Mutations in the Satellite Cell Gene MEGF10 Cause a Recessive Congenital Myopathy with Minicores

We ascertained a nuclear family in which three of four siblings were affected with an unclassified autosomal recessive myopathy characterized by severe weakness, respiratory impairment, scoliosis, joint contractures, and an unusual combination of dystrophic and myopathic features on muscle biopsy. Whole genome sequence from one affected subject was filtered using linkage data and variant databases. A single gene, MEGF10, contained nonsynonymous mutations that co-segregated with the phenotype. Affected subjects were compound heterozygous for missense mutations c.976T > C (p.C326R) and c.2320T > C (p.C774R). Screening the MEGF10 open reading frame in 190 patients with genetically unexplained myopathies revealed a heterozygous mutation, c.211C > T (p.R71W), in one additional subject with a similar clinical and histological presentation as the discovery family. All three mutations were absent from at least 645 genotyped unaffected control subjects. MEGF10 contains 17 atypical epidermal growth factor-like domains, each of which contains eight cysteine residues that likely form disulfide bonds. Both the p.C326R and p.C774R mutations alter one of these residues, which are completely conserved in vertebrates. Previous work showed that murine Megf10 is required for preserving the undifferentiated, proliferative potential of satellite cells, myogenic precursors that regenerate skeletal muscle in response to injury or disease. Here, knockdown of megf10 in zebrafish by four different morpholinos resulted in abnormal phenotypes including unhatched eggs, curved tails, impaired motility, and disorganized muscle tissue, corroborating the pathogenicity of the human mutations. Our data establish the importance of MEGF10 in human skeletal muscle and suggest satellite cell dysfunction as a novel myopathic mechanism

Association between Bone Mineral Density and LDL Receptor-Related Protein 5 Gene Polymorphisms in Young Korean Men

Recently, It has been reported that the LDL receptor-related protein 5 (LRP5) regulates bone formation, and that mutations of the gene cause osteoporosis-pseudoglioma syndrome or high bone mass phenotypes. However, the mutations cannot explain a genetic trait for osteoporosis in the general population because of their rarity. From 219 Korean men aged 20-34 yr, we looked for six known polymorphisms causing amino acid changes in the LRP5 coding region, and investigated their association with bone mineral density (BMD) at the following anatomical sites: lumbar spine (L2-L4) and the left proximal femur (femoral neck, Ward's triangle, trochanter and shaft). We found that the Q89R polymorphism was significantly associated with BMD at the femoral neck and Ward's triangle (p=0.004 and <0.001, respectively). However, after adjusting for age, weight and height, a statistically significant association only occurred at the Ward's triangle (p=0.043), and a marginal association was observed at the femoral neck (p=0.098). No A400V, V667M, R1036Q and A1525V polymorphisms were found, and no statistically significant association was found between the A1330V polymorphism and BMD at any sites. Although we failed to demonstrate a clear association between the LRP5 polymorphism and peak bone mass in young men, the present study suggests that larger-scale studies on the Q89R polymorphism need to be performed

KFPA Examinations of Young STellar Object Natal Environments (KEYSTONE): Hierarchical Ammonia Structures in Galactic Giant Molecular Clouds

We present initial results from the K-band focal plane array Examinations of Young STellar Object Natal Environments (KEYSTONE) survey, a large project on the 100-m Green Bank Telescope mapping ammonia emission across eleven giant molecular clouds at distances of $0.9-3.0$ kpc (Cygnus X North, Cygnus X South, M16, M17, MonR1, MonR2, NGC2264, NGC7538, Rosette, W3, and W48). This data release includes the NH$_3$ (1,1) and (2,2) maps for each cloud, which are modeled to produce maps of kinetic temperature, centroid velocity, velocity dispersion, and ammonia column density. Median cloud kinetic temperatures range from $11.4\pm2.2$ K in the coldest cloud (MonR1) to $23.0\pm6.5$ K in the warmest cloud (M17). Using dendrograms on the NH$_3$ (1,1) integrated intensity maps, we identify 856 dense gas clumps across the eleven clouds. Depending on the cloud observed, $40-100\%$ of the clumps are aligned spatially with filaments identified in H$_2$ column density maps derived from SED-fitting of dust continuum emission. A virial analysis reveals that 523 of the 835 clumps ($\sim63\%$) with mass estimates are bound by gravity alone. We find no significant difference between the virial parameter distributions for clumps aligned with the dust-continuum filaments and those unaligned with filaments. In some clouds, however, hubs or ridges of dense gas with unusually high mass and low virial parameters are located within a single filament or at the intersection of multiple filaments. These hubs and ridges tend to host water maser emission, multiple 70$\mu$m-detected protostars, and have masses and radii above an empirical threshold for forming massive stars

