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PubMed1992

Analysis of chromosome 22 deletions in neurofibromatosis type 2-related tumors.

The neurofibromatosis type 2 (NF2) gene has been hypothesized to be a recessive tumor suppressor, with mutations at the same locus on chromosome 22 that lead to NF2 also leading to sporadic tumors of the types seen in NF2. Flanking markers for this gene have previously been defined as D22S1 centromeric and D22S28 telomeric. Identification of subregions of this interval that are consistently rearranged in the NF2-related tumors would aid in better defining the disease locus. To this end, we have compared tumor and constitutional DNAs, isolated from 39 unrelated patients with sporadic and NF2-associated acoustic neuromas, meningiomas, schwannomas, and ependymomas, at eight polymorphic loci on chromosome 22. Two of the tumors studied revealed loss-of-heterozygosity patterns, which is consistent with the presence of chromosome 22 terminal deletions. By using additional polymorphic markers, the terminal deletion breakpoint found in one of the tumors, an acoustic neuroma from an NF2 patient, was mapped within the previously defined NF2 region. The breakpoint occurred between the haplotyped markers D22S41/D22S46 and D22S56. This finding redefines the proximal flanking marker and localizes the NF2 gene between markers D22S41/D22S46 and D22S28. In addition, we identified a sporadic acoustic neuroma that reveals a loss-of-heterozygosity pattern consistent with mitotic recombination or deletion and reduplication, which are mechanisms not previously seen in studies of these tumors. This finding, while inconsistent with models of tumorigenesis that invoke single deletions and their gene-dosage effects, lends further support to the recessive tumor-suppressor model.

Blotting, Southern↗
PubMed1992

Neurofibromatosis: from gene to phenotype.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disease which predominantly affects tissues derived from neural ectoderm. The gene has recently been cloned, and the biochemistry and cell biology of normal and mutant forms is gradually being elucidated. Despite the success of cloning the gene, there is a long way to go before the different features of the disease phenotype can be explained. Some of the questions which arise in the attempt to link the mutation to the phenotype are considered, with possible ways to approach them.

Gene Expression Regulation, Neoplastic↗
PubMed1992

Monosomy 7 myeloproliferative disease in children with neurofibromatosis, type 1: epidemiology and molecular analysis.

Loss of constitutional heterozygosity is a common molecular feature of cancers in which inactivation of one or more tumor suppressor genes is thought to contribute to tumorigenesis. Recent evidence suggests that the gene responsible for neurofibromatosis, type 1 (NF-1), belongs to this class of heritable cancer genes. Children with NF-1 show an increased incidence of myeloid leukemia, including juvenile chronic myelogenous leukemia (JCML) and, perhaps, the myeloproliferative syndrome (MPS) associated with bone marrow monosomy 7 (Mo 7). We have investigated five children with Mo 7: three with NF-1 and two others with suggestive evidence of NF-1. Southern blotting experiments performed in four patients showed no loss of heterozygosity in bone marrow specimens using probes linked to the NF-1 locus on the long arm of chromosome 17. Both of our patients with familial NF-1 inherited the disease from their mothers, as did 14 of 19 other cases of myeloid leukemia in children with familial NF-1. Seventeen of these 21 children were boys. Myeloid leukemia developed in 12 boys and four girls who inherited NF-1 from their mothers, and in five boys who inherited the disease from their fathers. Father-to-daughter transmission was not observed. Taken together, the presence of chromosome 7 deletions in the leukemias of children with NF-1, a pattern of inheritance favoring maternal transmission of NF-1, and the marked predilection for boys to develop JCML and Mo 7 suggest a multistep mechanism of oncogenesis in which epigenetic factors might play a role. Further investigation is required to determine if the NF-1 genes in the leukemic bone marrows of these patients have acquired point mutations or small deletions.

Blotting, Southern↗
PubMed1992

[Central nervous findings in neurofibromatosis].

