SummaryTo induce post.transcriptional silencing of flower pigmentation genes by homologous sense transgenes in transgenic petunias, it is not necessary for the transgenes to be highly transcribed. Even promoterless transgenes can induce silencing. Here it is shown that in these cases silencing is mediated by multimeric transgene/T-DNA loci in which the T-DNAs are arranged as inverted repeats (IRs). With the transgene constructs used, monomeric T-DNA loci are unable to confer silencing even though they modulate IR-induced silencing. IRs with the silencing sequences proximal to the centre (IR c) induce a more severe silencing than IRs with these sequences distal to the centre (IR,). Somatic reversion of silencing, as observed in a side branch of one of the chalcone synthase (Chs) transformants, was associated with a deletion of the IR locus from L1 cells, the meristematic cell layer that expresses the endogenous Chs genes in the flower corolla. Taken together, these data indicate that the post-transcriptional silencing mechanism can be activated by inverted transgene repeats. It is also shown that a silent IR UidA-ChsA locus silences the expression of a monomeric 35S promoter-driven UidA-ChsA transgene only in corollas where the endogenous Chs genes are highly transcribed. These results are consistent with a model in which an IR, by virtue of its palindromic sequence organization, is able to promote the production of aberrant RNAs from the endogenous homologs as a result of ectopic pairing.

No abstract

General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Download date: 27 Apr 2019Germline SMARCB1 mutation and somatic NF2 mutations in familial multiple meningiomas Results Five affected members of a large family with multiple meningiomas were investigated for the presence of mutations in SMARCB1 and NF2. A missense mutation was identified in exon 2 of SMARCB1 as the causative germline mutation predisposing to multiple meningiomas; furthermore, it was demonstrated that, in accordance with the two-hit hypothesis for tumourigenesis, the mutant allele was retained and the wild-type allele lost in all four investigated meningiomas. In addition, independent somatically acquired NF2 mutations were identified in two meningiomas of one patient with concomitant losses of the wild-type NF2 allele. Conclusion It is concluded that, analogous to the genetic events in a subset of schwannomatosis associated schwannomas, a four-hit mechanism of tumour suppressor gene inactivation, involving SMARCB1 and NF2, might be operative in familial multiple meningiomas associated meningiomas.

Schwannomatosis is a rare hereditary cancer syndrome in which patients develop multiple non-vestibular schwannomas. The chromatin remodelling gene SMARCB1 (also known as INI1, hSNF5, and BAF47) has been identified as a schwannomatosis predisposing gene, being involved in a subset of sporadic and familial cases. Recent studies have shown that SMARCB1 may also be involved in the development of multiple meningiomas. Previously, we demonstrated that the SMARCB1 exon 2 missense mutation c.143 C > T segregates with the presence of meningiomas in five members of a large family with multiple meningiomas and schwannomas. We extended our genetic analyses by screening 44 additional at-risk family members and identified 13 new carriers. Eleven of these were subjected to magnetic resonance imaging (MRI) of brain and spine. In addition, we analyzed four meningiomas and two schwannomas from family members for the presence of schwannomatosis-specific changes. We found in each tumor retention of the SMARCB1 exon 2 mutation, acquisition of an independent neurofibromatosis type 2 (NF2) gene mutation, and loss of heterozygosity at SMARCB1 and NF2 by loss of the wild-type copy of both genes. The MRI scans revealed one or more falx meningiomas in seven of 11 (64%) newly identified SMARCB1 mutation carriers. We conclude that the SMARCB1 exon 2 missense mutation in this family predisposes to the development of meningiomas as well as schwannomas, occurring via the same genetic pathways, and that this mutation preferentially induces cranial meningiomas located at the falx cerebri.