Mild familial neurofibromatosis 2 associates with expression of merlin with altered COOH-terminus

Sainio, Markku; Jääskeläinen, Juha E.; Pihlaja, H.; Carpén, Olli

doi:10.1212/wnl.54.5.1132

Cited by 17 publications

(22 citation statements)

References 30 publications

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“…1). Surprisingly, the predicted amino acid sequence of this form of merlin corresponded exactly with that of a merlin isoform previously reported in an NF2 patient, designated isoform 3 [17]. However, isoform 3b, a second transcript that lacks only exon 15, detected in the same NF2 patient, was not detected in HEI-193 cells.…”

Section: Hei-193 Cells Express a Variant Nf2 Transcript Termed Isoformsupporting

confidence: 80%

“…Due to novel splicing, the amino acid sequence of this splice variant is significantly shorter and differs completely from either isoform 1 or 2 near the Cterminus. Unexpectedly, the amino acid sequence is identical to a merlin isoform described previously in a family with mild NF2 and designated isoform 3 [17]. It is also interesting to note that, unlike the mutation found in HEI-193 cells, the mutation reported by Sainio et al [17] is at the +3 position of the exon 15/intron 15 border (Table 1).…”

Section: Discussionsupporting

confidence: 64%

“…In this paper we report that the merlin protein expressed in HEI-193 cells has amino acid sequence identical to that of a splice variant previously designated as isoform 3 [17]. This isoform was first described in a family with a history of a mild form of NF2 and was shown to arise because of an A→T mutation within the NF2 gene at the +3 position of the donor site of intron 15 [17].…”

Section: Introductionmentioning

confidence: 78%

“…This isoform was first described in a family with a history of a mild form of NF2 and was shown to arise because of an A→T mutation within the NF2 gene at the +3 position of the donor site of intron 15 [17]. Interestingly, isoforms 1, 2 and 3 are simultaneously and equivalently expressed both at the RNA and protein levels in fibroblasts derived from this family, but in schwannoma cells only isoform 3 is expressed [17]. Based on the mild nature of the NF2 disease phenotype seen in this family, the authors of this study concluded that merlin isoform 3 retained mild tumor suppressive activity.…”

Section: Introductionmentioning

confidence: 99%

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Point mutation in the NF2 gene of HEI-193 human schwannoma cells results in the expression of a merlin isoform with attenuated growth suppressive activity

Lepont

Stickney

Foster

et al. 2008

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Neurofibromatosis type 2 (NF2) is a genetic disorder characterized by the formation of bilateral schwannomas of the eighth cranial nerve. Although the protein product of the NF2 gene (merlin) is a classical tumor suppressor, the mechanism by which merlin suppresses cell proliferation is not fully understood. The availability of isolated tumor cells would facilitate a better understanding of the molecular function of merlin, but primary schwannoma cells obtained from patients grow slowly and do not yield adequate numbers for biochemical analysis. In this study, we have examined the NF2 mutation in HEI-193 cells, an immortalized cell line derived from the schwannoma of an NF2 patient. Previous work showed that the NF2 mutation in HEI-193 cells causes a splicing defect in the NF2 transcript. We have confirmed this result and further identified the resultant protein product as an isoform of merlin previously designated as isoform 3. The level of isoform 3 protein in HEI-193 cells is comparable to the levels of merlin isoforms 1 and 2 in normal human Schwann cells and several other immortalized cell lines. In contrast to many mutant forms of merlin, isoform 3 is as resistant to proteasomal degradation as isoforms 1 and 2 and can interact with each of these isoforms in vivo. Cell proliferation assays showed that, in NF2 −/− mouse embryonic fibroblasts, exogenously expressed merlin isoform 3 does exhibit growth suppressive activity although it is significantly lower than that of identically expressed merlin isoform 1. These results indicate that, although HEI-193 cells have undetectable levels of merlin isoforms 1 and 2, they are, in fact, not a merlin-null model because they express the moderately active growth-suppressive merlin isoform 3.

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Section: Hei-193 Cells Express a Variant Nf2 Transcript Termed Isoformsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Point mutation in the NF2 gene of HEI-193 human schwannoma cells results in the expression of a merlin isoform with attenuated growth suppressive activity

Lepont

Stickney

Foster

et al. 2008

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

View full text Add to dashboard Cite

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“…12,19 To this family belongs also the tumor suppressor merlin (NF-2, schwannomin), whose loss is related to the development of tumors 20,21 and metastasis formation. 22 Recently, we reported ezrin involvement in a mostly neglected tumor function such as phagocytic activity or cannibalism of metastatic melanoma cells, that is an exclusive property of cells derived from metastatic lesions. 23,24 However, we did not identify the specific ezrin interaction with cannibal vacuoles.…”

