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
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 - https://doi.org/10.1172/JCI82890
DO - https://doi.org/10.1172/JCI82890
M3 - Article
C2 - 27427983
SN - 0021-9738
VL - 126
SP - 2881
EP - 2892
JO - The journal of clinical investigation
JF - The journal of clinical investigation
IS - 8
ER -