Mutations in a number of genes have been linked to inherited dilated cardiomyopathy (DCM). However, such mutations account for only a small proportion of the clinical cases emphasising the need for alternative discovery approaches to uncovering novel pathogenic mutations in hitherto unidentified pathways. Accordingly, as part of a large-scale N-ethyl-N-nitrosourea mutagenesis screen, we identified a mouse mutant, Python, which develops DCM. We demonstrate that the Python phenotype is attributable to a dominant fully penetrant mutation in the dynamin-1-like (Dnm1l) gene, which has been shown to be critical for mitochondrial fission. The C452F mutation is in a highly conserved region of the M domain of Dnm1l that alters protein interactions in a yeast two-hybrid system, suggesting that the mutation might alter intramolecular interactions within the Dnm1l monomer. Heterozygous Python fibroblasts exhibit abnormal mitochondria and peroxisomes. Homozygosity for the mutation results in the death of embryos midway though gestation. Heterozygous Python hearts show reduced levels of mitochondria enzyme complexes and suffer from cardiac ATP depletion. The resulting energy deficiency may contribute to cardiomyopathy. This is the first demonstration that a defect in a gene involved in mitochondrial remodelling can result in cardiomyopathy, showing that the function of this gene is needed for the maintenance of normal cellular function in a relatively tissue-specific manner. This disease model attests to the importance of mitochondrial remodelling in the heart; similar defects might underlie human heart muscle disease.

Background: TRIB1, a serine-threonine kinase-like molecule, is a biomarker of chronic antibody-mediated rejection. Results: TRIB1 is highly expressed in Tregs, where its expression correlates with Foxp3, a molecule with which it interacts directly. Conclusion: TRIB1 is a novel binding partner of Foxp3 in Tregs. Significance: TRIB1 may play a crucial role in Tregs in cooperation with Foxp3.

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Apoptosis is a key event in atherosclerotic plaque formation. The phosphoinositide-3-kinase (PI3K) cascade is involved in many cellular activities in plaques, such as migration and cell survival. Our previous data have identified an interaction between Tribbles 2 (Trb2) and signalling adaptor molecule Grb2 associated binder protein (Gab1). The functional consequences of this interaction are unknown. Gab1 interacts with the p85 domain of PI3K to mediate downstream activation of the Akt/PKB anti-apoptotic signalling pathway. We examined whether tribbles, a new family of signalling regulators, link with PI3K to control activation of Akt and potentially inhibit apoptosis.HEK293 cells were transfected with Trb2 and mutant or wt Gab1 and formation of Trb2/Gab1 complexes was quantified using a yellow fluorescent protein-based protein fragment complementation assay. We show that overexpression of the PI3Kδ and β (catalytic) and the PI3Kα (regulatory) subunits leads to an increase in Trb2–Gab1 interaction (relative binding intensity 2.48%± SEM vs 3.9%± SEM, p<0.05, and 2.52%± SEM vs 5.3%± SEM, respectively). These data suggest that Trb2/Gab1 binding is modulated via a PI3K dependent feedback loop and raise the possibility that that Trb2 may act as a co-regulator of Gab1. In addition, we show that Gab1 has an effect on cell morphology upon PI3K cascade activation, and this morphological consequence is potentiated further in the presence of Trb2. These findings in turn suggest that the Gab1–Trb2 interaction may participate in controlling cell survival and morphology and potentially, atherosclerotic plaque development or rupture.