LATEST DATA RELEASE HIGHLIGHTS INCLUDING NEW HEART DEFECT ASSOCIATIONS

Our latest data release includes HREM image data for an additional 5 lines, and HREM phenotyping data for 4 lines. Five additional early lethal lines have also been identified, as well as placental phenotype data for more than 100 mutant lines, with associated placenta morphology and yolk sac images.

Throughout the DMDD project we continue to add data for existing lines, and in this release we have added P14 viability for mutant lines, Theiler stage (where assessed), and the voxel size of each HREM image stack.

Initial analysis of the new HREM phenotyping data shows two lines newly associated with heart defects.


Oaz1 ASSOCIATED WITH DORV

Oaz1 is a gene regulating levels of polyamines within the cell and is widely distributed in cells and tissues of the body. Our data now shows that removal of this gene causes a serious abnormality in heart development in which the vessel normally carrying blood from the left ventricle of the heart (the aorta) is in fact attached to the right ventricle (a defect known as “double outlet right ventricle” or DORV). As with many mutant lines, the embryos also show extensive swelling of the body (“edema”).

Left panel: a view of the heart seen from the right side and showing both the pulmonary trunk (red arrow) and the aorta (yellow arrow) drain from the right ventricle. Right panel: a cross section through the body at the level of the heart shows the extent of swelling (arrows) in tissue beneath the skin.

 


Cc2d2a ASSOCIATED WITH VSD AND OSTIUM PRIMUM DEFECT

Cc2d2a encodes a protein that plays a critical role in formation of cell cilia and mutations in this gene are associated with diseases such as Meckel syndrome type 6, which results in a broad range of symptoms such as polydactyly, cleft palate and kidney malformations. Our data reveals that removal of the Cc2d2a gene also has profound effects on heart development. Not only do the embryo hearts fail to complete separation of the left and right ventricular chambers (a “ventricular septal defect”), they also fail to form a proper wall between the left and right atrial chambers (an “ostium primum defect”). In addition, they have lost a swath of tissue at the junction between the atria and ventricles (the “vestibular spine”) that is essential for completing chamber separation.

Shows three views of the embryo heart. The lefthand panel shows the ventricular septal defect; the middle panel shows the osmium primum defect and the right panel shows the absence of vestibular spine tissue which normally enables the atrial and ventricular septal walls to attach to each other.

Many of the genes studied by DMDD do not currently appear to be associated with any disease, however careful analysis of the phenotypes from lines such as these could contribute to the identification of new disease models, and our data is freely available at dmdd.org.uk in order to encourage this. For more information please email contact@dmdd.org.uk.


A FULL LIST OF NEW DATA IN THE LATEST RELEASE

EDEMA – A SIGN OF UNDERLYING DEVELOPMENTAL DEFECTS

In around 30% of the knockout lines studied by DMDD, the embryos have edema – swelling due to fluid trapped in the embryo’s tissues.┬áMost of us have experienced edema at some point, after a bee sting, an infection or perhaps from hitting your thumb with a hammer. One reason that it happens is if small blood vessels start to leak, releasing fluid into the surrounding tissue. And in some cases it can be helpful – for example the additional white blood cells in the fluid can help fight infection more quickly.

In embryos from our embryonic lethal knockout lines, however, edema is more generalised, often surrounding the brain, abdomen or the entire body. We spot it in the initial checks of the embryo, where we look for major abnormalities that are visible without detailed imaging. In the image below, a Traf6 knockout embryo clearly shows edema around the skull and back.

A Traf6 homozygous knockout embryo shows edema around the back of the skull and body.

 

In adult humans, we know that more generalised edema can be caused by heart failure. If the heart is not able to pump blood around the body quickly enough then fluid can build up in the legs, lungs and abdomen. It can also be caused by liver and kidney diseases, as well as many other critical conditions.

The equivalent phenotype in human foetuses is known as hydrops fetalis. It’s an excessive accumulation of fluid in the body cavities, and can have a root cause in the foetus itself, in the placenta or in the mother. It’s the end stage of many different disorders. [1]

 

It’s almost never the edema that kills, but the underlying etiology. (Dr Fowzan Alkuraya, King Faisal Hospital, Riyadh).

 

The edema we see in embryonic lethal knockout mice is therefore unlikely to be a direct cause of lethality. As we might expect, many DMDD embryos with edema also show a wide range of other abnormalities, like this Ssr2 knockout that has a ventricular septal defect as well as subcutaneous edema.

 

Click to view larger image.
An Ssr2 knockout embryo has a ventricular septal defect as well as subcutaneous edema.

 

So when we see this general type of edema in our initial checks, it’s a huge clue that there may be serious underlying abnormalities that have led to the embryo’s demise. And to identify these we need detailed imaging.

[1] C. Bellini et al., Etiology of non-immune fetal hydrops: a systematic review, Am Gen Med Genet A, 149A (2009) p844-851.