Neurofibromatosis (NF) is subdivided into at least two different forms: NF-1, which is characterized by café-au-lait spots, cutaneous neurofibromas, Lisch nodules and osseous dysplasias, and NF-2, the hallmarks of which are bilateral acoustic neuromas. Neuropathological findings in 5 cases of NF-1 and 3 cases of NF-2 are presented.

Adult↗
PubMed2006

Neurofibromatosis.

Neurofibromatosis is a heritable disease characterized by disordered growth of ectodermal tissues.

Genetic Testing↗
PubMed1991

The hunt for the neurofibromatosis gene.

The neurofibromatosis type 1 (NF1) gene has been localized to the pericentromeric region of the long arm of chromosome 17. A chronology of events leading to the cloning of the NF1 gene is offered as a summary of modern gene hunting techniques. The gene was identified by its location rather than its function using positional cloning. Linkage analysis, based on DNA polymorphisms, is already available for prenatal and presymptomatic testing. This technique works only in cases when affected family members are available and is useless in spontaneous cases. The complete NF1 gene is huge, has a large number of exons, and is approximately 240,000 base pairs long. Its large size is consistent with the very high spontaneous mutation rate. The NF1 gene is evolutionarily conserved and expressed ubiquitously, not just in neural crest derivatives. Functional and structural homology with GAP (GTP [guanosine triphosphate]ase-activating protein) has been described. The GAP controls (or is controlled by) the ras oncogene. Aberration of ras function, which plays a fundamental role in growth, development, and differentiation, may play a role in the NF1 phenotype. Direct DNA diagnosis of mutations in the NF1 gene in clinical practice is premature. Current data suggest that the NF1 gene product may act as a tumor suppressor.

DNA↗
PubMed1995

[Type 2 neurofibromatosis without acoustic neuroma].

Bilateral vestibular schwannomas (VSs) are the hallmark of neurofibromatosis type 2 and the crucial criteria for the diagnosis of this autosomal dominant disorder according to the criteria of the National Institutes of Health Consensus Statement. We describe three patients without VSs aged 47, 52 and 69 years, in whom a NF2 gene carrier status was diagnosed by spinal tumors, a cataract and schwannoma of cranial and peripheral nerves. In one case the diagnosis was ascertained by mutation analysis, which revealed a 163bp deletion in the NF2 cDNA, and by the fact that two daughters had the same deletion and NF2 according to the NIH criteria. Our finding suggests that patients with spinal tumors, multiple brain tumors, associated neurinomas or cataract might be carriers of a mutated NF2-gene. The study suggests that the NIH criteria are too restrictive, since NF2 seems to show up for a broader spectrum of phenotypes.

Aged↗
PubMed1995

[A clinical study of 21 patients with neurofibromatosis I and II].

Neurofibromatosis (NF) 2, associated with bilateral acoustic neurinomas has been shown to be an entity distinct from NF 1, since their chromosomal abnormalities are completely different. NF 2 has a very low occurrence rate, but would be a terrible disease by its high prevalence of offsprings. In addition, compared to the majority of unilateral, nonfamiliar neurinoma, acoustic neurinomas of NF 2 have been shown to be refractory to treatments. Therefore, it is crucial to know the clinical characteristics of patients with NF 2. In this study, we analyzed 14 cases of NF 2 and 7 cases of NF 1 in whom brain tumors are main symptoms. Brain tumors associated with NF 1 were five neurinomas, two gliomas and a meningioma. The mean age of NF 1 patients accompanied with brain tumors was 37.6 years old, younger than the overall age of NF 1 patients. In patients with NF 2 there was often association with cranial, and spinal neurinomas and meningiomas. NF 2 especially, in younger patients was accompanied with multiple spinal neurinomas. Twenty acoustic neurinomas in 14 NF 2 patients were treated by surgery. Operative results showed that total resection was achieved in only 5 cases, 13 were subtotally and 2 were partially resected. Hearing preservation was attained in only three cases. In addition, all but two patients were complicated with postoperative facial palsy. From this analysis, it is clear that NF 2-associated acoustic neurinomas are not responsive to surgical intervention. We also reviewed genetical problems briefly.