mentioning

confidence: 99%

Pleiotropic function of ezrin in human metastatic melanomas

Federici

Brambilla

Lozupone

et al. 2009

Intl Journal of Cancer

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The membrane cytoskeleton cross-linker, ezrin, has recently been depicted as a key regulator in the progression and metastasis of several pediatric tumors. Less defined appears the role of ezrin in human adult tumors, especially melanoma. We therefore addressed ezrin involvement in the metastatic phenotype of human adult metastatic melanoma cells. Our results show that cells resected from melanoma metastatic lesions of patients, display marked metastatic spreading capacity in SCID mice organs. Stable transfection of human melanoma cells with an ezrin deletion mutant comprising only 146 N-terminal aminoacids led to the abolishment of metastatic dissemination. In vitro experiments revealed ezrin direct molecular interactions with molecules related to metastatic functions such as CD44, merlin and Lamp-1, consistent with its participation to the formation of phagocitic vacuoles, vesicular sorting and migration capacities of melanoma cells. Moreover, the ezrin fragment capable of binding to CD44 was shorter than that previously reported, and transfection with the ezrin deletion mutant abrogated plasma membrane Lamp-1 recruitment. This study highlights key involvement of ezrin in a complex machinery, which allows metastatic cancer cells to migrate, invade and survive in very unfavorable conditions. Our in vivo and in vitro data reveal that ezrin is the hub of the metastatic behavior also in human adult tumors. ' UICCKey words: CD44; merlin; Lamp-1; phagocytic vacuole; organelle acidity The molecular events governing progression from a primary tumor to an invasive, malignant tumor remain poorly defined despite intense scientific endeavor mostly due to molecular biology and biochemical data collected from non human models. 1 The metastatic phenomenon is characterized by a cascade of events that assumes the existence of very harmful cells within the primitive tumor mass. These cells must acquire the ability to breach underlying basement membrane, migrate through interstitial stroma, gain access to and migrate through blood or lymphatic vessels, attach, enter, survive and proliferate within metastatic organs.Mounting evidence suggesting that ezrin contributes to tumor metastasis promotion, arose mainly from experiments employing syngeneic implantation models correlated to gene expression profiling performed on pediatric tumors. 1,2 In human tumors, ezrin deregulation or impaired functionality is related to poor prognosis. [3][4][5][6][7][8][9] Ezrin belongs to the MERM family of cytoskeleton-associated proteins 10 and functions as a linker between the actin cortical cytoskeleton and various membrane-bound molecules 11,12 through its C-terminal and N-terminal domains, respectively.ERM proteins are implicated in a wide variety of important cellular processes. 10,13-18 Notably, ezrin is primarily involved in both cell-to-cell adhesion and cell adhesion to the ECM through association with ICAMs, CD44, E-cadherin and b-catenin. 12,19 To this family belongs also the tumor suppressor merlin (NF-2, schwannomin), whose loss is r...

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Intrafamilial correlation of clinical manifestations in neurofibromatosis 2 (NF2)

Zhao

Kumar

Baser³

et al. 2002

Genetic Epidemiology

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Measuring correlation in clinical traits among relatives is important to our understanding of the causes of variable expressivity in Mendelian diseases. Random effects models are widely used to estimate intrafamilial correlations, but such models have limitations. We incorporated survival techniques into a random effects model so that it can be used to estimate intrafamilial correlations in continuous variables with right censoring, such as age at onset. We also describe a negative-binomial gamma mixture model to determine intrafamilial correlations of discrete (e.g., count) data. We demonstrate the utility of these methods by analyzing intrafamilial correlations among patients with neurofibromatosis 2 (NF2), an autosomal-dominant disease caused by mutations of the NF2 tumor-suppressor gene. We estimated intrafamilial correlations in age at first symptom of NF2, age at onset of hearing loss, and number of intracranial meningiomas in 390 NF2 nonprobands from 153 unrelated families. A significant intrafamilial correlation was observed for each of the three features: age at onset (0.35; 95% confidence interval (CI) 0.23-0.47), age at onset of hearing loss (0.51; 95% CI, 0.35-0.64), and number of meninginomas (0.29; 95% CI, 0.15-0.43). Significant correlations were also observed for age at first symptom within NF2 families with truncating mutations (0.41; 95% CI, 0.06-0.68) or splice-site mutations (0.29; 95% CI, 0.03-0.51), for age at onset of hearing loss within families with missense mutations (0.67; 95% CI, 0.18-0.89), and for number of meningiomas within families with splice-site mutations (0.39; 95% CI, 0.13-0.66). Our findings are consistent with effects of both allelic and nonallelic familial factors on the clinical variability of NF2.

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Mild familial neurofibromatosis 2 associates with expression of merlin with altered COOH-terminus

Cited by 17 publications

References 30 publications

Point mutation in the NF2 gene of HEI-193 human schwannoma cells results in the expression of a merlin isoform with attenuated growth suppressive activity

Point mutation in the NF2 gene of HEI-193 human schwannoma cells results in the expression of a merlin isoform with attenuated growth suppressive activity

Pleiotropic function of ezrin in human metastatic melanomas

Intrafamilial correlation of clinical manifestations in neurofibromatosis 2 (NF2)

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