An international team of researchers have sought to identify genetic mutations that produce abnormal forms of a key heart muscle protein.
As a result of the mutations, the heart muscles weaken and produce a condition known as ‘dilated cardiomyopathy.’
The increased strain that is then put on the heart can lead to heart failure where the organ is unable to pump the requisite quantities of blood.
Changes to titin, a protein that is part of the mechanism muscles use to contract and relax, have been implicated as a cause for dilated cardiomyopathy.
Titin is the largest human protein
It is produced by a gene whose genetic information exists as 364 separate segments, known as exons.
Variations in how the genetic data from these exons are assembled mean that the protein can exist in a variety of forms.
A 2012 study carried out in severe and familial cases of dilated cardiomyopathy found that disruptive mutations in the gene, resulting in truncated titin variants being produced, were the commonest genetic cause for the ailment.
Researchers who carried out that study have gone on to examine titin gene sequences from over 5,200 individuals, with and without the condition, as well as scrutinising 150 heart tissue samples collected from patients who underwent heart surgery.
According to James S. Ware from the Royal Brompton & Harefield NHS Foundation Trust & Imperial College in U.K., another of the senior authors of the paper: The latest study indicated that disease-causing mutations typically occurred in exons that are very highly used in the heart to produce titin.
Mutations in the general population, on the other hand, tended to be in exons often omitted in the heart.
Moreover, the disease-causing variants were towards one end of the titin gene.
It was found that patients with dilated cardiomyopathy due to titin mutations had more severe disease, with more life-threatening heart rhythm problems and ultimately poorer survival, he said during the press briefing.
So such mutations may define a group of patients who could benefit from a tailored therapeutic approach.
The foreshortened titin protein produced by the disease-causing mutations appeared to be poisoning the heart muscle cells.
Understanding how this occurred would allow development of directed therapeutics for the condition.