Exploring pathogenetic mechanisms of Jamuar Syndrome: focus on transcriptomics and brain extracellular matrix changes

Jamuar syndrome (JS) is an ultra-rare genetic disease with only 30 cases identified so far. Patients have typical features, including developmental delay, epilepsy, mild dysmorphism, and motor disorders. JS is caused by mutations in the UGDH gene, which provides instructions to make a protein that regulates the synthesis of the brain's extracellular matrix (ECM). ECM is composed of protein and sugar chains, and it guides the development of the brain. Therefore, we hypothesize that in JS, the absence of UGDH causes an incorrect formation of the ECM; consequently, neurons can not correctly develop or communicate with each other. To test this assumption, we will generate a 3D brain model in a dish, the so-called brain organoid. We will follow the development of brain organoids in the presence or absence of the UGDH gene. We will evaluate the neurons, the composition of ECM, and the signals that the latter send to the formers while guiding the development. The results we expect to achieve will shed new light on the pathological mechanisms at the basis of Jamuar Syndrome.