Hypomorphism in human NSMCE2 linked to primordial dwarfism and insulin resistance

J Clin Invest. 2014 Sep;124(9):4028-38. doi: 10.1172/JCI73264. Epub 2014 Aug 8.


Structural maintenance of chromosomes (SMC) complexes are essential for maintaining chromatin structure and regulating gene expression. Two the three known SMC complexes, cohesin and condensin, are important for sister chromatid cohesion and condensation, respectively; however, the function of the third complex, SMC5-6, which includes the E3 SUMO-ligase NSMCE2 (also widely known as MMS21) is less clear. Here, we characterized 2 patients with primordial dwarfism, extreme insulin resistance, and gonadal failure and identified compound heterozygous frameshift mutations in NSMCE2. Both mutations reduced NSMCE2 expression in patient cells. Primary cells from one patient showed increased micronucleus and nucleoplasmic bridge formation, delayed recovery of DNA synthesis, and reduced formation of foci containing Bloom syndrome helicase (BLM) after hydroxyurea-induced replication fork stalling. These nuclear abnormalities in patient dermal fibroblast were restored by expression of WT NSMCE2, but not a mutant form lacking SUMO-ligase activity. Furthermore, in zebrafish, knockdown of the NSMCE2 ortholog produced dwarfism, which was ameliorated by reexpression of WT, but not SUMO-ligase-deficient NSMCE. Collectively, these findings support a role for NSMCE2 in recovery from DNA damage and raise the possibility that loss of its function produces dwarfism through reduced tolerance of replicative stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / physiology
  • Chromosomal Proteins, Non-Histone
  • Cytochalasin B / pharmacology
  • Dwarfism / etiology*
  • Female
  • Haplotypes
  • Humans
  • Insulin Resistance*
  • Ligases / genetics
  • Ligases / physiology*
  • Mutation
  • RecQ Helicases / physiology
  • Zebrafish


  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • SMC5 protein, human
  • SMC6 protein, human
  • Cytochalasin B
  • Bloom syndrome protein
  • RecQ Helicases
  • Ligases
  • NSMCE2 protein, human