Missense Mutations in a Retinal Pigment Epithelium Protein, Bestrophin-1, Cause Retinitis Pigmentosa

Bestrophin-1 is preferentially expressed at the basolateral membrane of the retinal pigmented epithelium (RPE) of the retina. Mutations in the BEST1 gene cause the retinal dystrophies vitelliform macular dystrophy, autosomal-dominant vitreochoroidopathy, and autosomal-recessive bestrophinopathy. Here, we describe four missense mutations in bestrophin-1, three that we believe are previously unreported, in patients diagnosed with autosomal-dominant and -recessive forms of retinitis pigmentosa (RP). The physiological function of bestrophin-1 remains poorly understood although its heterologous expression induces a Cl⁻-specific current. We tested the effect of RP-causing variants on Cl⁻ channel activity and cellular localization of bestrophin-1. Two (p.L140V and p.I205T) produced significantly decreased chloride-selective whole-cell currents in comparison to those of wild-type protein. In a model system of a polarized epithelium, two of three mutations (p.L140V and p.D228N) caused mislocalization of bestrophin-1 from the basolateral membrane to the cytoplasm. Mutations in bestrophin-1 are increasingly recognized as an important cause of inherited retinal dystrophy.     

Genetic and environmental influences on factors associated with cardiovascular disease and the metabolic syndrome

The relative influence of genetics and the environment on factors associated with cardiovascular disease (CVD) and metabolic syndrome (MetS) remains unclear. We performed model-fitting analyses to quantify genetic, common environmental, and unique environmental variance components of factors associated with CVD and MetS [waist circumference, blood pressure, fasting plasma glucose and insulin, homeostatic model assessment of insulin resistance (HOMA-IR), and fasting plasma lipids] in adult male and female monozygotic twins reared apart or together. We also investigated whether MetS components share common influences. Plasma cholesterol and triglyceride concentrations were highly heritable (56–77%, statistically significant). Waist circumference, plasma glucose and insulin, HOMA-IR, and blood pressure were moderately heritable (43–57%, statistically significant). Unique environmental factors contributed to the variance of all variables (20–38%, perforce statistically significant). Common environmental factors contributed 23, 30, and 42% (statistically significant) of the variance of waist circumference, systolic blood pressure, and plasma glucose, respectively. Two shared factors influenced MetS components; one influenced all components except HDL cholesterol, another influenced only lipid (triglyceride and HDL cholesterol) concentrations. These results suggest that genetic variance has a dominant influence on total variance of factors associated with CVD and MetS and support the proposal of one or more underlying pathologies of MetS.     

Randomized Trial of a Behavioral Weight Loss Intervention for Low‐income Women: The Weight Wise Program

Low‐income women in the United States have the highest rates of obesity, yet they are seldom included in weight loss trials. To address this research gap, components of two evidence‐based weight loss interventions were adapted to create a 16‐week intervention for low‐income women (Weight Wise Program), which was evaluated in a randomized trial with the primary outcome of weight loss at 5‐month follow‐up. Participants were low‐income women (40–64 years) with a BMI of 25–45. Of 143 participants, 72 were randomized to the Weight Wise Program (WWP) and 71 to the Control Group (CG). Five‐month follow‐up data were obtained from 64 (89%) WWP and 62 (87%) CG participants. With baseline values carried forward for missing data, WWP participants had a weight change of ?3.7 kg compared to 0.7 kg in the CG (4.4 kg difference, 95% confidence interval (CI), 3.2–5.5, P < 0.001). For systolic blood pressure (SBP), change in the WWP was ?6.5 mm Hg compared to ?0.4 mm Hg among controls (6.2 mm Hg difference, 95% CI, 1.7–10.6, P = 0.007); for diastolic BP (DBP), changes were ?4.1 mm Hg for WWP compared to ?1.3 mm Hg for controls (2.8 mm Hg difference, 95% CI, 0.0–5.5, P = 0.05). Of the 72 WWP participants, 64, 47, and 19% lost at least 3, 5, and 7% of their initial body weight, respectively. In conclusion, the WWP was associated with statistically significant and clinically important short‐term weight loss.     

Mitochondrial DNA Variants of Respiratory Complex I that Uniquely Characterize Haplogroup T2 Are Associated with Increased Risk of Age-Related Macular Degeneration

Background

Age-related macular degeneration (AMD), a chronic neurodegenerative and neovascular retinal disease, is the leading cause of blindness in elderly people of western European origin. While structural and functional alterations in mitochondria (mt) and their metabolites have been implicated in the pathogenesis of chronic neurodegenerative and vascular diseases, the relationship of inherited variants in the mitochondrial genome and mt haplogroup subtypes with advanced AMD has not been reported in large prospective cohorts.

