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Abstract: Objective: Defects in myocardial mitochondrial structure and function have been associated with heart failure in humans and animal models. Mice lacking the muscle LIM protein (MLP) develop morphological and clinical signs resembling human dilated cardiomyopathy and heart failure. We tested the hypothesis that defects in the cytoskeleton lead to dilated cardiomyopathy through mitochondrial dysfunction in the MLP mouse model. Methods and results: Oxidative phosphorylation activity was determined in left ventricles of MLP knockout (KO) mice and control littermates by measuring complex activities of the electron transport chain (I–IV) and ATP synthase (complex V). All complexes and citrate synthase (CS) showed decreased activities in the KO mice, although activity per amount of CS, a measure for mitochondrial density, was normal. Light and electron microscopy revealed a disorganization of mitochondria and a dramatic decrease in mitochondrial density, even revealing regions completely lacking mitochondria in the KO hearts. Real-time PCR analysis showed decreased transcript levels of mtDNA and nuclear encoded mitochondrial genes and of peroxisome proliferator activated receptor gamma co-activator 1α (PGC-1α), a key regulator of mitochondrial biogenesis. MtDNA copy number (ratio mtDNA/nuclear DNA) was slightly increased in the MLP KO mice. Conclusion: Our results show that the absence of MLP causes a local loss of mitochondria. We hypothesize that this is caused by a disturbed interaction between cytoskeleton and mitochondria, which interferes with energy sensing and energy transfer. Recovery of energy depletion by stimulating mitochondrial biogenesis might be a useful therapeutic strategy for improving the energy imbalance in heart failure. [Copyright &y& Elsevier]

Leptin acts as a satiety signal regulating food intake and energy expenditure. The relation between variants in the leptin (LEP; 19 G>A) gene and its receptor (LEPR; Q223R and K109R) with obesity and type 2 diabetes has been studied extensively, but results are inconclusive and the relation remains unclear. In a population-based association study, we examined the effect of these variants on pre-diabetic phenotypes measured in young healthy twins. In this study, 396 monozygotic and 230 dizygotic twins (286 men and 340 women, mean age 25 years) were recruited from the East Flanders Prospective Twin Survey. Several diabetes-related traits were measured, including birth weight, adult body composition, fasting concentrations of cholesterol (LDL and HDL), triglycerides, free fatty acids, leptin, insulin and glucose. Genotyping was performed using Pyrosequencing. Linear mixed models, including a random effect term for twin pair membership, were used to evaluate associations between the variants and the measured traits. When appropriate, traits were adjusted for covariates including sex, (gestational) age, height and fat. Subjects carrying the 19 G allele of LEP had higher HDL-cholesterol levels compared to 19 A homozygotes (GX vs AA (95% CI): 1.62 (1.58-1.66) vs 1.49 (1.40-1.58) mmol/1;p=0.008). The K109R variant in the LEPR was associated with birth weight (KK, KR and RR (95% CI): 2507 (2462-2553), 2577 (2519-2536) and 2762 (2643-2882) gram; p=0.0002). Also the Q223R variant in the LEPR showed association with birth weight (QQ, QR and RR (95% CI): 2493 (2431-2554), 2542 (2492-2591) and 2670 (2583-2756) gram; p=0.002). These results indicate that genetic variation in the LEP gene affects HDL-cholesterol levels. Furthermore, this study suggests a possible role for the LEPR in explaining the inverse relationship between birth weight and the development of metabolic diseases in adult life. [ABSTRACT FROM AUTHOR]

Introduction: Unclassified variants (UVs) in the BRCA1/BRCA2 genes are a frequent problem in counseling breast cancer and/or ovarian cancer families. Information about cancer family history is usually available, but has rarely been used to evaluate UVs. The aim of the present study was to identify which is the best combination of clinical parameters that can predict whether a UV is deleterious, to be used for the classification of UVs., Methods: We developed logistic regression models with the best combination of clinical features that distinguished a positive control of BRCA pathogenic variants (115 families) from a negative control population of BRCA variants initially classified as UVs and later considered neutral (38 families)., Results: The models included a combination of BRCAPRO scores, Myriad scores, number of ovarian cancers in the family, the age at diagnosis, and the number of persons with ovarian tumors and/or breast tumors. The areas under the receiver operating characteristic curves were respectively 0.935 and 0.836 for the BRCA1 and BRCA2 models. For each model, the minimum receiver operating characteristic distance (respectively 90% and 78% specificity for BRCA1 and BRCA2) was chosen as the cutoff value to predict which UVs are deleterious from a study population of 12 UVs, present in 59 Dutch families. The p.S1655F, p.R1699W, and p.R1699Q variants in BRCA1 and the p.Y2660D, p.R2784Q, and p.R3052W variants in BRCA2 are classified as deleterious according to our models. The predictions of the p.L246V variant in BRCA1 and of the p.Y42C, p.E462G, p.R2888C, and p.R3052Q variants in BRCA2 are in agreement with published information of them being neutral. The p.R2784W variant in BRCA2 remains uncertain., Conclusions: The present study shows that these developed models are useful to classify UVs in clinical genetic practice.