Germline deletion in a neurofibromatosis type 2 kindred inactivates the NF2 gene and a candidate meningioma locus

Neurofibromatosis type 2 (NF2) is an autosomal dominant diseasewhich predisposes to the development of schwannomas, meningiomas,ependymomas, and juvenile cataracts. The NF2 gene (NF2) hasrecently been isolated and maps to chromosome 22q12 betweenthe loci D22S212 and D22S32. Deletion studies in sporadic andNF2 associated schwannomas and meningiomas, and the presenceof Inactivating mutations in NF2 in patients suggest that itacts as a tumor suppressor gene. A candidate meningioma gene(MEN) has also been isolated from the same Interval. A new highlypolymorphic (CA)n marker, D22S268, which maps very near to NF2,has allowed us to Identify a kindred with three living affectedindividuals, where the disease Is presumably caused by a largegermline deletion. Fluorescence ^{in situ} hybridization and pulsedfield gel electrophoresis confirm the presence of a 700kb deletionwhich includes the neurofllament heavy chain subunit gene locus(NEFH), D22S268, NF2 and the putative MEN gene. The absenceof meningiomas In this pedigree raises doubts as to the existenceof a separate MEN locus In this region. These results supportthe hypothesis that NF2 results from the Inactivation of a tumorsuppressor gene on chromosome 22q.