Congenital heart defects (CHD) are collectively the most common form of congenital malformation. Studies of human cases and animal models have revealed that mutations in several genes are responsible for both familial and sporadic forms of CHD. We have previously shown that a mutation in MYH6 can cause an autosomal dominant form of atrial septal defect (ASD), whereas others have identified mutations of the same gene in patients with hypertrophic and dilated cardiomyopathy. In the present study, we report a mutation analysis of MYH6 in patients with a wide spectrum of sporadic CHD. The mutation analysis of MYH6 was performed in DNA samples from 470 cases of isolated CHD using denaturing high-performance liquid chromatography and sequence analysis to detect point mutations and small deletions or insertions, and multiplex amplifiable probe hybridization to detect partial or complete copy number variations. One non-sense mutation, one splicing site mutation and seven non-synonymous coding mutations were identified. Transfection of plasmids encoding mutant and non-mutant green fluorescent protein-MYH6 fusion proteins in mouse myoblasts revealed that the mutations A230P and A1366D significantly disrupt myofibril formation, whereas the H252Q mutation significantly enhances myofibril assembly in comparison with the non-mutant protein. Our data indicate that functional variants of MYH6 are associated with cardiac malformations in addition to ASD and provide a novel potential mechanism. Such phenotypic heterogeneity has been observed in other genes mutated in CHD.

Atrial septal defect (ASD) is one of the most frequent congenital heart defects (CHDs) with a variable phenotypic effect depending on the size of the septal shunt. We identified two pedigrees comprising 20 members segregating isolated autosomal dominant secundum ASD. By genetic mapping, we identified the gene-encoding alpha-cardiac actin (ACTC1), which is essential for cardiac contraction, as the likely candidate. A mutation screen of the coding regions of ACTC1 revealed a founder mutation predicting an M123V substitution in affected individuals of both pedigrees. Functional analysis of ACTC1 with an M123V substitution shows a reduced affinity for myosin, but with retained actomyosin motor properties. We also screened 408 sporadic patients with CHDs and identified a case with ASD and a 17-bp deletion in ACTC1 predicting a non-functional protein. Morpholino (MO) knockdown of ACTC1 in chick embryos produces delayed looping and reduced atrial septa, supporting a developmental role for this protein. The combined results indicate, for the first time, that ACTC1 mutations or reduced ACTC1 levels may lead to ASD without signs of cardiomyopathy.

Global rates of obesity continue to rise and are necessarily the consequence of a long-term imbalance between energy intake and energy expenditure. This is the result of an expansion of adipose tissue due to both the hypertrophy of existing adipocytes and hyperplasia of adipocyte pre-cursors. Exercise elicits numerous physiological benefits on adipose tissue, which are likely to contribute to the associated cardiometabolic benefits. More recently it has been demonstrated that exercise, through a range of mechanisms, induces a phenotypic switch in adipose tissue from energy storing white adipocytes to thermogenic beige adipocytes. This has generated the hypothesis that the process of adipocyte ‘browning’ may partially underlie the improved cardiometabolic health in physically active populations. Interestingly, ‘browning’ also occurs in response to various stressors and could represent an adaptive response. In the context of exercise, it is not clear whether the appearance of beige adipocytes is metabolically beneficial or whether they occur as a transient adaptive process to exercise-induced stresses. The present review discusses the various mechanisms (e.g. fatty acid oxidation during exercise, decreased thermal insulation, stressors and angiogenesis) by which the exercise-induced ‘browning’ process may occur.