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Smedemark-Margulies, Niklas

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Smedemark-Margulies

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Niklas

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Smedemark-Margulies, Niklas
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    Next-Generation Roadmap for Patient-Centered Genomics
    (2016-05-25) Smedemark-Margulies, Niklas; Yu, Timothy; Park, Peter
    In the era of precision medicine, understanding genetic variation has grown from a topic of research interest into a tangible source of therapeutic benefit for patients. As the list of confirmed links between genetic lesions and disease continues to grow, so does the list of actionable genetic diagnoses. The workup of a childhood-onset schizophrenia case provides a useful foil for discussion of current methods for genomic diagnostics, both to demonstrate some of the important available analyses, and to highlight areas of ongoing need. In brief, the stages of this case as pertains to the general diagnostic process are: clinical workup, sequencing and technical processing, analysis and interpretation of results, and follow-up research study. The patient in this case presented with command auditory hallucinations at age 6 and began empirical treatment for schizophrenia; he was subsequently found to have a novel de novo heterozygous missense mutation in ATP1A3 NM_152296.4 c.385G>A, predicted to cause the coding change p.V129M. This gene codes for a neuron-specific isoform of the alpha subunit of the sodium-potassium pump complex that helps establish transmembrane ion gradients necessary for neuronal function. The variant found in this case is now being replicated in a patient-derived iPS-neuron model to seek greater insight into the mechanism of disease and possible therapeutic opportunities. Generalizing from this case, researchers and clinicians hoping to replicate or improve upon this patient-centric genomics workflow can benefit from reviewing technical and infrastructural best practices. This case may also help illustrate some of the key difficulties in connecting genomic evidence with appropriate functional validation and other clinical markers to support well-informed decision-making.
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    Gene expression analysis in Fmr1KO mice identifies an immunological signature in brain tissue and mGluR5-related signaling in primary neuronal cultures
    (BioMed Central, 2015) Prilutsky, Daria; Kho, Alvin T.; Palmer, Nathan; Bhakar, Asha L.; Smedemark-Margulies, Niklas; Margulies, David; Kong, Sek Won; Bear, Mark F.; Kohane, Isaac
    Background: Fragile X syndrome (FXS) is a neurodevelopmental disorder whose biochemical manifestations involve dysregulation of mGluR5-dependent pathways, which are widely modeled using cultured neurons. In vitro phenotypes in cultured neurons using standard morphological, functional, and chemical approaches have demonstrated considerable variability. Here, we study transcriptomes obtained in situ in the intact brain tissues of a murine model of FXS to see how they reflect the in vitro state. Methods: We used genome-wide mRNA expression profiling as a robust characterization tool for studying differentially expressed pathways in fragile X mental retardation 1 (Fmr1) knockout (KO) and wild-type (WT) murine primary neuronal cultures and in embryonic hippocampal and cortical murine tissue. To study the developmental trajectory and to relate mouse model data to human data, we used an expression map of human development to plot murine differentially expressed genes in KO/WT cultures and brain. Results: We found that transcriptomes from cell cultures showed a stronger signature of Fmr1KO than whole tissue transcriptomes. We observed an over-representation of immunological signaling pathways in embryonic Fmr1KO cortical and hippocampal tissues and over-represented mGluR5-downstream signaling pathways in Fmr1KO cortical and hippocampal primary cultures. Genes whose expression was up-regulated in Fmr1KO murine cultures tended to peak early in human development, whereas differentially expressed genes in embryonic cortical and hippocampal tissues clustered with genes expressed later in human development. Conclusions: The transcriptional profile in brain tissues primarily centered on immunological mechanisms, whereas the profiles from cell cultures showed defects in neuronal activity. We speculate that the isolation and culturing of neurons caused a shift in neurological transcriptome towards a “juvenile” or “de-differentiated” state. Moreover, cultured neurons lack the close coupling with glia that might be responsible for the immunological phenotype in the intact brain. Our results suggest that cultured cells may recapitulate an early phase of the disease, which is also less obscured with a consequent “immunological” phenotype and in vivo compensatory mechanisms observed in the embryonic brain. Together, these results suggest that the transcriptome of cultured primary neuronal cells, in comparison to whole brain tissue, more robustly demonstrated the difference between Fmr1KO and WT mice and might reveal a molecular phenotype, which is typically hidden by compensatory mechanisms present in vivo. Moreover, cultures might be useful for investigating the perturbed pathways in early human brain development and genes previously implicated in autism. Electronic supplementary material The online version of this article (doi:10.1186/s13229-015-0061-9) contains supplementary material, which is available to authorized users.