TY - JOUR
T1 - Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease
AU - Van Der Crabben, Saskia N.
AU - Hennus, Marije P.
AU - McGregor, Grant A.
AU - Ritter, Deborah I.
AU - Nagamani, Sandesh C.S.
AU - Wells, Owen S.
AU - Harakalova, Magdalena
AU - Chinn, Ivan K.
AU - Alt, Aaron
AU - Vondrova, Lucie
AU - Hochstenbach, Ron
AU - Van Montfrans, Joris M.
AU - Terheggen-Lagro, Suzanne W.
AU - Van Lieshout, Stef
AU - Van Roosmalen, Markus J.
AU - Renkens, Ivo
AU - Duran, Karen
AU - Nijman, Isaac J.
AU - Kloosterman, Wigard P.
AU - Hennekam, Eric
AU - Orange, Jordan S.
AU - Van Hasselt, Peter M.
AU - Wheeler, David A.
AU - Palecek, Jan J.
AU - Lehmann, Alan R.
AU - Oliver, Antony W.
AU - Pearl, Laurence H.
AU - Plon, Sharon E.
AU - Murray, Johanne M.
AU - Van Haaften, Gijs
N1 - Funding Information:
We thank the families of the patients for participating in our research studies, including providing the necessary biological and photographic material. We thank Glen Monroe for assistance on the figures. We thank Paulien Terhal and Tom Letteboer for their assistance in clinical genetics. J.M. Murray and A.R. Lehmann acknowledge MRC grant G0901011 and J.M. Murray, A. Alt, A.W. Oliver, and L.H. Pearl acknowledge MRC grant G1001668. O.S. Wells acknowledges MRC grant G1100074. J.J. Palecek acknowledges Czech Science Foundation grant GA13-00774S and Ministry of Education, Youth and Sports of the Czech Republic project CEITEC 2020 (LQ1601), S.E. Plon acknowledges Cancer Prevention Research Institute of Texas grant RP10189 and NIH R01-CA138836, and D.I. Ritter acknowledges the National Institute of General Medical Sciences and Institutional Research and Academic Career Development K12 GM084897-06. S.C.S. Nagamani is a recipient of the Doris Duke Charitable Foundation (DDCF) Clinical Scientist Development Award. This work was supported by DDCF grant 2013095. The project described was supported by Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (IDDRC) grant 1 U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development or the NIH
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84983355031&partnerID=8YFLogxK
U2 - 10.1172/JCI82890
DO - 10.1172/JCI82890
M3 - Article
C2 - 27427983
AN - SCOPUS:84983355031
SN - 0021-9738
VL - 126
SP - 2881
EP - 2892
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 8
ER -