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

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 eng...

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Autores principales: Lana-Elola, Eva, Watson-Scales, Sheona, Slender, Amy, Gibbins, Dorota, Martineau, Alexandrine, Douglas, Charlotte, Mohun, Timothy, Fisher, Elizabeth MC, Tybulewicz, Victor LJ
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764572/
https://www.ncbi.nlm.nih.gov/pubmed/26765563
http://dx.doi.org/10.7554/eLife.11614
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author Lana-Elola, Eva
Watson-Scales, Sheona
Slender, Amy
Gibbins, Dorota
Martineau, Alexandrine
Douglas, Charlotte
Mohun, Timothy
Fisher, Elizabeth MC
Tybulewicz, Victor LJ
author_facet Lana-Elola, Eva
Watson-Scales, Sheona
Slender, Amy
Gibbins, Dorota
Martineau, Alexandrine
Douglas, Charlotte
Mohun, Timothy
Fisher, Elizabeth MC
Tybulewicz, Victor LJ
author_sort Lana-Elola, Eva
collection PubMed
description 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, two of 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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spelling pubmed-47645722016-02-25 Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel Lana-Elola, Eva Watson-Scales, Sheona Slender, Amy Gibbins, Dorota Martineau, Alexandrine Douglas, Charlotte Mohun, Timothy Fisher, Elizabeth MC Tybulewicz, Victor LJ eLife Developmental Biology 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, two of 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. eLife Sciences Publications, Ltd 2016-01-14 /pmc/articles/PMC4764572/ /pubmed/26765563 http://dx.doi.org/10.7554/eLife.11614 Text en © 2016, Lana-Elola et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Developmental Biology
Lana-Elola, Eva
Watson-Scales, Sheona
Slender, Amy
Gibbins, Dorota
Martineau, Alexandrine
Douglas, Charlotte
Mohun, Timothy
Fisher, Elizabeth MC
Tybulewicz, Victor LJ
Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel
title Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel
title_full Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel
title_fullStr Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel
title_full_unstemmed Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel
title_short Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel
title_sort genetic dissection of down syndrome-associated congenital heart defects using a new mouse mapping panel
topic Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764572/
https://www.ncbi.nlm.nih.gov/pubmed/26765563
http://dx.doi.org/10.7554/eLife.11614
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