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Cited by 88Down syndrome and intellectual disability researchGenetics and Neurodevelopmental DisordersGenomic variations and chromosomal abnormalities

Genetic dissection of the down syndrome critical region

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Jiang, Xiaoling, Liu, Chunhong, Yu, Tao, Zhang, Li, Meng, Kai, Xing, Zhuo, Belichenko, Pavel V., Kleschevnikov, Alexander M. +5 more·2015·Human Molecular Genetics
DOI 10.1093/hmg/ddv364PMC PMC4614710
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Abstract

Down syndrome (DS), caused by trisomy 21, is the most common chromosomal disorder associated with developmental cognitive deficits. Despite intensive efforts, the genetic mechanisms underlying developmental cognitive deficits remain poorly understood, and no treatment has been proven effective. The previous mouse-based experiments suggest that the so-called Down syndrome critical region of human chromosome 21 is an important region for this phenotype, which is demarcated by Setd4/Cbr1 and Fam3b/Mx2. We first confirmed the importance of the Cbr1-Fam3b region using compound mutant mice, which carry a duplication spanning the entire human chromosome 21 orthologous region on mouse chromosome 16 [Dp(16)1Yey] and Ms1Rhr. By dividing the Setd4-Mx2 region into complementary Setd4-Kcnj6 and Kcnj15-Mx2 intervals, we started an unbiased dissection through generating and analyzing Dp(16)1Yey/Df(16Setd4-Kcnj6)Yey and Dp(16)1Yey/Df(16Kcnj15-Mx2)Yey mice. Surprisingly, the Dp(16)1Yey-associated cognitive phenotypes were not rescued by either deletion in the compound mutants, suggesting the possible presence of at least one causative gene in each of the two regions. The partial rescue by a Dyrk1a mutation in a compound mutant carrying Dp(16)1Yey and the Dyrk1a mutation confirmed the causative role of Dyrk1a, whereas the absence of a similar rescue by Df(16Dyrk1a-Kcnj6)Yey in Dp(16)1Yey/Df(16Dyrk1a-Kcnj6)Yey mice demonstrated the importance of Kcnj6. Our results revealed the high levels of complexities of gene actions and interactions associated with the Setd4/Cbr1-Fam3b/Mx2 region as well as their relationship with developmental cognitive deficits in DS.

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  • Subtracting one copy of Dyrk1a at conception from otherwise trisomic mice improved T-maze and contextual fear conditioning tests.

    “Subtracting one copy of Dyrk1a at conception from otherwise trisomic mice improved cognitive, neurological and Alzheimer disease-like phenotypes (Garcia-Cerro et al., 2014; Garcia-Cerro et al., 2017) and improved T-maze and contextual fear conditioning tests (Jiang et al., 2015).”

    From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Jiang et al., 2015

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Cited by

Sorted by citations

Authors
Jiang, X., Liu, C., Yu, T., Zhang, L., Meng, K., Xing, Z., Belichenko, P. V., Kleschevnikov, A. M., Pao, A., Peresie, J., Wie, S., Mobley, W. C., & Yu, Y. E.
Affiliations
  • Roswell Park Comprehensive Cancer Center (US)
  • University of California San Diego (US)
Corresponding author
Yu, Y. Eugene
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2015-09-15
Volume
24
Issue
22
Pages
6540-6551
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddv364
PMC
PMC4614710
OpenAlex
W2303984800
Cited by
88
References
4
Citations by year
2026: 7 · 2025: 8 · 2024: 7 · 2023: 5 · 2022: 9 · 2021: 4 · 2020: 8 · 2019: 11 · 2018: 6 · 2017: 15 · 2016: 7
FWCI
10.01
Type
journal article
Language
en
Open access
Locations
  • Human Molecular Genetics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health (R01NS66072, R01HL91519, R21GM114645, P30CA16056)
  • Roswell Park Alliance Foundation
  • Louis Sklarow Memorial Fund
  • Jerome Lejeune Foundation
  • the Children's Guild Foundation
  • National Natural Science Foundation of China (81100844)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
Down syndrome, Down syndrome critical region, chromosome 21, DYRK1A, KCNJ6, KCNJ15, compound mutant mice, mouse chromosome 16, gene dosage, intellectual disability
MeSH terms
Animals, Chromosome Deletion, Cognition Disorders, Disease Models, Animal, Down Syndrome, Humans, Mice, Mutant Strains, Sequence Deletion, Mice, Genetic Association Studies

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