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SMC5 Plays Independent Roles in Congenital Heart Disease and Neurodevelopmental Disability.
O'Brien, Matthew P; Pryzhkova, Marina V; Lake, Evelyn M R; Mandino, Francesca; Shen, Xilin; Karnik, Ruchika; Atkins, Alisa; Xu, Michelle J; Ji, Weizhen; Konstantino, Monica; Brueckner, Martina; Ment, Laura R; Khokha, Mustafa K; Jordan, Philip W.
  • O'Brien MP; Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
  • Pryzhkova MV; Biochemistry and Molecular Biology Department, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA.
  • Lake EMR; Department of Biochemistry and Molecular Biology, Uniformed Services, University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814, USA.
  • Mandino F; Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
  • Shen X; Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
  • Karnik R; Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
  • Atkins A; Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
  • Xu MJ; Biochemistry and Molecular Biology Department, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA.
  • Ji W; Biochemistry and Molecular Biology Department, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA.
  • Konstantino M; Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
  • Brueckner M; Pediatric Genomics Discovery Program, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
  • Ment LR; Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
  • Khokha MK; Pediatric Genomics Discovery Program, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
  • Jordan PW; Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
Int J Mol Sci ; 25(1)2023 Dec 28.
Article en En | MEDLINE | ID: mdl-38203602
ABSTRACT
Up to 50% of patients with severe congenital heart disease (CHD) develop life-altering neurodevelopmental disability (NDD). It has been presumed that NDD arises in CHD cases because of hypoxia before, during, or after cardiac surgery. Recent studies detected an enrichment in de novo mutations in CHD and NDD, as well as significant overlap between CHD and NDD candidate genes. However, there is limited evidence demonstrating that genes causing CHD can produce NDD independent of hypoxia. A patient with hypoplastic left heart syndrome and gross motor delay presented with a de novo mutation in SMC5. Modeling mutation of smc5 in Xenopus tropicalis embryos resulted in reduced heart size, decreased brain length, and disrupted pax6 patterning. To evaluate the cardiac development, we induced the conditional knockout (cKO) of Smc5 in mouse cardiomyocytes, which led to the depletion of mature cardiomyocytes and abnormal contractility. To test a role for Smc5 specifically in the brain, we induced cKO in the mouse central nervous system, which resulted in decreased brain volume, and diminished connectivity between areas related to motor function but did not affect vascular or brain ventricular volume. We propose that genetic factors, rather than hypoxia alone, can contribute when NDD and CHD cases occur concurrently.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Cardiopatías Congénitas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Año: 2023 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Cardiopatías Congénitas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Año: 2023 Tipo del documento: Article