Germline mutation of INI1/SMARCB1 in familial schwannomatosis

Abstract

Patients with schwannomatosis develop multiple schwannomas but no vestibular schwannomas diagnostic of neurofibromatosis type 2. We report an inactivating germline mutation in exon 1 of the tumor-suppressor gene INI1 in a father and daughter who both had schwannomatosis. Inactivation of the wild-type INI1 allele, by a second mutation in exon 5 or by clear loss, was found in two of four investigated schwannomas from these patients. All four schwannomas displayed complete loss of nuclear INI1 protein expression in part of the cells. Although the exact oncogenetic mechanism in these schwannomas remains to be elucidated, our findings suggest that INI1 is the predisposing gene in familial schwannomatosis.

Figure  1.

Sequence analysis of parts of INI1 in blood and tissues of proband and parents. The C→T mutation in exon 1 of INI1 was detected in DNA from blood and from the schwannoma of the sacral region of the proband (a and b). It was also detected in DNA from the seborrheic keratosis lesion and from the schwannomas of the right thumb, right index finger, and right upper arm of the father (c–f) but not in blood DNA of the mother (g). An additional C→T mutation in exon 5 of INI1 was detected in DNA of the right thumb tumor of the father (i) but not in DNA of his seborrheic keratosis lesion (h).

Figure  2.

Immunohistochemical INI1/BAF47 staining of schwannomas of the proband (a, sacral region) and her father (b, right index finger; c, right thumb; d, right upper arm), as well as of a seborrheic keratosis lesion of the father (e) and of a schwannoma of a patient not affected with schwannomatosis (f). Note the mosaic staining of cell nuclei in schwannomas of both the proband and her father. In contrast, the nuclei of cells in the tumor vessels in panels a–d (arrowheads), as well as the nuclei in a seborrheic keratosis lesion of the father and in a schwannoma in a patient unaffected with schwannomatosis, all show unequivocal staining. The arrow in panel c indicates palisading of tumor cell nuclei in a Verocay body. Original magnification ×200.