TY - JOUR
T1 - Familial stag2 germline mutation defines a new human cohesinopathy
AU - Soardi, Fernanda C.
AU - Machado-Silva, Alice
AU - Linhares, Natália D.
AU - Zheng, Ge
AU - Qu, Qianhui
AU - Pena, Heloísa B.
AU - Martins, Thaís M.M.
AU - Vieira, Helaine G.S.
AU - Pereira, Núbia B.
AU - Melo-Minardi, Raquel C.
AU - Gomes, Carolina C.
AU - Gomez, Ricardo S.
AU - Gomes, Dawidson A.
AU - Pires, Douglas E.V.
AU - Ascher, David B.
AU - Yu, Hongtao
AU - Pena, Sérgio D.J.
N1 - Funding Information:
We are grateful to the patients and their family. Their cooperation made this work possible. F.C.S. was initially supported by a visiting researcher program fellowship from Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) (BPV- 00059-14) and by a fellowship from the Programa de Formação de Recursos Humanos em Áreas Estratégicas (RHAE) of the Conselho Nacional de Pesquisa (CNPq) (351030/2015-8). A.M.-S. was also supported by a fellowship from the Programa de Formação de Recursos Humanos em Áreas Estratégicas (RHAE) of the Conselho Nacional de Pesquisa (CNPq). N.D.L. was supported by a fellowship from Programa Nacional de Pós-doutorado (PNPD) Institucional of Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (2792/2011). D.B.A. and D.E.V.P. received funding from a Newton Fund RCUK-CONFAP Grant awarded by The Medical Research Council (MRC) and Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) (MR/M026302/1). D.E.V.P. received support from the René Rachou Research Center (CPqRR/FIOCRUZ Minas), Brazil. D.B.A. was supported by an NHMRC CJ Martin Fellowship (APP1072476) and the Jack Brockhoff Foundation (JBF 4186, 2016). H.Y. is an Investigator with the Howard Hughes Medical Institute, and is supported by grants from the Cancer Prevention Research Institute of Texas (RP110465-P3 and RP120717-P2) and the Welch Foundation (I-1441). S.D.J.P. receives support as a Scientist 1A of the Conselho Nacional de Pesquisa (CNPq). The work done in Brazil was funded by the Conselho Nacional de Pesquisa (CNPq) and the Fundação de Pesquisa do Estado de Minas Gerais (FAPEMIG).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41525-017-0009-4
DO - 10.1038/s41525-017-0009-4
M3 - Article
C2 - 29263825
AN - SCOPUS:85023179283
SN - 2056-7944
VL - 2
JO - npj Genomic Medicine
JF - npj Genomic Medicine
IS - 1
M1 - 7
ER -