Mutations of Presenilin Genes in Dilated Cardiomyopathy and Heart Failure

Familial Dilated Cardiomyopathy Research Program, Division of Cardiovascular Medicine and the Department of Medicine, Oregon Health and Science University, Portland, OR 97239, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 01/2007; 79(6):1030-9. DOI: 10.1086/509900
Source: PubMed


Two common disorders of the elderly are heart failure and Alzheimer disease (AD). Heart failure usually results from dilated cardiomyopathy (DCM). DCM of unknown cause in families has recently been shown to result from genetic disease, highlighting newly discovered disease mechanisms. AD is the most frequent neurodegenerative disease of older Americans. Familial AD is caused most commonly by presenilin 1 (PSEN1) or presenilin 2 (PSEN2) mutations, a discovery that has greatly advanced the field. The presenilins are also expressed in the heart and are critical to cardiac development. We hypothesized that mutations in presenilins may also be associated with DCM and that their discovery could provide new insight into the pathogenesis of DCM and heart failure. A total of 315 index patients with DCM were evaluated for sequence variation in PSEN1 and PSEN2. Families positive for mutations underwent additional clinical, genetic, and functional studies. A novel PSEN1 missense mutation (Asp333Gly) was identified in one family, and a single PSEN2 missense mutation (Ser130Leu) was found in two other families. Both mutations segregated with DCM and heart failure. The PSEN1 mutation was associated with complete penetrance and progressive disease that resulted in the necessity of cardiac transplantation or in death. The PSEN2 mutation showed partial penetrance, milder disease, and a more favorable prognosis. Calcium signaling was altered in cultured skin fibroblasts from PSEN1 and PSEN2 mutation carriers. These data indicate that PSEN1 and PSEN2 mutations are associated with DCM and heart failure and implicate novel mechanisms of myocardial disease.

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Available from: Donna Burgess, May 11, 2015
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    • "Notably, age is the main risk factor for developing sporadic AD [36]. Moreover, PS1 mutations are also associated with heart failure and cardiac diseases because of similar alterations in ER calcium signaling as in AD [37]. Therefore, targeting intracellular store calcium homeostasis in HTS assays may allow the identification of drugs relevant for treatment of undesired effects associated with physiological aging and a wide range of neurodegenerative and cardiac diseases. "
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    • "The Malpighian tubules are analogous to the mammalian kidney and the fat body shares functional similarity with the liver and adipose tissue [23], [24]. Li and colleagues recently reported that heart-specific PSN knockdown did not cause lethality and that these flies displayed cardiac defects, an important finding given the identification of presenilin gene mutations in patients with dilated cardiomyopathy [25], [26]. Investigation of other tissue-specific effects in Drosophila may elucidate additional presenilin functions of relevance to human health. "
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