The ongoing dissection of the genetic architecture of autistic spectrum disorder

The development of robust, non-hypothesis based case/control studies has led to a large push forward towards identifying common genetic variants that contribute to complex traits. However, despite many attempts, the search for common disease-predisposing variants in childhood developmental disorders has largely failed. Recently, a role for rare causal variants and de novo mutations is emerging in the genetic architecture of some of these disorders, particularly those that incur a large degree of selection against the phenotype. In this paper, we examine these data and use classic genetic epidemiological approaches to gain insights into the genetic architecture of ASD. Future studies using next generation sequencing should elucidate the precise role de novo mutations play in disorders traditionally thought to have resulted from polygenic or common disease, common variants inheritance

Amyotrophic lateral sclerosis: new genes, new models, and new mechanisms

Research aimed at understanding amyotrophic lateral sclerosis (ALS) has seen exceptional growth in the past few years. New genes, new models, and new mechanisms have not only improved our understanding, but also contributed to the increasing complexity of ALS pathogenesis. The focus of this piece is to highlight some of the more notable developments in the field and to encourage a re-appreciation for the superoxide dismutase 1 (SOD1) mouse models

Congenital mirror movements in a new Italian family

Mirror movements (MMs) occur on the contralateral side of a limb being used intentionally. Because few families with congenital MMs and no other neurological signs have been reported, the underlying mechanisms of MMs are still not entirely clear. We report on the clinical, genetic, neurophysiological and neuroimaging findings of 10 of 26 living members of a novel four-generation family with congenital MMs. DCC and RAD51 were sequenced in affected members of the family. Five of the ten subjects with MMs underwent neurophysiological and neuroimaging evaluations. The neurophysiological evaluation consisted of electromyographic (EMG) mirror recordings, investigations of corticospinal excitability, and analysis of interhemispheric inhibition using transcranial magnetic stimulation techniques. The neuroimaging evaluation included functional MRI during finger movements. Eight (all females) of the ten members examined presented MMs of varying degrees at the clinical assessment. Transmission of MMs appears to have occurred according to an autosomal-dominant fashion with variable expression. No mutation in DCC or RAD51 was identified. EMG mirror activity was higher in MM subjects than in healthy controls. Short-latency interhemispheric inhibition was reduced in MM subjects. Ipsilateral motor-evoked potentials were detectable in the most severe case. The neuroimaging evaluation did not disclose any significant abnormalities in MM subjects. The variability of the clinical features of this family, and the lack of known genetic abnormalities, suggests that MMs are heterogeneous disorders. The pathophysiological mechanisms of MMs include abnormalities of transcallosal inhibition and corticospinal decussatio

Characterization of Sirtuin Inhibitors in Nematodes Expressing a Muscular Dystrophy Protein Reveals Muscle Cell and Behavioral Protection by Specific Sirtinol Analogues

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Sensory and motor neuronopathy in a patient with the A382P TDP-43 mutation

Patients with TARDBP mutations have so far been classified as ALS, sometimes with frontal lobe dysfunction. A 66-year-old patient progressively developed a severe sensory disorder, followed by a motor disorder, which evolved over nine years. Symptoms started in the left hand and slowly involved the four limbs. Investigations were consistent with a mixed sensory and motor neuronopathy. A heterozygous change from an alanine to a proline at amino acid 382 was identified in exon 6 of the TARDPB gene (p.A382P). This case expands the phenotypic spectrum associated with mutations in the TARDBP gene and shows that sensory neurons can be severely damaged early in the course of the disease, following a propagating process, with an orderly progression from a focal starting point. A combination of severe sensory and motor neuronopathy is rarely encountered in clinical practice. The possibility of an A382P TDP-43 mutation should be considered in patients with such an association

PARPs database: A LIMS systems for protein-protein interaction data mining or laboratory information management system

<p>Abstract</p> <p>Background</p> <p>In the "post-genome" era, mass spectrometry (MS) has become an important method for the analysis of proteins and the rapid advancement of this technique, in combination with other proteomics methods, results in an increasing amount of proteome data. This data must be archived and analysed using specialized bioinformatics tools.</p> <p>Description</p> <p>We herein describe "PARPs database," a data analysis and management pipeline for liquid chromatography tandem mass spectrometry (LC-MS/MS) proteomics. PARPs database is a web-based tool whose features include experiment annotation, protein database searching, protein sequence management, as well as data-mining of the peptides and proteins identified.</p> <p>Conclusion</p> <p>Using this pipeline, we have successfully identified several interactions of biological significance between PARP-1 and other proteins, namely RFC-1, 2, 3, 4 and 5.</p