This report describes fly models relevant to cardiomyopathies that are TNNT2-related. The human gene implicated in these diseases (TNNT2) cardiac-type troponin T, a component of sarcomere thin filaments. TNNT2 is implicated in several forms of heart disease (see OMIM:191045), including CMD1D (FBhh0000163), CMH2 (FBhh0000413), and familial restrictive cardiomyopathy 3 (OMIM:612422); cardiomyopathy-associated variants act as autosomal dominants. Involvement of TNNT2 with both dilated cardiomyopathy and hypertrophic cardiomyopathy is supported by a large-scale WES analysis (Walsh, et al., 2016; pubmed:27532257).
There is one fly ortholog of TNNT2, up; Dmel\up is also orthologous to human genes TNNT1 and TNNT3, which are described as skeletal-type troponins. RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical missense alleles have been generated for the up gene. Animals homozygous for mutant alleles survive to adulthood, but are flightless and exhibit and abnormal wing posture; after eclosion, indirect flight muscles exhibit hypercontraction and progressive degeneration. Genetic and physical interactions of Dmel\up have been described; see below and the up gene report.
A UAS construct of a tagged wild-type human Hsap\TNNT2 gene has been introduced into flies, but has not been used to characterize this disease model.
[updated Oct. 2016 by FlyBase; FBrf0222196]
The troponin complex is located on the thin filament of striated muscle and is composed of 3 component polypeptides: troponin T (TNNT1, OMIM:191041; and TNNT2), troponin I (TNNI1, OMIM:191042; TNNI2, OMIM:191043; and TNNI3, OMIM:191044), and troponin C (TNNC1, OMIM:191040; and TNNC2 OMIM:191039). Three troponin T genes have been described on the basis of molecular cloning in humans and other vertebrates. These are expressed in a tissue-specific manner and encode the troponin T isoforms expressed in cardiac muscle, slow skeletal muscle (TNNT1), and fast skeletal muscle (TNNT3; OMIM:600692). Each of these genes is subject to alternative splicing, resulting in the production of multiple tissue-specific isoforms. [From OMIM:191045, 2016.02.02]
Many to one: 3 human to 1 Drosophila; additional human orthologs are TNNT1 and TNNT3. TNNT2 is described as cardiac-type T troponin; TNNT1 and TNNT3 are described as skeletal-type T troponins.