Review paper: http://www.sciencedirect.com/science/article/pii/S1471491415001562

Question

Review paper: http://www.sciencedirect.com/science/article/pii/S1471491415001562

Discussion paper: http://www.pnas.org/content/113/31/8759.full.pdf?with-ds=yes

1) How was the LOX mutation found in TAAD?
2) Which experimental methodologies were used to address the specific mutation, M298R, is causative for human TAAD.
3) Describe the similarities and differences between the mouse model and human patients having heterozygous mutation of LOX gene.
4) What is the phenotype of mice having homozygous LOX gene mutation?

Explanation / Answer

1. Mutation detected in whole genome sequencing of two first cousins with TAAD, were checked for the below conditions:

i) Shared in these two individuals in heterozyous state.

ii) Should be rare and has less allele frequency when compared in National Heart Lung and Blood Institute Exome Sequencing Program and Exome Aggregation Consortium of 0.01% or less.

iii) Should have funtional effect on the gene product. (o missense, nonsense, frameshift, or splice site variants).

iv) Should cosegregate with disease.

2. Preparation of heterozygous mutant (Lox+/Mut) and homozygous mutant (LoxMut/Mut) mice by clustered regularly interspaced short palindromic repeats (CRISPR)/clustered regularly interspaced short palindromic repeats-associated protein-9 nuclease (Cas9) genome editing. Then these were compared with the wild-type for Aortic diameter, ascending aortic length measured from the aortic root to the brachiocephalic artery, blood pressure, Circumferential vessel wall stiffness, Ultrastructural analysis, Autofluorescence of elastin.

3. Disease is produced in human in autosomal dominant manner. But, in mouse model, it occurs in homozygous state.

Increased ascending aortic length and fragmented elastic fibers in Lox+/Mut mice have vascular diseases because of weakened vessel walls and this is similar to the arterial tortuosity developed without aneurysm or dissection development in human.

4. Though homozygous LoxMut/Mut mice were born, they did not survive longer. These had  similar in size to their Lox+/+ and Lox+/Mut littermates with frequent cranial, thoracic, and abdominal hemorrhages associated with internal bleeding. Some had severe kyphosis and ruptured diaphragms. All the LoxMut/Mut mice had highly tortuous vessels with aneurysms in the ascending aorta and/or aortic arch and frequent aneurysms in the descending abdominal aorta near the renal artery branches.

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