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Hypomorphism in human NSMCE2 linked to primordial dwarfism and insulin resistance

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journal contribution
posted on 2023-06-08, 18:15 authored by Felicity Payne, Rita Colnaghi, Nuno Rocha, Asha Seth, Julie Harris, Gillian Carpenter, William E Bottomley, Eleanor Wheeler, Stephen Wong, Vladimir Saudek, David Savage, Stephen O'Rahilly, Jean-Claude Carel, Inês Barroso, Mark O'DriscollMark O'Driscoll, Robert Semple
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.

History

Publication status

  • Published

File Version

  • Published version

Journal

The Journal of Clinical Investigation

ISSN

0021-9738

Publisher

American Society for Clinical Investigation

Issue

9

Volume

124

Page range

4028-4038

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2014-09-09

First Open Access (FOA) Date

2014-09-09

First Compliant Deposit (FCD) Date

2014-09-09

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