Heart Failure: A Result of a Faulty Gene

Researchers at Imperial College London have discovered 1% of of people carry faulty versions of a gene that can lead to heart failure. The gene itself codes for a protein called titin, which can trigger heart failure if the organ comes under stress. The gene variants for the titin protein causes a heart condition known as dilated cardiomyopathy. According to Dr. Stuart Cook, a professor of clinical and molecular cardiology, dilated cardiomyopathy is where the heart enlarges, thus stretching and thinning the muscle. This eventually impair's the organ's ability to pump blood and oxygen around the body.

By doing a study on healthy rats with the faulty genes, researchers have discovered that the animals appeared healthy, but still contained the abnormal stress on the hearts, in which could trigger dilated cardiomyopathy. By doing a comparison on adults through MRI scans, analysts indeed found that 1% of the tested adults carried the titin gene variants. Surprisingly enough, the adults that carried the gene looked completely healthy.   

On a closer analysis through 3-D heart models of the carriers, researchers indeed detected a slightly enlarged heart in comparison to those without the gene variants. In addition, the pattern detected in gene variant carriers were shown to be similar in heart failure patients. Scientists also concluded that those with the titin gene variants may have silenced genes in which may not cause dilated cardiomyopathy directly but can still be triggered indirectly though genetic stress. If the results holds true for beyond the tested patients, patients who appear healthy may be in danger of not realizing that they carry the gene variant that causes dilated cardiomyopathy. With this research in mind, this can be very useful for genetic researchers in comparing other genetic mutations that act similar to the litin gene. By targeting the specific gene that may cause the disease, drugs can be made to silence the gene or altered to prevent the mutation from triggering the heart condition. Hopefully, these results can serve as the foundation for advancements in genetic analysis for conditions that are caused by genetic mutations.  

Expressing Mutations

It started as a simple experiment - scientist Heidi Rehm wanted to understand why her daughter's adult teeth had not emerged yet - but got a result she was not expecting. According to her daughter's genetic code, she had the coding only before seen in patients diagnosed with dilated cardiomyopathy, a fatal heart condition. Proceeding tests proved that her daughter had a healthy heart. Heidi had both her and her mother genetically tested, only to find that her and her mother also had the genetic code for the mutation, but also had healthy hearts. This is not the first story to come out of genetic coding and cardiomyopathy. Almost ten years ago, many African American people had been told they contained this mutation, meaning they had an increased chance of developing this condition. Years and many experiments later, it has been found that this mutation is too common in the population to be lethal.
Genetics is a growing field that is increasing in popularity and demand. Studies are now being conducted to understand the connection between genetic coding and expressed characteristics, such as heart disease and cancer. Although it is extremely difficult and time consuming to make direct correlations, scientists are working on it and making some headway. It was revealed in August that, on average, a person has about fifty four "lethal" mutations in the DNA. However, that does not mean that each of these mutations are necessarily harming each and every person. Heidi, her mother, and her daughter (so far) are all proof that genetics still has a lot of research left to be done.

Researchers Identify New Gene Mutations that Cause Heart Disorder

According to an article published recently in HHMI, Christine Seidman, a Howard Hughes Medical Institute (HHMI) investigator at Brigham and Women’s Hospital in Boston, and her team have done extensive research on at least forty separate genes responsible for dilated cardiomyopathy.  Dilated cardiomyopathy is a medical condition in which the heart becomes enlarged and weakened, thereby reducing its capacity to pump blood with enough vigor to deliver oxygen to the body effectively.  Debilitating symptoms include shortness of breathe and persistent fatigue.  Dilated cardiomyopathy tends to run in families, and so genetic causation is a likely explanation of its pathology.  The fact that dilated cardiomyopathy is influenced by at least forty known genes means it can be considered polygenic inheritance, or an additive effect of two or more genes on a single phenotype, perhaps even resulting in a gradation termed quantitative character.    Until recently, the genes suspected of contributing to dilated cardiomyopathy that have been sequenced have been relatively short, anywhere from the 675 amino acid residues of Lamin A/C to the 2,000 amino acid residues of the motor protein myosin.  Titin, a protein which helps assemble the sarcomere as the heart muscle grows and also plays a role in muscle contractions, on the other hand is a staggering 33,000 amino acid residues long.  As Dr. Seidman explains, "It wasn’t that we weren’t aware that titin caused disease—we were.  The problem was that the technology was not sufficiently robust to allow comprehensive analysis of that gene in a large collection of patients.”  As a result, genetic causation of dilated cardiomyopathy had remained not fully understood.

However, recent technological innovations which have made DNA sequencing fast and relatively inexpensive have allowed Dr. Seidman and her team to finally sequence the giant gene sequence of titin and record genetic mutations in the gene in patients who suffered from dilated cardiomyopathy.  The results were fruitful:  28 percent of the people who had dilated cardiomyopathy also had dramatic mutations in the DNA encoding titin, mutatations which resulted in non-functional protein products.  Among the forty known genes known to influence dilated cardiomyopathy, titin by far had the highest percent correlation between gene mutation and phenotypically observable disease state.

Dr. Seidman hopes that her team's findings demonstrating the strong correlation between titin mutation and dilated cardiomyopathy will result in a more proactive approach to preventive medicine and prophylactic treatments.  She also hopes that scientifically mapping the congenital causes of dilated cardiomyopathy might shed light on the pathophysiological mechanisms which enlarge and weaken the heart in afflicted patients in the first place, which would further lead scientists to curative medicines.

[caption id="attachment_3808" align="aligncenter" width="775" caption="Sliding filament model of muscle contraction. (Titin labeled at upper right)."][/caption]