This report describes dilated cardiomyopathy (postulated), CNOT3-related. Work in mice and flies implicates the human gene CNOT3 in the development of dilated cardiomyopathy and other cardiac pathologies. CNOT3 encodes a component of the CCR4-NOT complex, a major cellular mRNA deadenylase that is involved in mRNA degradation, translational repression, and general transcription regulation. There is a single orthologous gene in Drosophila, Dmel\Not3, for which RNAi targeting constructs and an allele caused by insertional mutagenesis have been generated.
The human CNOT3 gene has not been introduced into flies.
Multiple members of the CCR4-NOT complex were identified in a knockdown screen for Drosophila genes that impact cardiac function. The role of Dmel\Not3 was characterized further. Cardiac-specific knockdown of Not3 significantly increased both diastolic and systolic diameters and resulted in reduced systolic fractional shortening relative to control flies. An insertional loss-of-function mutation of Not3 is lethal and exhibits a defect in embryonic heart tube organization. Many physical interactions of Dmel\Not3 have been described; see below and in the Not3 gene report.
For transgenic human constructs, fly transgenic constructs and classical alleles, detailed phenotypic descriptions can be found in the allele reports; allele reports can be accessed from the gene report or by clicking on the allele symbols in the Disease Ontology and Reagent tables below.
[updated Feb. 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]
CNOT3 encodes a component of the CCR4-NOT complex, which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. Can repress transcription and may link the CCR4-NOT complex to transcriptional regulation; the repressive function may involve histone deacetylases. [Gene Cards, CNOT3; 2018.02.22]
One to one: 1 human to 1 Drosophila.
Moderate-scoring ortholog of human CNOT3; Dmel\Not3 shares 40% identity and 54% similarity with the human gene.
