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publicado em 26/03/2011 às 12h00:00
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Revealed how mutations in the protein interfere in the heart of Leopard syndrome

Researchers from Harvard Unicamp and show how you can "roll back" changes in heart disease

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Foto: Antonio Scarpinetti/Ascom/Unicamp
Foto: Antonio Scarpinetti/Ascom/Unicamp
Talita Miguel Marin, author of the study Franchini Kleber, a cardiologist at the Faculty of Medical Sciences (FCM)
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Talita Miguel Marin, author of the study
Franchini Kleber, a cardiologist at the Faculty of Medical Sciences (FCM)

Leopard syndrome is a rare inherited disorder characterized by abnormalities in skin, heart, inner ear, craniofacial, among others, which has news of some 500 carriers worldwide. Approximately 90% of them have cardiac hypertrophy, whose cause is a mutation of the SHP2 protein, a tyrosine phosphatase. As rare as the disease is its description in literature and Internet search engines.

Recently the issue has gained a great impact on a scientific paper - Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of Leopard syndrome-associated PTPN11 mutation - which has just been published by researchers from Unicamp, in partnership with researchers from Harvard Medical School, in The Journal of Clinical Investigation (JCI), high impact in the medical field. Besides the article, the work also received in the February issue, highlighted in an editorial called RAS signaling pathway mutations and hypertrophic cardiomyopathy: getting into and out of the thick of it, published in view/44972 and

Studies of physiotherapist Tali Miguel Marin indicated a new way of how mutations in this protein, anchored in molecular principles, perform interference at heart. The researcher has shown that interfering in this way, you can reverse the cardiac abnormalities, which are the leading cause of mortality in these individuals.

According to the cardiologist, Faculty of Medical Sciences (FCM) Kleber Franchini, supervisor of the doctoral thesis of Talia Marin, recently defended at the Graduate Program in Pathophysiology, Medical School, which was known until now was that these mutations induced part syndrome, with no certainty of their effects on the cardiovascular system. By studying the protein SHP2, the physical therapist noted how she was involved in this process and genes of cardiac hypertrophy.

Work by the physiotherapist has received an award from the Department of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School and other American Heart Association. The research, funded by the Foundation for Research Support of São Paulo (FAPESP), was developed during the doctoral Talia Marin at the Laboratory of Cardiovascular Pathophysiology, in collaboration with Harvard Medical School, United States. The first tests were generally positive in animal cells. The idea is to define the molecular approach of cardiac hypertrophy, because mostly it happens due to an overload of the heart and the mutation.

The next step is the stage of clinical testing in humans. It will probably be a global multicenter study based in the U.S. and perhaps contribute to some patients. Because the expectation is to know how changes in protein determines functional changes in cells. That still does not know, says Franchini.


The physiotherapist also proposed a specific treatment that can result in benefit to patients with this syndrome. She found that treatment even being conducted for a limited period of time (four weeks), managed to reverse the syndrome in animals, significantly improving their heart function. The question is whether this model can also be replicated in humans.

The substance that is suggested from this study, the treatment of cardiac hypertrophy in patients with Leopard syndrome, is rapamycin, an immunosuppressive drug used especially to prevent rejection of transplanted organs. The hope is this treatment for an extended enough unless you reverse the process. A longer follow-up may indicate that this is the best approach or whether to seek alternative forms of treatment. Hence the concern of Talita studying protein structure and that these mutations promote, Franchini stresses.

In Leopard syndrome, Talia Marin, Kleber Franchini his supervisor and the group of professor Maria Kontaridis sought to describe the molecular mechanisms responsible for phenotypic and genetic alterations of the heart hypertrophied. The identification of some of these mechanisms allowed to point the region most subject to pharmacological interference in order to act on it to prevent heart diseases. This may help the treatment to be instituted.


Talia Marin's work represents part of a broader line of research - entitled Molecular mechanisms of hypertrophy in heart failure - that has existed for ten years at Unicamp and has been trying to unravel the molecular mechanisms involved in cardiac hypertrophy, which has resulted in several international publications, and added about 70 jobs.

In fact, compares the cardiologist, this hypertrophy appears involved in physiological and pathological situations such as in the case of valve diseases in myocardial infarction and hypertension. Furthermore, it is a harbinger of changes that lead the individual to have heart failure.

For him, the collaboration with Harvard reinforces the strength of the scientific environment of Unicamp, its easy to insert in an international context and the performance of his graduate studies, which attracts students of excellent quality. The research on this topic began with the Masters of the researcher.

The main finding of Talia Marin confirm your hypothesis was validated previously in cardiac cells in culture, in an animal model (LEOPARD), emphasizing that FAK is very important and is related to the genesis of cardiac hypertrophy. We found this protein activated in this model, yet the paper proposes is a treatment for this syndrome based on a model already proposed cell activation in cascade of other proteins. With it, we were able to make visible the way that we believed she was being crucial for cardiac hypertrophy, reports the physiotherapist.


   Palavras-chave:   Leopard Syndrome    Disorder    Heart anomaly    Skin    Unicamp   
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