Investigating the molecular basis for Charcot Marie Tooth 1C (360G-Wellcome-203995_Z_16_A)

Charcot-Marie-Tooth disease 1c (CMT1c) is a peripheral neuropathy that involves progressive damage to myelin, the protective covering surrounding nerve cells. CMT1c is caused by genetic mutations in lipopolysaccharide-induced tumour necrosis factor-alpha factor (LITAF). LITAF is involved in endocytosis, the pathway whereby material is internalised from the cell surface and trafficked to subcellular compartments, but its precise function is unknown. Disease-associated mutations may result in subcellular mislocalisation of LITAF and cause a toxic gain-of-function that leads to symptoms of the disease. I aim to characterise the function of LITAF and how this is altered during disease using both cultured cells and transgenic zebrafish. I will use cell biology and biochemistry techniques to characterise the cellular function of LITAF, including its dynamic subcellular localisation and influence on interacting partners. I will explore how these parameters are affected by disease-causing mutations and why. I will generate transgenic zebrafish expressing LITAF mutation and characterise the phenotype, initially focusing on changes in myelin producing cells which are relevant to the human disease. These studies will help to elucidate the function of LITAF and how it is dysregulated in CMT1c. The project will contribute to our understanding of how mutations in LITAF result in CMT1c neuropathy.