This report describes dilated cardiomyopathy 1V (CMD1V), which is a subtype of dilated cardiomyopathy; CMD1V exhibits an autosomal dominant pattern of inheritance. The human gene implicated in this disease is PSEN2 (Presenilin 2), the catalytic component of a gamma-secretase complex. 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. PSEN2 is also associated with the disease Alzheimer disease 4 (MIM:606889, FBhh0000121). Dmel\Psn is orthologous to a second human gene, PSEN1, which is also implicated in a form of dilated cardiomyopathy (MIM:613694, FBhh0000154).
Multiple UAS constructs of the human Hsap\PSEN2 gene have been introduced into flies, including wild-type PSEN2. 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, 1V; CMD1V](https://omim.org/entry/613697)
[PRESENILIN 2; PSEN2](https://omim.org/entry/600759)
Li et al. (2006, pubmed:17186461) described 2 families with dilated cardiomyopathy segregating with mutation in the PSEN2 gene (CMD1V). The mutation was present in heterozygous state. Both were white families. Onset of cardiovascular disease occurred at the age of 48 to 55 years in one family. A mutation-positive family member had normal results on cardiovascular screening, suggesting reduced penetrance. One obligate carrier from the same family had the onset of dementia at age 75 years without evidence of cardiovascular disease. In the second family, 3 sibs received the diagnosis of DCM between ages 36 and 45 years. Two of the 5 mutation carriers in this family aged more than 35 years did not show evidence of cardiovascular disease, suggesting reduced penetrance and/or variable age at onset. [From MIM:613694, 2016.01.27]
Dilated cardiomyopathy-1V is caused by heterozygous mutation in the PSEN2 gene. Li et al. (2006, pubmed:17186461) hypothesized that, since the presenilins are expressed in the heart and are critical to cardiac development, mutations in presenilins may also be associated with dilated cardiomyopathy. They evaluated a total of 315 index patients with DCM for sequence variation in PSEN1 (MIM:104311) and PSEN2. In 2 families, Li et al. (2006, pubmed:17186461) found that idiopathic dilated cardiomyopathy segregated with a ser130-to-leu amino acid change (S130L; MIM:600759.0008). This mutation had been reported in association with Alzheimer disease (MIM:606889) in a small kindred by Tedde et al. (2003, pubmed:14623725). Li et al. (2006, pubmed:17186461) also identified a novel mutation in the PSEN1 gene (MIM:104311.0034) in one family (CMD1U; MIM:613694). Families positive for mutations underwent additional clinical, genetic, and functional studies. 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 fibroblasts from PSEN1 and PSEN2 mutation carriers.[From MIM:613697 2016.01.27]
PSEN2 encodes presenilin 2, a probable catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). PSEN2 requires the other members of the gamma-secretase complex to have a protease activity. It may play a role in intracellular signaling and gene expression or in linking chromatin to the nuclear membrane. It may function in the cytoplasmic partitioning of proteins. [From UniProt, uniprot:P49810 2016.02.04]
Many to one: 2 human to 1 Drosophila.
