Kurzfassung

Opitz BBB/G Syndrom (OS) is a monogenetic hereditary disease which is characterized by defects in the development of the anterior midline. This disease also can cause intellectual disability and intellectual developmental delay. OS is caused by mutations in the MID1 gene. MID1 regulates the ubiquitin-mediated modification and degradation of the microtubuli-associated catalytic subunit of the protein phosphatase 2A (PP2Ac). As counter actor of the mTOR kinase PP2A is an important regulator of...Opitz BBB/G Syndrom (OS) is a monogenetic hereditary disease which is characterized by defects in the development of the anterior midline. This disease also can cause intellectual disability and intellectual developmental delay. OS is caused by mutations in the MID1 gene. MID1 regulates the ubiquitin-mediated modification and degradation of the microtubuli-associated catalytic subunit of the protein phosphatase 2A (PP2Ac). As counter actor of the mTOR kinase PP2A is an important regulator of local protein synthesis at synapses and thereby of long term potentiation, learning and memory. Dysfunction of the mTOR/PP2A axis is the molecular basis of many forms of intellectual disability including Down-, fragile X- and RETT-Syndrome.  In mice deficient for the MID1 gene overgrowth of axons has been observed. However, many of the nervous system defects described in OS patients are not fully recapitulated in MID1 deficient mice. This renders it necessary to study the pathophysiological role of MID1/mTOR/PP2A in a human model system. We have generated induced pluripotent stem cells (iPSC) from 5 OS patients. In the present project we combine the expertise of the Dr. Schweiger who is one of the leaders regarding the research of the pathogenesis of OS with the stem cell, neurogenesis, and neuronal connectivity expertise of Dr. Berninger. Using a broad methodological approach will allow us to address fundamental questions regarding the genesis of OS and other syndromes with intellectual disability and mTOR dysfunction. OS patient-derived iPS cells will be differentiated into neurons and cerebral organoids and compared to isogenic controls. We will characterize these models biochemically and morphologically and thereby establish a link between mTOR deficiency and neuron morphology. Furthermore we will employ a rabies virus-based method of tracing of synaptic connectivity in neuron cultures, cerebral organoids, and after transplantation of patient-derived neurons into mouse cortex to examine the functionality and connectivity of OS neurons. Our results will help to understand how the mTOR/PP2A axis influences morphology, function and connectivity of neurons and thereby can cause intellectual disability.
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