1. Developmental Biology

Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel

  1. Eva Lana-Elola
  2. Sheona Watson-Scales
  3. Amy Slender
  4. Dorota Gibbins
  5. Alexandrine Martineau
  6. Charlotte Douglas
  7. Timothy Mohun
  8. Elizabeth MC Fisher
  9. Victor LJ Tybulewicz  Is a corresponding author
  1. The Francis Crick Institute, United Kingdom
  2. UCL Institute of Neurology, United Kingdom
https://doi.org/10.7554/eLife.11614
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  1. Eva Lana-Elola
  2. Sheona Watson-Scales
  3. Amy Slender
  4. Dorota Gibbins
  5. Alexandrine Martineau
  6. Charlotte Douglas
  7. Timothy Mohun
  8. Elizabeth MC Fisher
  9. Victor LJ Tybulewicz
(2016)
Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel
eLife 5:e11614.
https://doi.org/10.7554/eLife.11614
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  3. Download .RIS

Abstract

Down syndrome (DS), caused by trisomy of human chromosome 21 (Hsa21), is the most common cause of congenital heart defects (CHD), yet the genetic and mechanistic causes of these defects remain unknown. To identify dosage-sensitive genes that cause DS phenotypes, including CHD, we used chromosome engineering to generate a mapping panel of 7 mouse strains with partial trisomies of regions of mouse chromosome 16 orthologous to Hsa21. Using high-resolution episcopic microscopy and three-dimensional modeling we show that these strains accurately model DS CHD. Systematic analysis of the 7 strains identified a minimal critical region sufficient to cause CHD when present in 3 copies, and showed that it contained at least two dosage-sensitive loci. Furthermore, these new strains model a specific subtype of atrio-ventricular septal defects with exclusive ventricular shunting and demonstrate that, contrary to current hypotheses, these CHD are not due to failure in formation of the dorsal mesenchymal protrusion.

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Author details

  1. Eva Lana-Elola

    Mill Hill Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  2. Sheona Watson-Scales

    Mill Hill Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  3. Amy Slender

    Mill Hill Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  4. Dorota Gibbins

    Mill Hill Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Alexandrine Martineau

    Mill Hill Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  6. Charlotte Douglas

    Mill Hill Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  7. Timothy Mohun

    Mill Hill Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  8. Elizabeth MC Fisher

    Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  9. Victor LJ Tybulewicz

    Mill Hill Laboratory, The Francis Crick Institute, London, United Kingdom
    For correspondence
    Victor.T@crick.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All animal work was carried out under a Project Licence granted by the UK Home Office.

Copyright

© 2016, Lana-Elola et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Eva Lana-Elola
  2. Sheona Watson-Scales
  3. Amy Slender
  4. Dorota Gibbins
  5. Alexandrine Martineau
  6. Charlotte Douglas
  7. Timothy Mohun
  8. Elizabeth MC Fisher
  9. Victor LJ Tybulewicz
(2016)
Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel
eLife 5:e11614.
https://doi.org/10.7554/eLife.11614

Share this article

https://doi.org/10.7554/eLife.11614

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