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Cited by 67Down syndrome and intellectual disability researchMicrotubule and mitosis dynamicsGenetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

Consequences of aneuploidy in human fibroblasts with trisomy 21

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Hwang, Sunyoung, Cavaliere, Paola, Li, Rui, Zhu, Lihua Julie, Dephoure, Noah, Torres, Eduardo M.·2021·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2014723118PMC PMC8017964

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Abstract

Significance: An abnormal number of chromosomes or aneuploidy accounts for most spontaneous abortions, as missegregation of a single chromosome during development is often lethal. Only individuals with trisomy 21, which causes Down syndrome, can live to adulthood but show cognitive disabilities, increased risk for leukemias, autoimmune disorders, and clinical symptoms associated with premature aging. The mechanisms by which aneuploidy affects cellular function to cause Down syndrome are not understood. Our studies revealed that aneuploidy causes several defects in cells from individuals with Down syndrome. These include increased gene and protein expression, lower viability, and increased dependency on serine to proliferate. Our studies establish a critical role of aneuploidy, independent of triplicated gene identity, in driving cellular defects associated with trisomy 21.

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  • Some have reported dosage compensation for some genes.

    “A frequent assumption regarding gene dosage effects in trisomy is that expression of all trisomic genes is upregulated according to the gene copy number (1.5-fold) in every cell in the body throughout the lifespan of the individual, though some have reported dosage compensation for some genes (Ait Yahya-Graison et al., 2007; Hwang et al., 2021; Kahlem et al., 2004; Lyle et al., 2004).”

    From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Hwang et al., 2021

    The Results section on posttranscriptional regulation reports that proteins encoded by 97 of 281 triplicated genes were attenuated, supporting compensation at the protein level. But their mRNA levels rose about 1.5-fold, and the Discussion says the findings support a lack of dosage compensation of human autosomes at the RNA level. The citation therefore supports the claim only if dosage compensation includes protein-level attenuation, not compensation of gene expression. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • A frequent assumption regarding gene dosage effects in trisomy is that expression of all trisomic genes is upregulated according to the gene copy number (1.5-fold) in every cell in the body throughout the lifespan.

    “A frequent assumption regarding gene dosage effects in trisomy is that expression of all trisomic genes is upregulated according to the gene copy number (1.5-fold) in every cell in the body throughout the lifespan of the individual, though some have reported dosage compensation for some genes (Ait Yahya-Graison et al., 2007; Hwang et al., 2021; Kahlem et al., 2004; Lyle et al., 2004).”

    From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Hwang et al., 2021

    The Results (Transcriptome Analyses; page not provided) report an average 1.5-fold increase in expression for most genes on trisomic chromosomes in the fibroblast cell lines studied. They also report outliers, and the Discussion limits its conclusion to average mRNA levels. The paper does not establish that all trisomic genes are upregulated 1.5-fold in every cell throughout an individual's lifespan. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Hwang, S., Cavaliere, P., Li, R., Zhu, L. J., Dephoure, N., & Torres, E. M.
Affiliations
  • University of Massachusetts Chan Medical School (US)
  • Weill Cornell Medicine (US)
Corresponding author
Torres, Eduardo M.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2021-02
Volume
118
Issue
6
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2014723118
PMC
PMC8017964
OpenAlex
W3127084535
Cited by
67
References
4
Citations by year
2026: 3 · 2025: 9 · 2024: 23 · 2023: 12 · 2022: 14 · 2021: 6
FWCI
11.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion, cc-by-nc-nd)
Funders
HHS | National Institutes of Health (1RO1GM118481)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
Keywords
aneuploidy, Down syndrome, trisomy 13, trisomy 18, human fibroblasts, transcriptome, proteome, post-transcriptional regulation, macromolecular complexes, dosage compensation, chromosomal domains, cell viability
MeSH terms
Aneuploidy, Cell Survival, Cells, Cultured, Fibroblasts, Gene Expression Regulation, Humans, Lipids, RNA, Messenger, Serine, Transcription, Genetic, Trisomy, Up-Regulation, Gene Dosage, Gene Expression Profiling, Macromolecular Substances, Cell Proliferation

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