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First gene linked to childhood-onset familial dilated cardiomyopathy identified
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Researchers for the first time have identified a gene that is linked to childhood-onset familial dilated cardiomyopathy.
They also determined that the disease, which currently has no cure and can lead to HF and premature death, could potentially be treated with rapamycin.
Bruce Gelb, MD, and colleagues resequenced the genes of 513 patients with dilated cardiomyopathy and 1,150 matched controls from various cohorts of distinct ancestry. In three of those cohorts — one South Indian, one North Indian and one Japanese — the researchers discovered rare functional mutations of the RAF1 gene.
Bruce Gelb
The frequency of RAF1 mutations in people with childhood-onset dilated cardiomyopathy was approximately 9%, but negligible in people without the condition.
“It’s the first gene that’s been discovered for nonsyndromic dilated cardiomyopathy that is mostly specific for childhood-onset [dilated cardiomyopathy],” Gelb, director and Gogel family professor of the Mindich Child Health and Development Institute at the Icahn School of Medicine at Mount Sinai, told Cardiology Today. “We’ve not had any genes like that. We’ve known that some of the sarcomeric genes that can present in childhood, but most of them are adult-onset disease.”
Gelb and colleagues also found that the RAF1 mutations increased activity of the protein mTOR, which can be inhibited with FDA-approved drugs.
The researchers modeled the mutations in zebrafish, then treated them with rapamycin, an FDA-approved drug known to inhibit mTOR.
“After treatment of embryos with rapamycin, heart defects in the embryos expressing the [dilated cardiomyopathy]-associated RAF1 mutants were partially rescued and Akt [protein] activation was normalized,” the researchers wrote. “These results suggest that the cardiac failure induced by [dilated cardiomyopathy]-associated mutant RAF1 is partially mediated by increased AKT signaling. Taken together with the genetic and biochemical data, these results provide compelling evidence that RAF1 mutations have a critical role in [dilated cardiomyopathy].”
There are two next steps in the near future, Gelb told Cardiology Today. “One, we need to know more about the epidemiology,” he said. “We worked closely with scientists in India, Italy and Japan, but we didn’t have any American cohorts. We would imagine the rates will be similar in an American cohort, but we just don’t know that until somebody looks at it. In terms of treatment, the next step is to develop a proper model that preclinical testing could be done with, and the obvious one would be a mouse model.”
Because rapamycin is already FDA-approved, the development process for a treatment can be fast-tracked, Gelb said. He added that there is already a trial of a rapamycin-like drug in progress for children with neurocognitive problems, which could inform the developmental process for treating childhood-onset familial dilated cardiomyopathy with the drug. – by Erik Swain
Disclosure: Mount Sinai has filed a provisional patent with the US Patent and Trademark Office.
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