Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurofibromatosis type 2 (NF2) is an autosomal dominantly-inherited disorder predisposing affected individuals to tumors of multiple cell types in the central nervous system, including meningiomas. A candidate tumor suppressor gene for this disorder has recently been cloned; the protein product of this gene has a predicted role in linking integral membrane proteins with the cytoskeleton. Utilizing reverse transcription-polymerase chain reaction (RT-PCR) analyses, we have identified a number of alternatively spliced transcription products encoded by the NF2 gene. These alternative splice variants were detected in RNA isolated from several sources, including primary leptomeningeal tissue and an established line of leptomeningeal cells (LMC). Several of these variants delete previously identified coding regions of this gene. Moreover, two of these splice variants add previously unrecognized exons to the NF2 coding region. These identified splice forms will serve as natural reagents for the functional dissection of the NF2 protein product(s). They also should be considered in studies investigating mutations of this gene in members of NF2 families and in tumor analyses.
Hum Mol Genet 1994 Apr
PMID:The neurofibromatosis 2 (NF2) tumor suppressor gene encodes multiple alternatively spliced transcripts. 806 98

To investigate a potential role of NF2, the gene responsible for hereditary bilateral acoustic neurinomas, during carcinogenesis of non-neurogenic tissues, we screened somatic mutations of NF2 in 55 breast cancers and 44 colorectal carcinomas by an RNase protection assay coupled with the reverse-transcriptase polymerase chain reaction (RT-PCR). By screening the entire coding region of the gene in these tumors, we detected missense mutations in the exon encoding the alpha-helical domain of the NF2 product in two colorectal carcinomas. No mutations were detected in any of the breast cancers. Our results suggested that inactivation of the NF2 gene was associated with carcinogenesis in some, but not the majority of, colorectal tumors. In the course of these analyses, we found various alternatively-spliced forms of NF2 transcript. These variants showed no specificity among the tissues examined except for one that resulted from alternative splicing at the 3'-region; this form was more abundantly expressed in skeletal and cardiac muscles than in other tissues.
Hum Mol Genet 1994 Apr
PMID:Alternative splicing of the NF2 gene and its mutation analysis of breast and colorectal cancers. 806 99

The recent identification of the NF2 tumour suppressor gene has enabled large scale screening for pathological mutations in the gene. We have sought germline mutations in the NF2 gene by SSCP and heteroduplex analysis of cDNA and genomic DNA samples followed by cloning and sequencing of mutant alleles. In the present report we describe 11 putative pathological mutations, including five nonsense mutations, three short insertions or deletions causing frameshifts and three missense mutations. Most stop mutations and frameshift mutations were found in individuals expressing a severe phenotype while one of the three missense mutations was associated with a mild phenotype. Four unrelated NF2 patients of the 93 tested were found to have identical nonsense mutations caused by a C to T transition (C169) in a CpG dinucleotide, which is a potential mutational hotspot in the NF2 tumour suppressor gene.
Hum Mol Genet 1994 May
PMID:Germline mutations in the neurofibromatosis type 2 tumour suppressor gene. 808 68

RFLP typing of members of a neurofibromatosis type 2 (NF2) family suggested that affected individuals were hemizygous at the neurofilament heavy chain (NEFH) locus, possibly as a result of a disease-associated deletion. Conventional karyotyping revealed no evidence for a deletion and all or a majority of the affected family members were heterozygous for closely linked markers which mapped proximal to the NEFH locus (D22S1 and D22S56) and for the distal marker D22S32. FISH analysis confirmed a disease-associated germinal deletion on 22q which encompassed the NEFH locus, which is known to be very closely linked to NF2, but did not extend as far as the proximal Ewing sarcoma region or the distal leukaemia factor (LIF) locus. PFGE analysis with a LIF cosmid subclone identified patient-specific NotI and MluI fragments and suggested that the deletion is about 700 kb in length. Although this large deletion could be expected to eliminate a considerable fraction, and possibly all of the NF2 gene, the resulting phenotype is the mild, so-called Gardner subtype of NF2. The deletion should provide a useful mapping resource for characterising the chromosomal region containing the NF2 locus.
Hum Mol Genet 1993 Jun
PMID:A disease-associated germline deletion maps the type 2 neurofibromatosis (NF2) gene between the Ewing sarcoma region and the leukaemia inhibitory factor locus. 810 69

