This report describes dilated cardiomyopathy 1U (CMD1U), which is a subtype of dilated cardiomyopathy; CMD1U exhibits autosomal dominant inheritance. The human gene implicated in this disease is PSEN1, which encodes presenilin 1, which forms the catalytic component of gamma-secretase. There is one high-scoring fly ortholog, Psn, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated. PSEN1 is also associated with the diseases Alzheimer disease 3 (MIM:607822, FBhh0000120), frontotemporal dementia (MIM:600274, FBhh0000809), Pick disease (MIM:172700, FBhh0000112), and familial acne inversa 3 (MIM:613737). Dmel\Psn is orthologous to a second human gene, PSEN2, which is also implicated in a form of dilated cardiomyopathy (MIM:613697, FBhh0000155).
Multiple different UAS constructs of the human gene Hsap\PSEN1 have been introduced into flies, including wild-type and genes carrying mutational lesions implicated in AD3. Human variants implicated in cardiomyopathy have not been characterized in the fly system.
For data concerning disease models of cardiomyopathy using the fly Psn gene, see the report for 'dilated cardiomyopathy, presenilin-related' (FBhh0000751).
[updated Mar. 2018 by FlyBase; FBrf0222196]
Nonsyndromic isolated dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and systolic dysfunction, a reduction in the myocardial force of contraction. DCM usually presents with any one of the following: (1) Heart failure with symptoms of congestion (edema, orthopnea, paroxysmal nocturnal dyspnea) and/or reduced cardiac output (fatigue, dyspnea on exertion); (2) arrhythmias and/or conduction system disease; (3) thromboembolic disease (from left ventricular mural thrombus) including stroke. [from Dilated Cardiomyopathy Overview, pubmed:20301486 2016.01.26]
Dilated cardiomyopathy (CMD) is characterized by cardiac dilatation and reduced systolic function. CMD is the most frequent form of cardiomyopathy and accounts for more than half of all cardiac transplantations performed in patients between 1 and 10 years of age. A heritable pattern is present in 20 to 30% of cases. Most familial CMD pedigrees show an autosomal dominant pattern of inheritance, usually presenting in the second or third decade of life (summary by Levitas et al., 2010, pubmed:20551992). [from MIM:115200, 2016.01.27]
[CARDIOMYOPATHY, DILATED, 1U; CMD1U](https://omim.org/entry/613694)
[PRESENILIN 1; PSEN1](https://omim.org/entry/104311)
Li et al. (2006, pubmed:17186461) described an African American family with dilated cardiomyopathy segregating with mutation in the PSEN1 gene (CMD1U). Affected members were identified in 3 generations. Onset of dilated cardiomyopathy and heart failure ranged from age 24 to 69 years. Mortality from progressive heart failure usually followed within a few years of diagnosis. The index patient presented with symptomatic heart failure due to idiopathic dilated cardiomyopathy at age 52 years. Another family member, who presented with idiopathic dilated cardiomyopathy and heart failure at the age of 51 years, required cardiac transplantation at age 62 years. Extensive hospital records showed that the affected member in the first generation received the diagnoses of heart failure and nonischemic dilated cardiomyopathy at age 69 years and of dementia at the age of 71 years. Both the cardiomyopathy and dementia progressed and resulted in repeated hospitalizations until the patient's death at age 78 years, in advanced heart failure. [From MIM:613694, 2016.01.27]
Dilated cardiomyopathy-1U is caused by heterozygous mutation in the PSEN1 gene. While familial Alzheimer disease (see MIM:607822) can be caused by presenilin mutations, these genes are also expressed in the heart and are critical to cardiac development. Li et al. (2006, pubmed:17186461) hypothesized that mutations in presenilin may also be associated with dilated cardiomyopathy (DCM; see MIM:115200) and that their discovery could provide new insight into the pathogenesis of DCM and heart failure. They evaluated a total of 315 index patients with DCM for sequence variation in PSEN1 and PSEN2 (MIM:600759). Families positive for mutations underwent additional clinical, genetic, and functional studies. This group identified a novel heterozygous PSEN1 missense mutation (D333G; MIM:104311.0034) in 1 family and a single heterozygous PSEN2 missense mutation (MIM:600759.0008) in 2 other families (CMD1V; MIM:613697). 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. [From MIM:613694, 2016.01.27]
The PSEN1 gene encodes presenilin-1, which forms the catalytic component of gamma-secretase. Gamma-secretase is responsible for proteolytic cleavage of amyloid precursor protein (APP; MIM:104760) and NOTCH receptor proteins (see MIM:190198). Gamma-secretase is a multiprotein complex consisting of PSEN1 or its homolog PSEN2 (MIM:600759), nicastrin (MIM:605254), APH1 (see APH1A, MIM:607629), and PEN2 (PSENEN; MIM:607632) (summary by De Strooper, 2003, pubmed:12691659; Chau et al., 2012, pubmed:22461631). [From MIM:104311, 2016.01.27]
Many to one: 2 human to 1 Drosophila.