R17C Mutation in Photoreceptor Disc-Specific Protein, PRCD, Results in Additional Lipidation Altering Protein Stability and Subcellular Localization

Progressive rod-cone degeneration (PRCD) is a photoreceptor outer segment (OS) disc-specific protein essential for maintaining OS structures while contributing to rhodopsin packaging densities and distribution in disc membranes. Previously, we showed PRCD undergoing palmitoylation at the sole cysteine (Cys2), where a mutation linked with retinitis pigmentosa (RP) in humans and dogs demonstrates the importance of palmitoylation for protein stability and trafficking to the OS. We demonstrate a mutation, in the polybasic region (PBR) of PRCD (Arg17Cys) linked with RP where an additional lipidation is observed through acyl-RAC. Immunolocalization of transiently expressed R17C in hRPE1 cells depicts similar characteristics to wild-type PRCD; however, a double mutant lacking endogenous palmitoylation at Cys2Tyr with Arg17Cys is comparable to the C2Y protein as both aggregate, mislocalized to the subcellular compartments within the cytoplasm. Subretinal injection of PRCD mutant constructs followed by electroporation in murine retina exhibit mislocalization in the inner segment. Despite being additionally lipidated and demonstrating strong membrane association, the mutation in the PBR affects protein stability and localization to the OS. Acylation within the PBR alone neither compensates for protein stability nor trafficking, revealing defects in the PBR likely lead to dysregulation of PRCD protein associated with blinding diseases

The Educational Rights of Asylum-Seeking and Refugee Children within the Neo-Liberal State and Inclusive Schools in the UK

In the age of globalisation states exercise their power through the control of their physical and material borders, which has implications for the symbolic spaces of citizenship and belonging. Those seeking asylum are trapped within such spaces, not able to traverse the borders of hospitality and membership. Asylum-seeking and refugee children are defined as ‘a migrant first and a child second’ yet, as children, they carry rights to education and protection under the 1989 UNCRC. In the context of neo-liberal economic policies which define those ‘deserving’ and the ‘undeserving’ (Sales 2002) of protection, educational institutions become one of the few sites promoting human rights and ‘personhood’. This paper indicates what happens when asylum-seeking and refugee children cross these territorial and symbolic borders into liberal democratic educational systems. It reports the findings of a recent study of the ethico-political conditions affecting asylum-seeking and refugee children in the UK, contrasting inhospitable immigration policies that deny these children’s human rights with inclusive schooling approaches (Pinson, Arnot and Candappa, 2010). Teachers’ responses to such hostile agendas by drawing on child-centred approaches or on more radical interventions on behalf of the refugee child challenge these government actions. The paper raises the question about how the tension between the strong and weak aspects of the neo-liberal state has considerable significance for these young people’s lives

In the child's best interests? Legislation on children's work in Ethiopia

An abolitionist approach to children's work bans all work; a regulatory approach bans harmful work and regulates other work. I argue for a regulatory approach, using the ‘least restrictive’ alternative test applied in law. I contend, however, that definitions of harmful work must be appropriate to local contexts and informed by working children's views. I support this with a case study of a village in Ethiopia where the current abolitionist approach is overly restrictive. However, a regulatory approach based on international definitions of harmful work would probably not protect children in the case study village against some harmful work. Children and parents in the village are able to define harmful work more precisely than international definitions, suggesting that locally specific definitions developed with working children should form the basis of regulatory legislation. Copyright (C) 2010 John Wiley & Sons, Ltd.children's work , child labour , hazardous work , Convention on the Rights of the Child , Minimum Age Convention , International Labour Organisation ,