Methodology/Prinicipal Findings

We examined the relationship of inherited mtDNA variants with advanced AMD in 1168 people using a three-stage design on samples from 12-year and 10-year prospective studies on the natural history of age-related eye disease. In Stage I we resequenced the entire genome in 99 elderly AMD-free controls and 215 people with advanced AMD from the 12-year study. A consistent association with AMD in 14 of 17 SNPs characterizing the mtDNA T haplogroup emerged. Further analysis revealed these associations were driven entirely by the T2 haplogroup, and characterized by two variants in Complex I genes (A11812G of MT-ND4 and A14233G of MT-ND6). We genotyped T haplogroups in an independent sample of 490 cases and 61 controls from the same study (Stage II) and in 56 cases and 246 controls from the 10-year study (Stage III). People in the T2 haplogroup were approximately 2.5 times more likely to have advanced AMD than their peers (odds ratio [OR] = 2.54, 95%CI 1.36–4.80, P≤0.004) after considering the totality of evidence. Findings persisted after considering the impact of AMD-associated variants A69S and Y402H (OR = 5.19, 95%CI 1.19–22.69, P≤0.029).

Conclusion

Loci defining the mtDNA T2 haplogroup and Complex I are reasonable targets for novel functional analyses and therapeutic research in AMD.     

Observation of Static Pictures of Dynamic Actions Enhances the Activity of Movement-Related Brain Areas

Background

Physiological studies of perfectly still observers have shown interesting correlations between increasing effortfulness of observed actions and increases in heart and respiration rates. Not much is known about the cortical response induced by observing effortful actions. The aim of this study was to investigate the time course and neural correlates of perception of implied motion, by presenting 260 pictures of human actions differing in degrees of dynamism and muscular exertion. ERPs were recorded from 128 sites in young male and female adults engaged in a secondary perceptual task.

Principal Findings

Our results indicate that even when the stimulus shows no explicit motion, observation of static photographs of human actions with implied motion produces a clear increase in cortical activation, manifest in a long-lasting positivity (LP) between 350–600 ms that is much greater to dynamic than less dynamic actions, especially in men. A swLORETA linear inverse solution computed on the dynamic-minus-static difference wave in the time window 380–430 ms showed that a series of regions was activated, including the right V5/MT, left EBA, left STS (BA38), left premotor (BA6) and motor (BA4) areas, cingulate and IF cortex.

Conclusions and Significance

Overall, the data suggest that corresponding mirror neurons respond more strongly to implied dynamic than to less dynamic actions. The sex difference might be partially cultural and reflect a preference of young adult males for highly dynamic actions depicting intense muscular activity, or a sporty context.     

Kisspeptin Signalling in the Hypothalamic Arcuate Nucleus Regulates GnRH Pulse Generator Frequency in the Rat

Background

Kisspeptin and its G protein-coupled receptor (GPR) 54 are essential for activation of the hypothalamo-pituitary-gonadal axis. In the rat, the kisspeptin neurons critical for gonadotropin secretion are located in the hypothalamic arcuate (ARC) and anteroventral periventricular (AVPV) nuclei. As the ARC is known to be the site of the gonadotropin-releasing hormone (GnRH) pulse generator we explored whether kisspeptin-GPR54 signalling in the ARC regulates GnRH pulses.

Methodology/Principal Findings

We examined the effects of kisspeptin-10 or a selective kisspeptin antagonist administration intra-ARC or intra-medial preoptic area (mPOA), (which includes the AVPV), on pulsatile luteinizing hormone (LH) secretion in the rat. Ovariectomized rats with subcutaneous 17β-estradiol capsules were chronically implanted with bilateral intra-ARC or intra-mPOA cannulae, or intra-cerebroventricular (icv) cannulae and intravenous catheters. Blood samples were collected every 5 min for 5–8 h for LH measurement. After 2 h of control blood sampling, kisspeptin-10 or kisspeptin antagonist was administered via pre-implanted cannulae. Intranuclear administration of kisspeptin-10 resulted in a dose-dependent increase in circulating levels of LH lasting approximately 1 h, before recovering to a normal pulsatile pattern of circulating LH. Both icv and intra-ARC administration of kisspeptin antagonist suppressed LH pulse frequency profoundly. However, intra-mPOA administration of kisspeptin antagonist did not affect pulsatile LH secretion.

Conclusions/Significance

These data are the first to identify the arcuate nucleus as a key site for kisspeptin modulation of LH pulse frequency, supporting the notion that kisspeptin-GPR54 signalling in this region of the mediobasal hypothalamus is a critical neural component of the hypothalamic GnRH pulse generator.