Schwannomas are tumors arising from schwann cells surrounding peripheral nerves. Although most schwannomas are sporadic, they are seen in approximately 90% of individuals with neurofibromatosis type 2 (NF2), an autosomal dominantly inherited disease with an incidence of 1:40000 live births. The NF2 gene has recently been isolated on chromosome 22 and encodes a putative membrane organizing protein named schwannomin. It is believed to act as a tumor suppressor gene based on the high frequency of loss of heterozygosity (LOH) on this autosome in both sporadic and NF2 associated schwannomas and meningiomas and the identification of inactivating mutation in NF2 patients. In this study we examined 61 schwannomas including 48 sporadic schwannomas (46 of which are vestibular schwannomas) and 12 schwannomas obtained from NF2 patients, for mutations in 10 of the 16 coding exons of the NF2 gene. Twelve inactivating mutations were identified, 8 in sporadic tumours and 4 in tumors from people with NF2. These results support the hypothesis that loss of function of schwannomin is a frequent and fundamental event in the genesis of schwannomas.
Hum Mol Genet 1994 Jan
PMID:The neurofibromatosis type 2 gene is inactivated in schwannomas. 816 16

Neurofibromatosis type 2 (NF2) is a complex nervous system disorder characterized by the development of schwannomas (especially vestibular), meningiomas, ependymomas and juvenile lens opacities. Mutation in the NF2 gene, which encodes for the schwannomin protein (SCH), a member of the band 4.1 superfamily of genes, predisposes carriers to these central nervous system tumors. We have isolated a mouse cDNA from a brain library which contains the complete open reading frame of the mouse homologue of the NF2 gene. This cDNA encodes for a 596 amino acid protein with 98% identity to the human SCH. Cross species hybridization experiments predict that the NF2 gene is highly conserved in other vertebrates. Northern analysis detects a 4.5 kb transcript in mouse brain, kidney, cardiac muscle, skin and lung suggesting ubiquitous expression. The predicted secondary structure of SCH, which is shared by all members of the band 4.1 superfamily, includes a highly conserved amino-terminal domain which is believed to bind to proteins in the plasma membrane and a large highly charged alpha-helix domain proposed to associate with the cytoskeleton. The NF2 gene is the first example of a tumor suppressor gene whose protein product appears to act as a membrane cytoskeleton-linker. These results show that the NF2 gene is highly conserved and suggests that the analysis of the mouse NF2 gene might yield insights into the function of the human gene.
Hum Mol Genet 1994 Jan
PMID:The mouse homologue of the neurofibromatosis type 2 gene is highly conserved. 816 23

Neurofibromatosis type 2 (NF2) is an autosomal dominant disease which predisposes to the development of schwannomas, meningiomas, ependymomas, and juvenile cataracts. The NF2 gene (NF2) has recently been isolated and maps to chromosome 22q12 between the loci D22S212 and D22S32. Deletion studies in sporadic and NF2 associated schwannomas and meningiomas, and the presence of inactivating mutations in NF2 in patients suggest that it acts as a tumor suppressor gene. A candidate meningioma gene (MEN) has also been isolated from the same interval. A new highly polymorphic (CA)n marker, D22S268, which maps very near to NF2, has allowed us to identify a kindred with three living affected individuals, where the disease is presumably caused by a large germline deletion. Fluorescence in situ hybridization and pulsed field gel electrophoresis confirm the presence of a 700kb deletion which includes the neurofilament heavy chain subunit gene locus (NEFH), D22S268, NF2 and the putative MEN gene. The absence of meningiomas in this pedigree raises doubts as to the existence of a separate MEN locus in this region. These results support the hypothesis that NF2 results from the inactivation of a tumor suppressor gene on chromosome 22q.
Hum Mol Genet 1993 Aug
PMID:Germline deletion in a neurofibromatosis type 2 kindred inactivates the NF2 gene and a candidate meningioma locus. 840 4

