EPHA2 Is Associated with Age-Related Cortical Cataract in Mice and Humans

Age-related cataract is a major cause of blindness worldwide, and cortical cataract is the second most prevalent type of age-related cataract. Although a significant fraction of age-related cataract is heritable, the genetic basis remains to be elucidated. We report that homozygous deletion of Epha2 in two independent strains of mice developed progressive cortical cataract. Retroillumination revealed development of cortical vacuoles at one month of age; visible cataract appeared around three months, which progressed to mature cataract by six months. EPHA2 protein expression in the lens is spatially and temporally regulated. It is low in anterior epithelial cells, upregulated as the cells enter differentiation at the equator, strongly expressed in the cortical fiber cells, but absent in the nuclei. Deletion of Epha2 caused a significant increase in the expression of HSP25 (murine homologue of human HSP27) before the onset of cataract. The overexpressed HSP25 was in an underphosphorylated form, indicating excessive cellular stress and protein misfolding. The orthologous human EPHA2 gene on chromosome 1p36 was tested in three independent worldwide Caucasian populations for allelic association with cortical cataract. Common variants in EPHA2 were found that showed significant association with cortical cataract, and rs6678616 was the most significant in meta-analyses. In addition, we sequenced exons of EPHA2 in linked families and identified a new missense mutation, Arg721Gln, in the protein kinase domain that significantly alters EPHA2 functions in cellular and biochemical assays. Thus, converging evidence from humans and mice suggests that EPHA2 is important in maintaining lens clarity with age

ANS: Aberrant Neurodevelopment of the Social Cognition Network in Adolescents with Autism Spectrum Disorders

Background: Autism spectrum disorders (ASD) are characterized by aberrant neurodevelopment. Although the ASD brain undergoes precocious growth followed by decelerated maturation during early postnatal period of childhood, the neuroimaging approach has not been empirically applied to investigate how the ASD brain develops during adolescence. Methodology/Principal Findings: We enrolled 25 male adolescents with high functioning ASD and 25 typically developing controls for voxel-based morphometric analysis of structural magnetic resonance image. Results indicate that there is an imbalance of regional gray matter volumes and concentrations along with no global brain enlargement in adolescents with high functioning ASD relative to controls. Notably, the right inferior parietal lobule, a role in social cognition, have a significant interaction of age by groups as indicated by absence of an age-related gain of regional gray matter volume and concentration for neurodevelopmental maturation during adolescence. Conclusions/Significance: The findings indicate the neural correlates of social cognition exhibits aberrant neurodevelopment during adolescence in ASD, which may cast some light on the brain growth dysregulation hypothesis. The period of abnormal brain growth during adolescence may be characteristic of ASD. Age effects must be taken into account while measures of structural neuroimaging have been clinically put forward as potential phenotypes for ASD

Neurostimulatory and ablative treatment options in major depressive disorder: a systematic review

Introduction Major depressive disorder is one of the most disabling and common diagnoses amongst psychiatric disorders, with a current worldwide prevalence of 5-10% of the general population and up to 20-25% for the lifetime period. Historical perspective Nowadays, conventional treatment includes psychotherapy and pharmacotherapy; however, more than 60% of the treated patients respond unsatisfactorily, and almost one fifth becomes refractory to these therapies at long-term follow-up. Nonpharmacological techniques Growing social incapacity and economic burdens make the medical community strive for better therapies, with fewer complications. Various nonpharmacological techniques like electroconvulsive therapy, vagus nerve stimulation, transcranial magnetic stimulation, lesion surgery, and deep brain stimulation have been developed for this purpose. Discussion We reviewed the literature from the beginning of the twentieth century until July 2009 and described the early clinical effects and main reported complications of these methods. © The Author(s) 2010.Link_to_subscribed_fulltex

The Cardiac Phenotype in Patients With a CHD7 Mutation

Background- Loss-of-function mutations in CHD7 cause Coloboma, Heart Disease, Atresia of Choanae, Retardation of Growth and/or Development, Genital Hypoplasia, and Ear Abnormalities With or Without Deafness (CHARGE) syndrome, a variable combination of multiple congenital malformations including heart defects. Heart defects are reported in 70% to 92% of patients with a CHD7 mutation, but most studies are small and do not provide a detailed classification of the defects. We present the first, detailed, descriptive study on the cardiac phenotype of 299 patients with a CHD7 mutation and discuss the role of CHD7 in cardiac development. Methods and Results- We collected information on congenital heart defects in 299 patients with a pathogenic CHD7 mutation, of whom 220 (74%) had a congenital heart defect. Detailed information on the heart defects was available for 202 of these patients. We classified the heart defects based on embryonic cardiac development and compared the distribution to 1007 equally classified nonsyndromic heart defects of patients registered by EUROCAT, a European Registry of Congenital Anomalies. Heart defe Conclusions- CHD7 plays an important role in cardiac development, given that we found a wide range of heart defects in 74% of a large cohort of patients with a CHD7 mutation. Conotruncal defects and atrioventricular septal defects are over-represented in patients with CHD7 mutations compared with patients with nonsyndromic heart defects

Cardiovascular malformations caused by NOTCH1 mutations do not keep left:data on 428 probands with left-sided CHD and their families

Purpose: We aimed to determine the prevalence and phenotypic spectrum of NOTCH1 mutations in left-sided congenital heart disease (LS-CHD). LS-CHD includes aortic valve stenosis, a bicuspid aortic valve, coarctation of the aorta, and hypoplastic left heart syndrome. Methods: NOTCH1 was screened for mutations in 428 nonsyndromic probands with LS-CHD, and family histories were obtained for all. When a mutation was detected, relatives were also tested. Results: In 148/428 patients (35%), LS-CHD was familial. Fourteen mutations (3%; 5 RNA splicing mutations, 8 truncating mutations, 1 whole-gene deletion) were detected, 11 in familial disease (11/148 (7%)) and 3 in sporadic disease (3/280 (1%)). Forty-nine additional mutation carriers were identified among the 14 families, of whom 12 (25%) were asymptomatic. Most of these mutation carriers had LS-CHD, but 9 (18%) had right-sided congenital heart disease (RS-CHD) or conotruncal heart disease (CTD). Thoracic aortic aneurysms (TAAs) occurred in 6 mutation carriers (probands included 6/63 (10%)). Conclusion: Pathogenic mutations in NOTCH1 were identified in 7% of familial LS-CHD and in 1% of sporadic LS-CHD. The penetrance is high; a cardiovascular malformation was found in 75% of NOTCH1 mutation carriers. The phenotypic spectrum includes LS-CHD, RS-CHD, CTD, and TAA. Testing NOTCH1 for an early diagnosis in LS-CHD/RS-CHD/CTD/TAA is warranted