initials: DI
authors.lastname: Ritter
authors.forename: Sandesh C S
authors.initials: SC
authors.lastname: Nagamani
authors.forename: Owen S
authors.initials: OS
authors.lastname: Wells
authors.forename: Magdalena
authors.initials: M
authors.lastname: Harakalova
authors.forename: Ivan K
authors.initials: IK
authors.lastname: Chinn
authors.forename: Aaron
authors.initials: A
authors.lastname: Alt
authors.forename: Lucie
authors.initials: L
authors.lastname: Vondrova
authors.forename: Ron
authors.initials: R
authors.lastname: Hochstenbach
authors.forename: Joris M
authors.initials: JM
authors.lastname: van Montfrans
authors.forename: Suzanne W
authors.initials: SW
authors.lastname: Terheggen-Lagro
authors.forename: Stef
authors.initials: S
authors.lastname: van Lieshout
authors.forename: Markus J
authors.initials: MJ
authors.lastname: van Roosmalen
authors.forename: Ivo
authors.initials: I
authors.lastname: Renkens
authors.forename: Karen
authors.initials: K
authors.lastname: Duran
authors.forename: Isaac J
authors.initials: IJ
authors.lastname: Nijman
authors.forename: Wigard P
authors.initials: WP
authors.lastname: Kloosterman
authors.forename: Eric
authors.initials: E
authors.lastname: Hennekam
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.forename: Peter M
authors.initials: PM
authors.lastname: van Hasselt
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Palecek
authors.forename: Alan R
authors.initials: AR
authors.lastname: Lehmann
authors.forename: Antony W
authors.initials: AW
authors.lastname: Oliver
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Pearl
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Plon
authors.forename: Johanne M
authors.initials: JM
authors.lastname: Murray
authors.forename: Gijs
authors.initials: G
authors.lastname: van Haaften
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000483:Alleles; D001402:B-Lymphocytes / Q000166:cytology; D018797:Cell Cycle Proteins / Q000235:genetics*; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone; D019457:Chromosome Breakage; D020090:Chromosome Segregation; D002875:Chromosomes / Q000648:ultrastructure; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008171:Lung Diseases / Q000235:genetics*; D008297:Male; D008540:Meiosis; D008938:Mitosis; D020125:Mutation, Missense; D010375:Pedigree; D011995:Recombination, Genetic; D013577:Syndrome; D013601:T-Lymphocytes / Q000166:cytology
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D047908:Intracellular Signaling Peptides and Proteins; C469927:NSMCE3 protein, human; C432931:SMC5 protein, human; C432932:SMC6 protein, human