Neurofibromatosis 2 (NF2) is an inherited disorder characterized by a predisposition to multiple intracranial tumors. The protein encoded by the NF2 gene has striking similarities to ezrin, radixin and moesin (ERM) proteins which link membrane proteins to the cytoskeleton. Therefore, it can be speculated that the disruption of cytoskeletal organization by alterations in the NF2 gene is involved in the development of tumors. It has been reported that the majority of NF2 mutations were nonsense or frameshift mutations that result in premature termination of translation. To facilitate the detection of these mutations, we performed protein truncation test and found that 11 of 14 NF2 patients had truncational mutations (79%). Seven of the 11 patients (64%) had a splicing abnormality which lead to absence of exons in the ERM homology domain. To examine the biological significance of the exon-missing mutations in the ERM homology domain, we expressed the wild-type (wt-NF2) and the various mutant NF2s (mu-NF2s) in a fibroblast cell line by using both liposome-mediated transfection and nuclear microinjection of the expression plasmids. The wt-NF2 showed intense punctate staining in the perinuclear cytoplasm in addition to overall staining of the submembranous area, whereas the mu-NF2s lacking exons in the ERM homology domain showed granular staining at the perinuclear region without any accumulation at the submembrane region. Microinjection of wt-NF2 cDNA into the nucleus of VA13 cells revealed that wt-NF2 protein induced a progressive elongation of cell processes. Furthermore, cells that expressed mu-NF2 had decreased adhesion, which resulted in detachment from the substratum. These findings suggested that the exon-missing mutations in the ERM-homology domain may affect cell membrane-cytoskeleton signaling and consequently disrupt cell-to-cell or cell-to-matrix interaction.

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The neurofibromatosis type 2 (NF2) protein, known as merlin or schwannomin, is a tumor suppressor, and the NF2 gene has been found to be mutated in the majority of schwannomas and meningiomas, including both sporadically occurring and familial NF2 cases. Although the development of these tumors depends on the loss of merlin, the presence of tumors lacking detectable NF2 mutations suggests different mechanisms for inactivating merlin. Recent studies have demonstrated cleavage of merlin by calpain, a calcium-dependent neutral cysteine protease, and marked activation of the calpain system resulting in the degradation of merlin in these tumors. Increased turnover of merlin by calpain in some schwannomas and meningiomas exemplifies tumorigenesis linked to the calpain-mediated proteolytic pathway.

An 88-year-old woman presented with a supratentorial primitive neuroectodermal tumor (PNET) manifesting as disturbance of consciousness and left hemiplegia. Magnetic resonance imaging showed a large mass lesion in the right frontotemporal region. She underwent biopsy of the lesion that confirmed the diagnosis of PNET. Her poor condition only allowed chemotherapy with methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-a-D-glucopyranoside (MCNU), vincristine, and prednisolone to be performed. The patient died approximately 6 months after diagnosis due to enlargement of the tumor. Supratentorial PNET is a rare tumor, especially in adults. Multimodal therapy consisting of gross total or subtotal resection, radiation therapy, and chemotherapy is generally considered necessary for patients with supratentorial PNET. However, the condition of each patient should be considered in determining the therapeutic plan, especially in the case of extremely aged patients, since supratentorial PNET is malignant and long-term survival is rare despite aggressive treatment.

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