Duplication of FGF3, FGF4, FGF19 and ORAOV1 causes hair ridge and predisposition to dermoid sinus in Ridgeback dogs

The dorsal hair ridge in Rhodesian and Thai Ridgeback dogs is caused by a dominant mutation that also predisposes to the congenital developmental disorder dermoid sinus. Here we show that the causative mutation is a 133-kb duplication involving three fibroblast growth factor (FGF) genes. FGFs play a crucial role in development, suggesting that the ridge and dermoid sinus are caused by dysregulation of one or more of the three FGF genes during development.     

Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible

Nephrotic syndrome, a malfunction of the kidney glomerular filter, leads to proteinuria, edema and, in steroid-resistant nephrotic syndrome, end-stage kidney disease. Using positional cloning, we identified mutations in the phospholipase C epsilon gene (PLCE1) as causing early-onset nephrotic syndrome with end-stage kidney disease. Kidney histology of affected individuals showed diffuse mesangial sclerosis (DMS). Using immunofluorescence, we found PLCepsilon1 expression in developing and mature glomerular podocytes and showed that DMS represents an arrest of normal glomerular development. We identified IQ motif-containing GTPase-activating protein 1 as a new interaction partner of PLCepsilon1. Two siblings with a missense mutation in an exon encoding the PLCepsilon1 catalytic domain showed histology characteristic of focal segmental glomerulosclerosis. Notably, two other affected individuals responded to therapy, making this the first report of a molecular cause of nephrotic syndrome that may resolve after therapy. These findings, together with the zebrafish model of human nephrotic syndrome generated by plce1 knockdown, open new inroads into pathophysiology and treatment mechanisms of nephrotic syndrome.     

Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase

Neurodegenerative disorders such as Parkinson and Alzheimer disease cause motor and cognitive dysfunction and belong to a heterogeneous group of common and disabling disorders. Although the complex molecular pathophysiology of neurodegeneration is largely unknown, major advances have been achieved by elucidating the genetic defects underlying mendelian forms of these diseases. This has led to the discovery of common pathophysiological pathways such as enhanced oxidative stress, protein misfolding and aggregation and dysfunction of the ubiquitin-proteasome system. Here, we describe loss-of-function mutations in a previously uncharacterized, predominantly neuronal P-type ATPase gene, ATP13A2, underlying an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia (PARK9, Kufor-Rakeb syndrome). Whereas the wild-type protein was located in the lysosome of transiently transfected cells, the unstable truncated mutants were retained in the endoplasmic reticulum and degraded by the proteasome. Our findings link a class of proteins with unknown function and substrate specificity to the protein networks implicated in neurodegeneration and parkinsonism.     

The Self-Organization of Social Movements

The New Social Movement Approach and the Resource Mobilization Approach are the dominant approaches in social movement research. They focus either on macro-aspects and externalism or on micro-aspects and internalism. This paper suggests that the notion of self-organization is one way of taking into account both internal and external, structural- and action-based aspects of social movements and that it allows a dynamic concept of protest. The emergence of social movements is not determined, but a complex result of crisis, resource mobilization, cognitive mobilization, self-production—searching for singular laws of the emergence of movements is an expression of one-dimensional, linear, and deterministic thinking. Protest and social problems are non-linearly related. Social movements are part of the civil society system, by producing alternative topics and demands, they guarantee the dynamic of the political system. Existing system-theoretic approaches on social movements (Luhmann, Japp, Ahlemeyer, Hellmann) are rather uncritical and ignore the productive relationship between human actors and social structures in processes of social self-organization. Social movements are dynamic communication systems that permanently react to political and societal events with self-organized protest practices and protest communications that result in the emergence and differentiation (production and reproduction) of protest structures (events, oppositional topics, alternative values, regularized patterns of interaction and organization). The dynamic of social movements is based on the permanent emergence and mutual production of protest practices and protest structures. The self-organization of a social movement is a vivid process, it is based on the permanent movement and differentiation of actors and structures that communicate public protest, a social movement is only a movement, as long as it communicates protest and moves itself. In critical phases of protest new social systems of protest emerge whose form, content and effects are not determined, but dependent upon old structures, i.e., old structures enable and constrain new structures. The emergence of new protest issues, methods, identities, structures, and organizational forms starts as singular innovation, if it is widely imitated then it spreads within the protest system and transforms the system as a whole. In terms of Hegelian dialectics this means that novel qualities sublate the old structure of the total system, i.e., the system is transformed, reaches a higher level, incorporates old qualities, and creates new qualities. In critical phases protest can spontaneously and quickly spread and intensify itself. This reflects the idea of complexity thinking that small causes can spontaneously have large effects. The notion of self-organization as the idea of the networked, co-operative, synergetic production of emergent qualities and systems should be employed in order to arrive at a dynamic concept of protest. In order to reflect the increasing complexity of society and the emergence of a stratified knowledge society, a multidimensional model of class that is structurally coupled to the concept of social movements is suggested.