Mutations of presenilin genes in dilated cardiomyopathy and heart failure

Duanxiang Li, Sharie B. Parks, Jessica Kushner, Deirdre Nauman, Donna Burgess, Susan Ludwigsen, Julie Partain, Randal R. Nixon, Charles Allen, Robert P. Irwin, Petra M. Jakobs, Michael Litt, Ray E. Hershberger

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1030-1039
Number of pages10
JournalAmerican Journal of Human Genetics
Volume79
Issue number6
DOIs
StatePublished - Dec 2006

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Presenilins
Presenilin-2
Dilated Cardiomyopathy
Presenilin-1
Heart Failure
Mutation
Genes
Alzheimer Disease
Penetrance
Missense Mutation
Inborn Genetic Diseases
Calcium Signaling
Heart Transplantation
Cardiomyopathies
Neurodegenerative Diseases
Heart Diseases
Fibroblasts
Skin

ASJC Scopus subject areas

  • Genetics

Cite this

Li, D., Parks, S. B., Kushner, J., Nauman, D., Burgess, D., Ludwigsen, S., ... Hershberger, R. E. (2006). Mutations of presenilin genes in dilated cardiomyopathy and heart failure. American Journal of Human Genetics, 79(6), 1030-1039. https://doi.org/10.1086/509900

Mutations of presenilin genes in dilated cardiomyopathy and heart failure. / Li, Duanxiang; Parks, Sharie B.; Kushner, Jessica; Nauman, Deirdre; Burgess, Donna; Ludwigsen, Susan; Partain, Julie; Nixon, Randal R.; Allen, Charles; Irwin, Robert P.; Jakobs, Petra M.; Litt, Michael; Hershberger, Ray E.

In: American Journal of Human Genetics, Vol. 79, No. 6, 12.2006, p. 1030-1039.

Research output: Contribution to journalArticle

Li, D, Parks, SB, Kushner, J, Nauman, D, Burgess, D, Ludwigsen, S, Partain, J, Nixon, RR, Allen, C, Irwin, RP, Jakobs, PM, Litt, M & Hershberger, RE 2006, 'Mutations of presenilin genes in dilated cardiomyopathy and heart failure', American Journal of Human Genetics, vol. 79, no. 6, pp. 1030-1039. https://doi.org/10.1086/509900
Li D, Parks SB, Kushner J, Nauman D, Burgess D, Ludwigsen S et al. Mutations of presenilin genes in dilated cardiomyopathy and heart failure. American Journal of Human Genetics. 2006 Dec;79(6):1030-1039. https://doi.org/10.1086/509900
Li, Duanxiang ; Parks, Sharie B. ; Kushner, Jessica ; Nauman, Deirdre ; Burgess, Donna ; Ludwigsen, Susan ; Partain, Julie ; Nixon, Randal R. ; Allen, Charles ; Irwin, Robert P. ; Jakobs, Petra M. ; Litt, Michael ; Hershberger, Ray E. / Mutations of presenilin genes in dilated cardiomyopathy and heart failure. In: American Journal of Human Genetics. 2006 ; Vol. 79, No. 6. pp. 1030-1039.
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