All intermediate filament proteins possess three distinct domains: heads, rod and tail, and subdomains within the rod called helices 1A, 1B, 2A, and 2B. Subunit packing within a filament is a consequence of interactions among these domains. Several such interactions are known, but probably many more contribute to stabilizing filament structure. We examined a number of such potential interactions using the yeast two-hybrid system. Domains or subdomains of murine vimentin, a Type III intermediate filament protein, were fused with either the DNA-binding or trans-activating domain of GAL4, a transcription factor. Interaction between the vimentin domains/subdomains functionally reconstituted GAL4, thereby activating transcription of a GAL1-LacZ reporter gene. The oligomeric state at which the interactions took place, i.e. whether the domains/subdomains were dimeric or tetrameric as they interacted, was also determined. These studies revealed a number of interesting interactions, among which was a strong homotypic binding to helix 2B to form tetramers. They also demonstrated a lack of interaction among others expected to do so based on current structural models. From these results we deduced which of the candidates for interactions, suggested by current models, were true protein-protein interactions and which represented nearest-neighbors only. Thus, the A11 and A22 modes of molecular alignment identified by Steinert et al. (Steinert, P. M., Marekov, L. N., Fraser, R. D. B., and Parry, D. A. D. (1993) J. Mol. Biol. 230, 436-452) are probably true interactions, whereas the A12 and ACN modes may describe adjacent but non-interacting molecules.
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PMID:Intermediate filament protein domain interactions as revealed by two-hybrid screens. 857 58

Although schwannomin, the product of the neurofibromatosis type 2 gene, shares homology with three cytoskeleton-to-membrane protein linkers defining the ERM family, the mechanism by which it exerts a tumor suppressive activity remains elusive. Based on the knowledge of naturally occurring mutations, a functional study of schwannomin was initiated. Constructs encoding the two wild-type isoforms and nine mutant forms were transfected into HeLa cells. Transiently expressed wild-type isoforms were both observed underneath the plasma membrane. At this location they were detergent insoluble and redistributed by a cytochalasin D treatment, suggesting interaction with actin-based cytoskeletal structures. Proteins with single amino acid substitutions at positions 219 and 220 demonstrated identical properties. Three different truncated schwannomins, that are prototypic for most naturally occurring NF2 mutations, were affected neither in their location nor in their cytochalasin D sensitivity. However, they were revealed to be detergent soluble, indicating a relaxed interaction with the actin-based structures. An increased solubility was also observed for a mutant with a single amino acid substitution at position 360 in the C-terminal half of the protein. Mutant proteins with either a single amino acid deletion at position 118 or an 83 amino acid deletion within the N-terminal domain had lost the submembraneous localization and tended to accumulate in perinuclear patches that were unaffected by cytochalasin D treatment. A similar behavior was observed when the N-terminal domain was entirely deleted. Taken together these observations suggest that the N-terminal domain is the main determinant that localizes the protein at the membrane where it interacts weakly with actin-based cytoskeletal structures. The C-terminal domain potentiates this interaction. With rare exceptions, most naturally occurring mutant schwannomins that have lost their tumor suppressive activity are impaired in an interaction involving actin-based structures and are no longer firmly maintained at the membrane.
Hum Mol Genet 1998 Feb
PMID:Impaired interaction of naturally occurring mutant NF2 protein with actin-based cytoskeleton and membrane. 942 29

Neurofibromatosis 2 (NF2) is an inherited cancer syndrome resulting from mutations in the NF2 tumor suppressor gene. Analysis of NF2 mutations has revealed some general genotype-phenotype correlations. Severe disease has been associated with mutations that produce a premature termination while more mild disease has been associated with missense mutations. Here, we provide experimental proof for these genotype-phenotype correlations by demonstrating that nonsense mutations fail to produce stable merlin protein while missense mutations result in the generation of merlin proteins defective in negative growth regulation. This inability to suppress cell growth may result from defects in the function of merlin at several levels, including failure to form an intramolecular complex. Based on these findings, we propose a model for merlin growth suppression that provides a framework for analyzing NF2 patient mutations and merlin function.
Hum Mol Genet 1998 Mar
PMID:Defects in neurofibromatosis 2 protein function can arise at multiple levels. 946 88


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