Study of SPTAN1 pathomechanisms: the spectrin complex as a central hub in rare neurological and neuromuscular diseases.

Next Generation Sequencing technologies have accumulated genetic causes for Mendelian diseases, often without full insight into the cellular function of the gene involved. Conversely, patients with rare neurogenetic diseases are often lacking a genetic etiology. SPTAN1 (?-II-spectrin), a major cytoskeletal protein, is exemplary in this with a notably wide phenotypic spectrum but surprisingly little understanding of its molecular and cellular biology. Previously only associated with epilepsy and intellectual disability, we recently published novel mutations in SPTAN1 associated with Hereditary Motor Neuropathy and now also in Ataxia and Hereditary Spastic Paraplegia. ?-II-spectrin is the central component of the spectrin complex and is widely expressed in all cells but how its disturbances cause various neurological diseases is poorly understood. We will establish both cortical and motor neurons from patient-derived induced pluripotent stem-cells of three SPTAN1 mutations that are representative for the main associated diseases. Cytoskeletal abnormalities in these neurons will be studied using super-resolution microscopy, axonal transport assays and electrophysiological studies. Transcriptome-profiling of the neuronal cultures will allow to explore the interaction network of the spectrin complex. Ultimately, we will generate novel functional candidate genes that will be translated back to large genetic datasets of patients with diagnostically unresolved neurogenetic diseases.

Keywords:GENETICS, STEM CELLS, CYTOSKELETON

Disciplines:Computational transcriptomics and epigenomics, Cytoskeleton, Clinical genetics and molecular diagnostics, Stem cell biology, Neurological and neuromuscular diseases