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.

An acetyltransferase-independent function of Eso1 regulates centromere cohesion

“…Thus it will be important to understand whether there is a centromeric function for human ESCO1/2, as well as the relationship between the spindle checkpoint and ESCO1/2 (and other cohesin and Smc5/6 components) in the developmental disorders and cancers in which these genes are mutated (Skibbens et al , 2013; Price et al , 2014; Cucco and Musio, 2016; van der Crabben et al , 2016). Indeed, SAC dysfunction may be an explanation as to why some tumor cells can survive loss-of-function mutations in cohesin, whereas normal cells cannot.…”

A Comprehensive Guide to the MAGE Family of Ubiquitin Ligases

“…Consistent with this, SMC5 and SMC6 protein levels were significantly reduced while MAGE-G1 protein was not detectable in fibroblasts from affected individuals [135]. Moreover, cells from subject B exhibited increased numbers of micronuclei, a hallmark of genome instability [135]. These cells also demonstrated hypersensitivity to various DNA damaging agents and defective homologous recombination.…”

“…Recently, a report associated missense mutations in MAGE-G1 with an autosomal recessive chromosome breakage syndrome that leads to severe lung disease in early childhood (referred to as lung disease immunodeficiency and chromosome breakage syndrome, LICS) (Figure 6D) [135]. Two sisters (subjects A and B) with homozygous MAGE-G1 mutations (c.790C>T) exhibited B and T cell abnormalities, increased infection susceptibility, and eczema.…”

“…An affected brother and sister (subjects C and D, respectively) from a second family also developed a similar clinical history of progressive, severe PARDS and infectious pneumonia. Exome sequencing of the second family revealed compound heterozygous mutations in MAGE-G1 with a maternally inherited c.790C>T mutation (identical to the first family), and a paternally inherited c.626C>T mutation [135]. …”

“…Interestingly, the two identified variants of MAGE-G1 result in p.Leu264Phe (L264F) and p.Pro209Leu (P209L), and were both shown to disrupt interactions with NSMCE4 and destabilize the SMC5/6 complex [135]. Consistent with this, SMC5 and SMC6 protein levels were significantly reduced while MAGE-G1 protein was not detectable in fibroblasts from affected individuals [135]. Moreover, cells from subject B exhibited increased numbers of micronuclei, a hallmark of genome instability [135].…”