Characterizing the function of Neurobeachin, a candidate gene for autism spectrum disorders

Autism is a severe neurodevelopmental disorder. It belongs to a group of pervasive developmental disorders with a prevalence of 0,7%. Autism spectrum disorders are diagnosed purely on clinical grounds by impairment in social interactions and communication and repetitive, stereotyped patterns of behaviour and interests. Twin and family studies indicate a strong genetic contribution to the aetiology of autism, although environmental causes are not excluded. Recently we have identified a novel candidate genes for autism by positional cloning, starting from an autistic patient with a de novo balanced translocation. Neurobeachin (NBEA) is predicted to be involved in neuronal vesicle trafficking. Our functional studies show that this proteins is a negative regulator of secretion of large dense-core vesicles (LDCVs) in neuro-endocrine cell lines. LDCVs contain neuropeptides, monoamines and neurotrophins, which are implicated in important processes like synaptic plasticity and neural differentiation. On the basis of conserved structural motifs Neurobeachin is a member of the BEACH (beige and chediak-higashi) family, which seems to be implicated in vesicle biogenesis and trafficking. It is suggested that the BEACH-domain has a scaffolding function together with the pleckstrin homology domain and the WD40 repeats. Defining interaction partners could give us more insights into the functional role of Nbea in regulated vesicle secretion. Nbea-null mice have been generated by random transgene-mediated gene disruption. This disruption resulted in lethal paralysis in homozygous newborns because of a complete block of evoked synaptic transmission at the neuromuscular junctions. We are observing the viable heterozygous mice, which relate better to the haploinsufficient autistic patients. Behavioural studies showed comparable autistic traits (unpublished results). This infers that Nbea+/- mice are a good model to study the human disease. Hypothesis: Since Neurobeachin, a candidate gene for autism, is involved in the regulated secretory pathway of large dense-core vesicles (LDCVs), the hypothesis is that impaired LDCV secretion in neurons contributes to the pathogenesis of autism in a subgroup of patients. To clarify the role of NBEA and the involved molecular mechanisms in the regulated secretory pathway, the aims are to: 1. Perform ultrastructural studies of LDCVs (electron microscopy) 2. Study the effect of NBEA haploinsufficiency on biogenesis and secretion of LDCVs in neurons of the Nbea+/- mouse model 3. Clarify the molecular network of NBEA and its function by identifying interaction partners (Y2H)nrpages: 218status: publishe

Research Data Management in the Biomedical Sciences: how can a librarian join the game?

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Systematic reviews: Why don't researchers consider to include a medical librarian and would this collaboration have made things better?

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The Dwarf Phenotype in GH240B Mice, Haploinsufficient for the Autism Candidate Gene Neurobeachin, Is Caused by Ectopic Expression of Recombinant Human Growth Hormone

Two knockout mouse models for the autism candidate gene Neurobeachin (Nbea) have been generated independently. Although both models have similar phenotypes, one striking difference is the dwarf phenotype observed in the heterozygous configuration of the GH240B model that is generated by the serendipitous insertion of a promoterless human growth hormone (hGH) genomic fragment in the Nbea gene. In order to elucidate this discrepancy, the dwarfism present in this Nbea mouse model was investigated in detail. The growth deficiency in Nbea+/− mice coincided with an increased percentage of fat mass and a decrease in bone mineral density. Low but detectable levels of hGH were detected in the pituitary and hypothalamus of Nbea+/− mice but not in liver, hippocampus nor in serum. As a consequence, several members of the mouse growth hormone (mGH) signaling cascade showed altered mRNA levels, including a reduction in growth hormone-releasing hormone mRNA in the hypothalamus. Moreover, somatotrope cells were less numerous in the pituitary of Nbea+/− mice and both contained and secreted significantly less mGH resulting in reduced levels of circulating insulin-like growth factor 1. These findings demonstrate that the random integration of the hGH transgene in this mouse model has not only inactivated Nbea but has also resulted in the tissue-specific expression of hGH causing a negative feedback loop, mGH hyposecretion and dwarfism.status: publishe