2. Academic Validation
  3. Familial STAG2 germline mutation defines a new human cohesinopathy

Familial STAG2 germline mutation defines a new human cohesinopathy

  • NPJ Genom Med. 2017 Mar 20;2:7. doi: 10.1038/s41525-017-0009-4.
Fernanda C Soardi # 1 2 3,  Alice Machado-Silva # 1,  Natália D Linhares # 2 3,  Ge Zheng # 4,  Qianhui Qu 4,  Heloísa B Pena 1,  Thaís M M Martins 2,  Helaine G S Vieira 2,  Núbia B Pereira 5,  Raquel C Melo-Minardi 6,  Carolina C Gomes 5,  Ricardo S Gomez 7,  Dawidson A Gomes 2,  Douglas E V Pires 8,  David B Ascher 8 9 10,  Hongtao Yu 4,  Sérgio D J Pena 1 2 3
Affiliations

Affiliations

  • 1 GENE-Núcleo de Genética Médica, Belo Horizonte, MG Brazil.
  • 2 Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG Brazil.
  • 3 Faculdade de Medicina, Laboratório de Genômica Clínica, Universidade Federal de Minas Gerais, Belo Horizonte, MG Brazil.
  • 4 Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX USA.
  • 5 Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG Brazil.
  • 6 Departamento de Ciência da Computação, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Belo Horizonte, MG Brazil.
  • 7 Departamento de Clínica, Patologia e Cirurgia Odontológicas, Faculdade de Odontologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG Brazil.
  • 8 Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, MG Brazil.
  • 9 Department of Biochemistry, University of Cambridge, Cambridge, UK.
  • 10 Department of Biochemistry, University of Melbourne, Victoria, Australia.
  • # Contributed equally.
PMID: 29263825 DOI: 10.1038/s41525-017-0009-4
Abstract

We characterize a novel human cohesinopathy originated from a familial germline mutation of the gene encoding the cohesin subunit STAG2, which we propose to call STAG2-related X-linked Intellectual Deficiency. Five individuals carry a STAG2 p.Ser327Asn (c.980 G > A) variant that perfectly cosegregates with a phenotype of syndromic mental retardation in a characteristic X-linked recessive pattern. Although patient-derived cells did not show overt sister-chromatid cohesion defects, they exhibited altered cell cycle profiles and gene expression patterns that were consistent with cohesin deficiency. The protein level of STAG2 in patient cells was normal. Interestingly, STAG2 S327 is located at a conserved site crucial for binding to SCC1 and cohesin regulators. When expressed in human cells, the STAG2 p.Ser327Asn mutant is defective in binding to SCC1 and other cohesin subunits and regulators. Thus, decreased amount of intact cohesin likely underlies the phenotypes of STAG2-SXLID. Intriguingly, recombinant STAG2 p.Ser327Asn binds normally to SCC1, WAPL, and SGO1 in vitro, suggesting the existence of unknown in vivo mechanisms that regulate the interaction between STAG2 and SCC1.

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