This report describes dilated cardiomyopathy 2C (CMD2C), which is a subtype of dilated cardiomyopathy; CMD1V exhibits an autosomal recessive pattern of inheritance. The human gene implicated in this disease is PPCS (phosphopantothenoylcysteine synthetase), an enzyme required in the biosynthesis of coenzyme A (CoA). Coenzyme A is an essential cofactor for many enzymes involved in central metabolic reactions. There is a single orthologous gene in Drosophila, Dmel\Ppcs, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and an amorphic mutation caused by imprecise excision of a TE insertion have been generated.
The human PPCS gene has not been introduced into flies.
Animals homozygous for an amorphic (or severe loss-of-function) mutation of Dmel\Ppcs die during the first larval instar stage. Animals homozygous for a milder loss-of-function allele exhibit a range of phenotypes, including decreased survival to adulthood, locomotor defects, increased sensitivity to ROS, impaired DNA integrity in proliferating cells of the developing CNS, altered lipid homeostasis, and female sterility. Examined specifically for cardiac function, these homozygous animals showed a significant increase in heart rate, heart wall shortening, and arrhythmia index, and a decrease in systolic length. A small number of physical interactions have been described for Dmel\Ppcs; see below and in the Ppcs gene report.
Supplementation of the fly food with pantethine, which can serve as a source for CoA de novo biosynthesis, was tested for effect upon survival to adulthood. Using the characterized hypomorphic allele, partial rescue of the decrease in survival of Ppcs homozygous animals was observed.
[updated Mar. 2019 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, 2C; CMD2C](https://omim.org/entry/618189)
[PHOSPHOPANTOTHENOYLCYSTEINE SYNTHETASE; PPCS](https://omim.org/entry/609853)
CMD2C is characterized by dilated cardiomyopathy of variable severity, with age of onset ranging from 2 to 20 years. Affected individuals exhibit reduction in coenzyme A (CoA) levels. Some severely affected children die in the first few years of life (Iuso et al., 2018; pubmed:29754768). [from MIM:618189; 2019.03.08]
Dilated cardiomyopathy 2C (CMD2C) is caused by homozygous or compound heterozygous mutation in the PPCS gene. [from MIM:618189; 2019.03.08]
PPCS (phosphopantothenoylcysteine synthetase) is required in the biosynthesis of coenzyme A (CoA). Coenzyme A is an essential metabolic cofactor used by around 4% of cellular enzymes. (Iuso et al., 2018, FBrf0240899; and references cited therein).
Coenzyme A (CoA) is a ubiquitous and essential cofactor that is involved in a large proportion of all central metabolic reactions. (https://www.sciencedirect.com/topics/neuroscience/coenzyme-a)
One to one: 1 human to 1 Drosophila.
High-scoring ortholog of human PPCS; Dmel\Ppcs shares 40% identity and 60% similarity with the human gene.
