title: Hypomorphism in human NSMCE2 linked to primordial dwarfism and insulin resistance.
abstract: 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.
authors.forename: Felicity
authors.initials: F
authors.lastname: Payne
authors.forename: Rita
authors.initials: R
authors.lastname: Colnaghi
authors.forename: Nuno
authors.initials: N
authors.lastname: Rocha
authors.forename: Asha
authors.initials: A
authors.lastname: Seth
authors.forename: Julie
authors.initials: J
authors.lastname: Harris
authors.forename: Gillian
authors.initials: G
authors.lastname: Carpenter
authors.forename: William E
authors.initials: WE
authors.lastname: Bottomley
authors.forename: Eleanor
authors.initials: E
authors.lastname: Wheeler
authors.forename: Stephen
authors.initials: S
authors.lastname: Wong
authors.forename: Vladimir
authors.initials: V
authors.lastname: Saudek
authors.forename: David
authors.initials: D
authors.lastname: Savage
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Carel
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.forename: Mark
authors.initials: M
authors.lastname: O'Driscoll
authors.forename: Robert
authors.initials: R
authors.lastname: Semple
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone; D003571:Cytochalasin B / Q000494:pharmacology; D004392:Dwarfism / Q000209:etiology*; D005260:Female; D006239:Haplotypes; D006801:Humans; D007333:Insulin Resistance; D008025:Ligases / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D053484:RecQ Helicases / Q000502:physiology; D015027:Zebrafish
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C432931:SMC5 protein, human; C432932:SMC6 protein, human; D003571:Cytochalasin B; C097151:Bloom syndrome protein; D053484:RecQ Helicases; D008025:Ligases; C503501:NSMCE2 protein, human
references.citation: Genome Res. 2011 Jun;21(6):961-73
references.pmid: 20980555
references.citation: Am J Med Genet C Semin Med Genet. 2014 Jun;166C(2):124-39
references.pmid: 24816482
references.citation: Mol Biol Cell. 2004 Nov;15(11):4866-76
references.pmid: 15331764
references.citation: DNA Repair (Amst). 2012 Oct 1;11(10):799-810
references.pmid: 22921571
references.citation: Mol Cell Biol. 2006 Dec;26(24):9387-401
references.pmid: 17030601
references.citation: Mol Cell Biol. 2005 Aug;25(16):7021-32
references.pmid: 16055714
references.citation: Medicine (Baltimore). 1966 May;45(3):177-221
references.pmid: 5327241
references.citation: Nat Genet. 2003 Apr;33(4):497-501
references.pmid: 12640452
references.citation: Horm Res. 2006;66(3):111-7
references.pmid: 16763388
references.citation: Bioinformatics. 2009 Jul 15;25(14):1754-60
references.pmid: 19451168
references.citation: Mol Cell. 2009 Sep 11;35(5):657-68
references.pmid: 19748359
references.citation: Genetics. 1977 Oct;87(2):229-36
references.pmid: 200524
references.citation: J Biol Chem. 2003 Nov 14;278(46):45460-7
references.pmid: 12966087
references.citation: Physiol Rev. 2009 Jan;89(1):27-71
references.pmid: 19126754
references.citation: Cell. 2006 Nov 3;127(3):509-22
references.pmid: 17081974
references.citation: Nat Genet. 2011 Jun 12;43(7):712-4
references.pmid: 21666693
references.citation: Nature. 2010 Oct 28;467(7319):1061-73
references.pmid: 20981092
references.citation: Genome Res. 2010 Sep;20(9):1297-303
references.pmid: 20644199
references.citation: Nat Rev Genet. 2010 Jun;11(6):391-404
references.pmid: 20442714
references.citation: Annu Rev Genomics Hum Genet. 2006;7:175-99
references.pmid: 16722806
references.citation: Nat Genet. 2012 Jun 24;44(8):928-33
references.pmid: 22729222
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 29;102(13):4777-82
references.pmid: 15738391
references.citation: Chromosome Res. 2009;17(2):251-63
references.pmid: 19308705
references.citation: Mol Cell Biol. 2005 Jan;25(1):172-84
references.pmid: 15601840
references.citation: Mol Cell Biol. 2009 Aug;29(16):4363-75
references.pmid: 19528228
references.citation: Endocr Rev. 2011 Aug;32(4):498-514
references.pmid: 21536711
references.citation: Mol Cell Biol. 2005 Jan;25(1):185-96
references.pmid: 15601841
references.citation: EMBO J. 2009 Jan 21;28(2):144-55
references.pmid: 19158664
references.citation: Proc Natl Acad Sci U S A. 2014 Jun 17;111(24):8901-6
references.pmid: 24889630
references.citation: Genes Dev. 2011 Oct 1;25(19):2011-24
references.pmid: 21979914
references.citation: J Clin Invest. 2009 Feb;119(2):315-22
references.pmid: 19164855
references.citation: Medicine (Baltimore). 2004 Jul;83(4):209-222
references.pmid: 15232309
references.citation: N Engl J Med. 1996 Oct 31;335(18):1363-7
references.pmid: 8857020
references.citation: J Biol Chem. 2011 Apr 22;286(16):14516-30
references.pmid: 21324902
references.citation: J Clin Endocrinol Metab. 2012 Feb;97(2):E243-7
references.pmid: 22130793
references.citation: Bioinformatics. 2010 Aug 15;26(16):2069-70
references.pmid: 20562413
references.citation: Nat Genet. 2013 Aug;45(8):947-50
references.pmid: 23770608
references.citation: Nat Protoc. 2007;2(5):1084-104
references.pmid: 17546000
references.citation: Nature. 2003 Dec 18;426(6968):789-96
references.pmid: 14685227
references.citation: Cell Cycle. 2009 Jul 15;8(14):2211-8
references.pmid: 19502785
references.citation: Diabetes. 2011 Mar;60(3):925-35
references.pmid: 21270239
references.citation: Mol Cell Biol. 2008 Feb;28(4):1197-206
references.pmid: 18086888