Hypomorphism in human NSMCE2 linked to primordial dwarfism and insulin resistance

Abstract

R e s e a R c h a R t i c l e4 0 2 8 jci.org Volume 124 Number 9 September 2014 IntroductionPrimordial dwarfism denotes extreme linear growth impairment from early gestation. When severely reduced head size is also seen, primordial dwarfism is said to be microcephalic. This is generally taken to imply a global problem with either cellular or organismal growth and contrasts with primordial dwarfism in which the head size is relatively preserved, which is more likely to be accounted for by a more tissue-selective problem, affecting, for example, long bone growth (1). Many human genetic defects have now been described as underlying microcephalic primordial dwarfism. These may affect endocrine growth regulation by impairing production or action of IGF-1 (2, 3); however, most mutations reported to date affect cellautonomous growth. Some clustering of defects according to the cellular structure or process affected is apparent. For example, microcephalic primordial dwarfism can result from defects in genes involved in the licensing of DNA replication, in centrosome function, or in DNA damage response and repair pathways (reviewed in ref. 4).In keeping with the known roles of the defective genes, some syndromes feature a characteristic profile of chromosomal instability or impaired DNA damage repair. Some components of the syndromes cannot easily be explained by known functions of the affected gene, however. An example is the severe insulin resistance described in pericentrin deficiency (5). This usually appears during the first decade of life and is associated with severely fatty liver, elevated blood triglyceride levels, and diabetes, recapitulating in severe form the pandemic metabolic syndrome. Similar metabolic abnormalities are seen with milder growth impairment in both Bloom syndrome (6) and Werner syndrome (7), each caused by loss of a DNA helicase, and without growth impairment in patients with a heterozygous polymerase-inactivating mutation in DNA polymerase δ (8). However despite increasing evidence of a link between impaired DNA replication and/or damage responses and severe insulin resistance, the underlying mechanisms linking these remain unclear. ResultsA novel syndrome of primordial dwarfism. We identified 2 female patients with similar syndromes (details in Supplemental Material and Methods; supplemental material available online with this article; doi:10.1172/JCI73264DS1). The shared features are (a) severe primordial dwarfism, with facial dysmorphism, including 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 heterozygou...

Conditional mutation of Smc5 in mouse embryonic stem cells perturbs condensin localization and mitotic progression

“…Misregulation of condensin II has been implicated in the neurodevelopmental disorder autosomal recessive primary microcephaly (MCPH) (Hirano, 2012;Trimborn et al, 2006). Recently, hypomorphic mutations of a Smc5/6 component, NSMCE2, have been reported to cause primordial dwarfism and microcephaly in human (Payne et al, 2014). Furthermore, SMC mutations are associated with cancer (Leiserson et al, 2015;Jacome et al, 2015).…”

Emerging Roles for Human MMS21, NSMCE2, in Development and Disease

“…The truncated mutant protein corresponding to S116Lfs*18 was not readily detectable in the patient's cells whereas the A234Efs*4 mutant protein was less stable and expressed at a lower level in patient derived LCL (Epstein Barr virus immortalized lymphoblastoid cell lines) and dermal fibroblasts. The S116Lfs*18 mutant protein was autosumoylation defective while the auto-sumoylation of the A234Efs*4 mutant protein was not significantly different from the wild-type NSMCE2 protein [24]. However, the patient derived LCLs showed mild reduction of SMC5 and SMC6 proteins in whole cell extracts and chromatin fractions indicating some instability of the Smc5/6 complex in these cells.…”

“…The NSMCE2 hypomorphic patients displayed multiple developmental defects most notably primordial dwarfism, facial dysmorphism, primary gonadal failure and insulin resistant diabetes [24]. Numerous cellular defects were also observed in patient dermal fibroblasts and LCLs.…”

“…Numerous cellular defects were also observed in patient dermal fibroblasts and LCLs. The frequencies of micronuclei (MN) that may form from acentric broken chromosome fragments, and of nucleoplasmic bridges (NPB) that represent unresolved chromosome strands connecting two nuclei of a binucleate cell prior to cytokinesis, are indicative of chromosome instability, and were enhanced in patient cells especially following treatment with HU that induces replication fork stalling and collapse [24]. In addition, patient derived LCLs treated with low concentrations of HU showed impairment in recovery of replication relative to wild-type.…”

The (elusive) role of the SMC5/6 complex

“…2 Moreover, NSMCE2 hypomorphism in humans also leads to a genomic instability syndrome that limits lifespan. 7 Hence, understanding the function of the SMC5/6 complex is still an important task, which beyond its academic interest might yield unanticipated insights with potential applications to human health.…”