title: Mutations of presenilin genes in dilated cardiomyopathy and heart failure.
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.
authors.affiliation: Familial Dilated Cardiomyopathy Research Program, Division of Cardiovascular Medicine and the Department of Medicine, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Duanxiang
authors.initials: D
authors.lastname: Li
authors.forename: Sharie B
authors.initials: SB
authors.lastname: Parks
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Kushner
authors.forename: Deirdre
authors.initials: D
authors.lastname: Nauman
authors.forename: Donna
authors.initials: D
authors.lastname: Burgess
authors.forename: Susan
authors.initials: S
authors.lastname: Ludwigsen
authors.forename: Julie
authors.initials: J
authors.lastname: Partain
authors.forename: Randal R
authors.initials: RR
authors.lastname: Nixon
authors.forename: Charles N
authors.initials: CN
authors.lastname: Allen
authors.forename: Robert P
authors.initials: RP
authors.lastname: Irwin
authors.forename: Petra M
authors.initials: PM
authors.lastname: Jakobs
authors.forename: Michael
authors.initials: M
authors.lastname: Litt
authors.forename: Ray E
authors.initials: RE
authors.lastname: Hershberger
mesh_terms: D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics; D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D019683:Penetrance; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism; D053766:Presenilin-2 / Q000235:genetics* / Q000378:metabolism
chemical_list: D053764:Presenilin-1; D053766:Presenilin-2; D002118:Calcium