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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.

SUBMITTER: van der Crabben SN

PROVIDER: S-EPMC4966312 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

van der Crabben Saskia N SN Hennus Marije P MP McGregor Grant A GA Ritter Deborah I DI Nagamani Sandesh C S SC Wells Owen S OS Harakalova Magdalena M Chinn Ivan K IK Alt Aaron A Vondrova Lucie L Hochstenbach Ron R van Montfrans Joris M JM Terheggen-Lagro Suzanne W SW van Lieshout Stef S van Roosmalen Markus J MJ Renkens Ivo I Duran Karen K Nijman Isaac J IJ Kloosterman Wigard P WP Hennekam Eric E Orange Jordan S JS van Hasselt Peter M PM Wheeler David A DA Palecek Jan J JJ Lehmann Alan R AR Oliver Antony W AW Pearl Laurence H LH Plon Sharon E SE Murray Johanne M JM van Haaften Gijs G

The Journal of clinical investigation 20160718 8

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 ...[more]

PMID: 27427983

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Project description:Nijmegen breakage syndrome (NBS) is a rare autosomal recessive syndrome of chromosomal instability mainly characterized by microcephaly at birth, combined immunodeficiency and predisposition to malignancies. Due to a founder mutation in the underlying NBN gene (c.657_661del5) the disease is encountered most frequently among Slavic populations. The principal clinical manifestations of the syndrome are: microcephaly, present at birth and progressive with age, dysmorphic facial features, mild growth retardation, mild-to-moderate intellectual disability, and, in females, hypergonadotropic hypogonadism. Combined cellular and humoral immunodeficiency with recurrent sinopulmonary infections, a strong predisposition to develop malignancies (predominantly of lymphoid origin) and radiosensitivity are other integral manifestations of the syndrome. The NBN gene codes for nibrin which, as part of a DNA repair complex, plays a critical nuclear role wherever double-stranded DNA ends occur, either physiologically or as a result of mutagenic exposure. Laboratory findings include: (1) spontaneous chromosomal breakage in peripheral T lymphocytes with rearrangements preferentially involving chromosomes 7 and 14, (2) sensitivity to ionizing radiation or radiomimetics as demonstrated in vitro by cytogenetic methods or by colony survival assay, (3) radioresistant DNA synthesis, (4) biallelic hypomorphic mutations in the NBN gene, and (5) absence of full-length nibrin protein. Microcephaly and immunodeficiency are common to DNA ligase IV deficiency (LIG4 syndrome) and severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation due to NHEJ1 deficiency (NHEJ1 syndrome). In fact, NBS was most commonly confused with Fanconi anaemia and LIG4 syndrome. Genetic counselling should inform parents of an affected child of the 25% risk for further children to be affected. Prenatal molecular genetic diagnosis is possible if disease-causing mutations in both alleles of the NBN gene are known. No specific therapy is available for NBS, however, hematopoietic stem cell transplantation may be one option for some patients. Prognosis is generally poor due to the extremely high rate of malignancies.

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

Publications

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

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