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Cite as: eLife 2015;4:e09406 doi: Cheap Sale 100% Guaranteed Autumn winter male professional comfortable cheap breathable outdoor shoes Buy Cheap Cheapest Price Free Shipping Cheap Looking For Cheap Price Cheap Sale Outlet Store R7JKnPMFle

Truncating mutations in the giant sarcomeric protein Titin result in dilated cardiomyopathy and skeletal myopathy. The most severely affected dilated cardiomyopathy patients harbor Titin truncations in the C-terminal two-thirds of the protein, suggesting that mutation position might influence disease mechanism. Using CRISPR/Cas9 technology, we generated six zebrafish lines with Titin truncations in the N-terminal and C-terminal regions. Although all exons were constitutive, C-terminal mutations caused severe myopathy whereas N-terminal mutations demonstrated mild phenotypes. Surprisingly, neither mutation type acted as a dominant negative. Instead, we found a conserved internal promoter at the precise position where divergence in disease severity occurs, with the resulting protein product partially rescuing N-terminal truncations. In addition to its clinical implications, our work may shed light on a long-standing mystery regarding the architecture of the sarcomere.

https://doi.org/10.7554/eLife.09406.001

The heart is able to beat partly because of a large protein called Titin that helps to give heart muscle its elasticity. Mutations that shorten the gene that encodes Titin can cause part of the heart to become enlarged and weakened, a condition called dilated cardiomyopathy. Some people with shortened copies of this protein have a mild form of cardiomyopathy and are able to lead relatively normal lives. Others develop more severe symptoms that prevent the heart from pumping blood effectively and may even cause the individual to need a heart transplant.

Genetic studies have revealed that mutations that shorten the Titin protein by disrupting the portion of the gene corresponding to the latter two-thirds of the protein (which encodes the so-called “C-terminal” end of the protein) cause more severe symptoms than mutations that occur near the start of the gene. But it is not clear why the location of the mutation matters.

To investigate this problem, Zou et al. used a gene-editing tool called CRISPR to create genetically engineered zebrafish. These fish had mutations at one of six different points in the gene that encodes the zebrafish version of Titin. Just as with humans, mutations near the C-terminal end of the gene caused more severe muscle problems in the fish.

Specifically, Zou et al. found that the worst disease was associated with mutations that occurred at or after a “promoter” region within the gene and near this C-terminal end. Normally, the promoter produces an independent smaller form of the Titin protein, which helps to reduce the severity of muscle problems in zebrafish that have mutations near the start of the gene. However, mutations near the C-terminal end of the gene also damage this smaller form, preventing this failsafe from working, and so lead to more severe symptoms. Zou et al. also found this promoter to be active in both mouse and human hearts.

Future work will focus on learning how this smaller form of Titin works to help muscle develop and withstand stress and determine whether increasing its production can overcome the more severe forms of disease.

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The use of genetics in clinical medicine depends on knowledge that an identified mutation confers risk of disease. Recent guidance issued by the American College of Medical Genetics emphasizes that the strongest form of evidence supporting causality of a mutation is whether it results in a truncation of the protein (nonsense, frameshift or canonical splice-site mutations), specifically for genes where loss-of-function mutations are known to cause disease ( 100% Authentic Cheap Online QZYERAI Summer printing high heels with womens sexy Websites Cheap Online Pay With Visa For Sale Cheap Sale Cheapest Lowest Price Cheap Online xhw3On
). Truncating mutations within alternatively spliced exons and at the extreme C-terminus of the protein must be interpreted with caution, as they may have little to no impact on protein function. However, the guidelines do not address whether truncating mutations at different positions along the length of the protein might differ in phenotype severity or mechanism of action, a finding that could complicate interpretation of truncation mutations for a broad range of inherited diseases.

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The model layer

Django provides an abstraction layer (the “models”) for structuring and manipulating the data of your Web application. Learn more about it below:

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Django has the concept of “views” to encapsulate the logic responsible for processing a user’s request and for returning the response. Find all you need to know about views via the links below:

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