The SWI/SNF subunit INI1 contains an N-Terminal winged helix DNA binding domain that is a target for mutations in schwannomatosis


SWI/SNF complexes use the energy of ATP hydrolysis to remodel chromatin. In mammals they play a central role in regulating gene expression during differentiation and proliferation. Mutations in SWI/SNF subunits are among the most frequent gene alterations in cancer. The INI1/hSNF5/SMARCB1 subunit is mutated in both malignant rhabdoid tumor, a highly aggressive childhood cancer, and schwannomatosis, a tumor-predisposing syndrome characterized by mostly benign tumors of the CNS. Here, we show that mutations in INI1 that cause schwannomatosis target a hitherto unidentified N-terminal winged helix DNA binding domain that is also present in the BAF45a/PHF10 subunit of the SWI/SNF complex. The domain is structurally related to the SKI/SNO/DAC domain, which is found in a number of metazoan chromatin-associated proteins.


Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis.


Germline LZTR1 mutations were identified in 6 of 16 patients (37.5%) with schwannomatosis who had at least one affected relative, 11 of 49 (22%) sporadic patients, and 2 of 39 patients with a unilateral vestibular schwannoma (UVS), suggesting a relationship between mutations in LZTR1 and schwannomatosis. Germline mutations in LZTR1 appear to confer an increased risk of vestibular schwannoma, providing further overlap with NF2, and further causative genes for schwannomatosis remain to be identified.


Update from the 2013 International Neurofibromatosis Conference

American Journal of Medical Genetics

Recent schwannomatosis research presented included vectors that cause regression of schwannomas and a reduction in schwannoma-induced pain in mice, studies of underlying mechanisms of pain, analysis of SMARCE1 and SMARCB1 mutations and their role in tumor development, and progress on the International Schwannomatosis Database.


Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria

American Journal of Medical Genetics Part A

Schwannomatosis research presented included genetic studies that indicate that constitutional mutations in the SMARCB1 tumor suppressor gene occur in 40–50% of familial cases and in 8–10% of sporadic cases of schwannomatosis, insights from research on HIV and pediatric rhabdoid tumors that shed light on potential molecular pathways that are dysregulated in schwannomatosis-related schwannomas, mouse models of schwannomatosis that promise to further expand our understanding of tumorigenesis and the tumor microenvironment, and clinical reports that describe the occurrence of intracranial meningiomas in schwannomatosis patients and in families with germline SMARCB1 mutations.