The genetic landscape and possible therapeutics of neurofibromatosis type 2

Abstract

Neurofibromatosis type 2 (NF2) is a genetic condition marked by the development of multiple benign tumors in the nervous system. The most common tumors associated with NF2 are bilateral vestibular schwannoma, meningioma, and ependymoma. The clinical manifestations of NF2 depend on the site of involvement. Vestibular schwannoma can present with hearing loss, dizziness, and tinnitus, while spinal tumor leads to debilitating pain, muscle weakness, or paresthesias. Clinical diagnosis of NF2 is based on the Manchester criteria, which have been updated in the last decade. NF2 is caused by loss-of-function mutations in the NF2 gene on chromosome 22, leading the merlin protein to malfunction. Over half of NF2 patients have de novo mutations, and half of this group are mosaic. NF2 can be managed by surgery, stereotactic radiosurgery, monoclonal antibody bevacizumab, and close observation. However, the nature of multiple tumors and the necessity of multiple surgeries over the lifetime, inoperable tumors like meningiomatosis with infiltration of the sinus or in the area of the lower cranial nerves, the complications caused by the operation, the malignancies induced by radiotherapy, and inefficiency of cytotoxic chemotherapy due to the benign nature of NF-related tumors have led a march toward exploring targeted therapies. Recent advances in genetics and molecular biology have allowed identifying and targeting of underlying pathways in the pathogenesis of NF2. In this review, we explain the clinicopathological characteristics of NF2, its genetic and molecular background, and the current knowledge and challenges of implementing genetics to develop efficient therapies.

Keywords: Acoustic neuroma; Hearing loss; Meningiomas; Merlin; Molecular targeted therapy; NF2; Neurofibromatosis type 2; Vestibular schwannoma.

Fig. 1

Schematic illustration and magnetic resonance imaging (MRI) of tumors associate with neurofibromatosis type 2 (NF2). A Different clinical symptoms associated with NF2. B A schematic depiction of vestibular schwannoma arising from eighth cranial nerve. C MRI of bilateral vestibular schwannoma as a hallmark feature of NF2 patients. The figure is redrawn from refs [2, 13].

Fig. 2

A schematic depiction of protein domain structure and states merlin. A Merlin is a multidomain protein and consists of three parts. The first part is at the N-terminus, which is highly conserved and is called FERM or N-terminal ERM association domain. The FERM itself has three subdomains F1, F2, and F3. The second part is the α- helical domain, which consists of three α- helices (α1H, α2H, and α3H). The third part is a short, mainly helical C- terminus domain (CTD) or C-terminal ERM association domain. B Merlin’s head-to-tail folding between FERM and CTD domains in monomer structure renders the protein in closed inactive conformation upon phosphorylation of Ser 518

Fig. 3

Merlin signaling pathways and potential therapeutic targets in NF2. A schematic depiction of the main intracellular pathways regulated by the protein product of the NF2 gene (merlin (is shown by golden)). Merlin regulates cell survival, proliferation, and cell–cell interaction in response to multiple proliferative signaling pathways at the plasma membrane and in the nucleus. Merlin can predominantly block the RTKs’ activity on their downstream targets, including RAS, PI3K, and Rac. Merlin inhibits Wnt/β-catenin signaling through inhibit translocation of β-catenin to the nucleus. At the nucleus (inhibition CRL4^DCAF1) and cell cortex (promoting MST1/2), merlin can regulate Hippo signaling pathway. As a result, the expression of target genes of YAP will decrease. Merlin may also block LIN28B in the nucleus, reducing let-7 miRNA cluster repression and downregulating proto-oncogenic proteins including MYC and RAS. Diverse treatment options have been investigated for NF2 patients, including the suppression of merlin-regulated proteins and other cellular receptors. Pathogenic mutations in NF2 patients cause merlin function loss, which modulates downstream activity in each pathway, promoting cell growth, protein and fatty acid synthesis, proliferation, and survival. The five white boxes provided are current inhibitors of this pathway with their respective targets. Proteins are also illustrated in circular shapes, and each of them has been given a distinct color. the bilayer cellular plasma membrane with phospholipid compounds is presented at the top in pink. Also, the blue area in the cell represents the nucleus and the two blue straight lines within, represent genes involved in this pathway. Black arrows indicate the act of promotion and blocking lines indicate the act of suppression