Molecular and Cellular Functions of LZTR1 Mutations in Schwannomatosis

Neurofibromatosis type 3 or Schwannomatosis is a genetic disorder that affects 1 in 40,000 people worldwide. It is characterized by the appearance of several benign tumors arising from the peripheral and spinal nerves called schwannomas. Schwannomas develop from Schwann cells, a type of cell that produces myelin, which is a substance that serves as a sheath for the neuronal axons found in nerves. Patients affected by schwannomatosis are diagnosed due to the high number of schwannomas they develop through their life, because in non-affected individuals this tumor type is rare. The most significant symptom in these patients is chronic pain, which results from the mechanical pressure that schwannomas exert on the surrounding nerves. Schwannomatosis has been linked to familiar and sporadic mutations in a gene termed LZTR1, which encodes for a protein of unknown function. Such mutations inactivate the expression of LZTR1,resulting in the loss of the protein in Schwann cells. We have recently uncovered the main function of this protein and showed that it acts as a molecular scaffold that facilitates degradation of a specific substrate. In normal conditions, LZTR1 interacts with such substrate and promotes its degradation, but in the absence of LZTR1, as a result of mutations, the substrate can no longer be degraded and it accumulates in the cells causing an abnormal cell phenotype. However, the consequences of LZTR1 mutations in the context of schwannomatosis have never been explored. In this proposal, I hypothesize that loss of LZTR1 in Schwann cells results in accumulation of its substrate, a protein which causes uncontrolled proliferation and differentiation into schwannomas.