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.

Empirical development of improved diagnostic criteria for neurofibromatosis 2

“…11,12 Schwannomatosis has been defined as a distinct clinical entity, 9 excluded from the NF2 locus, 30 and shown to be related to mutations of the SMARCB1 locus in some patients. [31][32][33][34] Most importantly, we have begun to understand the molecular pathogenesis of NF2, 1,[35][36][37] and this is permitting the development of novel therapeutic initiatives. 25,38 -41 Both NF2 and other conditions with which it may be confused clinically are being recognized more frequently, 42 probably because of the availability of high-quality MRI.…”

Long-term survival and transmission of INI1-mutation via nonpenetrant males in a family with rhabdoid tumour predisposition syndrome

“…Primer sequences for mutation analysis of the 9 INI1 exons and the 17 NF2 exons have been given previously (Hulsebos et al, 2007). In degraded DNA samples, the exon 4 -intron 4 junction region of INI1 was sequenced using forward primer 5 0 -catgctccacaaccatcaac-3 0 and reverse primer 5 0 -aactgaaacgtgctggagaac-3 0 , generating a PCR-product of 131 bp.…”

“…Immunohistochemical analysis of the INI1 protein was performed using a BAF47/INI1 antibody (BD Transduction Laboratories, Franklin Lakes, NJ, USA) on formalin-fixed, paraffin-embedded tumour tissue as described previously (Hulsebos et al, 2007).…”

“…Two of these patients survived this tumour for over 15 years and one of these developed a (probably radiation induced) meningioma and a myoepithelioma in adulthood. We recently showed (Hulsebos et al, 2007) that INI1 is a predisposing gene in familial schwannomatosis, a disorder in which patients develop multiple schwannomas later in life and that is also characterised by variable expression and incomplete penetrance (MacCollin et al, 2003). It has been hypothesised that in patients with a germline INI1 mutation, a developmental window exists at young age in which most rhabdoid tumours occur (Janson et al, 2006).…”

Germline mutation contribution to chromosomal instability

“…Interestingly, loss of function of SNF5, a core component of the SWI/SNF chromatin remodeling complex, has been found to impair SAC signaling and promote chromosome mis-segregation in part by causing overexpression of MAD2 (Vries et al 2005). SNF is encoded by SMARCB1, which is a known cancer predisposition gene for malignant rhabdoid tumors and familial schwannomatosis (Hulsebos et al 2007, Eaton et al 2011. It was observed that SNF5-deficient malignant rhabdoid tumor cells exhibiting chromosomal instability in the form of polyploidy had overexpressed MAD2, which could be rescued by the introduction of wild-type SNF5, thus implying the indirect influence of SNF5 on SAC (Vries et al 2005).…”