Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease
Saskia N. van der Crabben ... Johanne M. Murray, Gijs van Haaften
Saskia N. van der Crabben ... Johanne M. Murray, Gijs van Haaften
Published August 1, 2016
Citation Information: J Clin Invest. 2016;126(8):2881-2892. doi:10.1172/JCI82890.
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Categories: Research Article Genetics

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

Saskia N. van der Crabben, Marije P. Hennus, Grant A. McGregor, Deborah I. Ritter, Sandesh C.S. Nagamani, Owen S. 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 R. Lehmann, Antony W. Oliver, Laurence H. Pearl, Sharon E. Plon, Johanne M. Murray, Gijs van Haaften

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Affected individuals with NSMCE3 mutations with severe lung disease immu...

Figure 1

Affected individuals with NSMCE3 mutations with severe lung disease immunodeficiency and chromosome breakage syndrome (LICS).

(A) Pedigree of family 1. (B) Facial appearance of affected individual A (note the thin skin and prominent veins). (C) Chest X-ray of individual A, 4 days before admission at the PICU, showing severe PARDS consisting of bilateral alveolar infiltrates and (D) 14 days after admission, showing diffuse interstitial and alveolar infiltrates, pneumomediastinum, and subcutaneous emphysema. (E) Facial appearance of affected individual B. No dysmorphic facial features were noted. (F) Chest X-ray of individual B on admission at the PICU showing a predominantly right-sided alveolar infiltrate and (G) 18 days after admission showing severe PARDS complicated by pneumomediastinum, pneumothorax, and subcutaneous emphysema. (H) Pedigree of family 2. (I) Chest X-ray showing bilateral interstitial infiltrates of affected individuals C and D. (J) Corresponding chest CT scan at the level of the carina showing bilateral ground glass haziness with areas of consolidation and interposed air bronchogram. (K) Lung biopsy of individual D at day 6 showing patchy acute interstitial infiltrates with lymphocyte predominance. In the areas of parenchymal injury, there was marked alveolar epithelial hyperplasia, consistent with early diffuse alveolar damage (original magnification, ×400). (L) Lung explant showing significant damage that includes overinflation, macroscopic cystic changes, and intracystic hemorrhage. (M) Schematic representation of the NSMCE3 protein with the identified missense mutations of the affected individuals. The homozygous mutations from the affected individuals from the Netherlands (NL; A and B) are indicated above and the compound heterozygous mutations from the affected individuals from the United States (US; C and D) are depicted below the figure.