Mouse model helps pinpoint genetic cause of Down syndrome heart defects

14 January 2016

Cross-sections through mouse embryonic hearts showing a normal heart on the left and a heart from mutant mouse that models Down Syndrome on the right. The red arrowhead indicates a break in the muscular wall that should separate the left and right sides of the heart.

Image: Cross-sections through mouse embryonic hearts showing a normal heart on the left and a heart from mutant mouse that models Down Syndrome on the right. The red arrowhead indicates a break in the muscular wall that should separate the left and right sides of the heart.

Researchers have created a mouse model of the heart defects that occur in Down syndrome, by making a mouse with an extra copy of many of the genes that correspond to the human genes on chromosome 21.

Down syndrome is the most common genetic cause of both intellectual disability and heart defects in humans, and is triggered by an extra copy of chromosome 21.

The work was led by Prof Victor Tybulewicz of the Francis Crick Institute and Imperial College London and Prof Elizabeth Fisher of University College London. Prof Tybulewicz explained: "The genetic change in Down Syndrome results in a complex condition that is characterised by learning difficulties, congenital heart defects, increased rates of leukaemia and early onset Alzheimer's disease, among others."

"Each of these different symptoms is caused by the extra chromosome, and presumably by an extra copy of one or more of the 230 or so genes on the chromosome. However it is not known which genes on chromosome 21 cause which defects."

The mouse model has allowed the team to visualise the detail of how the defects occur during embryonic development.

The scientists made a series of mouse strains, each with extra copies of different sets of mouse genes corresponding to the human genes on human chromosome 21. This enabled them to narrow down the genes that cause heart defects to 39 of the 230 genes on the chromosome. It also allowed them to show that at least two different genes contribute to the heart defects.

Dr Tybulewicz said: "This work is a major scientific advance. It provides important insights into the genetic basis of Down syndrome, and our panel of seven genetically engineered mouse strains will help others to identify genes that cause other Down syndrome symptoms.

The paper, Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel, is published in eLife.

  • Francis Crick Institute researchers have created several strains of a mouse model of Down syndrome, each replicating a different set of genes that correspond to the extra 230 genes found on chromosome 21 in humans with the condition. This has enabled them to reproduce the heart defects that are common in the condition and narrow down their genetic cause.
  • The current research was made possible by work published around 10 years ago by Dr Victor Tybulewicz of the Francis Crick Institute (previously the Medical Research Council's National Institute for Medical Research) and Professor Elizabeth Fisher of UCL (and Imperial College London at the time).
  • The current study was carried out in collaboration with UCL and funding was provided by the Medical Research Council and the Wellcome Trust.