Adult↗
PubMed1994

Mutational analysis of patients with neurofibromatosis 2.

Neurofibromatosis 2 (NF2) is a genetic disorder characterized by the development of multiple nervous-system tumors in young adulthood. The NF2 gene has recently been isolated and found to encode a new member of the protein 4.1 family of cytoskeletal associated proteins, which we have named merlin. To define the molecular basis of NF2 in affected individuals, we have used SSCP analysis to scan the exons of the NF2 gene from 33 unrelated patients with NF2. Twenty unique SSCP variants were seen in 21 patients; 10 of these individuals were known to be the only affected person in their kindred, while 7 had at least one other known affected relative. In all cases in which family members were available, the SSCP variant segregated with the disease; comparison of sporadic cases with their parents confirmed the de novo variants. DNA sequence analysis revealed that 19 of the 20 variants observed are predicted to lead to a truncated protein due to frameshift, creation of a stop codon, or interference with normal RNA splicing. A single patient carried a 3-bp deletion removing a phenylalanine residue. We conclude that the majority of NF2 patients carry an inactivating mutation of the NF2 gene and that neutral polymorphism in the gene is rare.

Base Sequence↗
PubMed1994

A mutation in the neurofibromatosis type 2 tumor-suppressor gene, giving rise to widely different clinical phenotypes in two unrelated individuals.

We have sought mutations in the recently identified neurofibromatosis type 2 (NF2) tumor-suppressor gene in a large panel of NF2 patients, using PCR-based SSCP and heteroduplex analysis, followed by cloning and sequencing of appropriate PCR products. Two unrelated NF2 patients were found to have identical nonsense mutations caused by a C-to-T transition in a CpG dinucleotide that is a potential mutational hot spot in the NF2 tumor-suppressor gene. Unexpectedly, the two individuals had widely different clinical phenotypes, representing the severe Wishart and mild Gardner clinical subtypes. Analysis of DNA samples from different tissues of the mildly affected patient suggests that he is a somatic mosaic for the mutation.

Adolescent↗
PubMed1994

Deletions spanning the neurofibromatosis 1 gene: identification and phenotype of five patients.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by marked variation in clinical severity. To investigate the contribution to variability by genes either contiguous to or contained within the NF1 gene, we screened six NF1 patients with mild facial dysmorphology, mental retardation, and/or learning disabilities, for DNA rearrangement of the NF1 region. Five of the six patients had NF1 gene deletions on the basis of quantitative densitometry, locus hemizygosity, and analysis of somatic cell hybrid lines. Analyses of hybrid lines carrying each of the patient's chromosomes 17, with 15 regional DNA markers, demonstrated that each of the five patients carried a deletion > 700 kb in size. Minimally, each of the deletions involved the entire 350-kb NF1 gene; the three genes--EVI2A, EVI2B, and OMG--that are contained within an NF1 intron; and considerable flanking DNA. For four of the patients, the deletions mapped to the same interval; the deletion in the fifth patient was larger, extending farther in both directions. The remaining NF1 allele presumably produced functional neurofibromin; no gene rearrangements were detected, and RNA-PCR demonstrated that it was transcribed. These data provide compelling evidence that the NF1 disorder results from haploid insufficiency of neurofibromin. Of the three documented de novo deletion cases, two involved the paternal NF1 allele and one the maternal allele. The parental origin of the single remaining expressed NF1 allele had no dramatic effect on patient phenotype. The deletion patients exhibited a variable number of physical anomalies that were not correlated with the extent of their deletion. All five patients with deletions were remarkable for exhibiting a large number of neurofibromas for their age, suggesting that deletion of an unknown gene in the NF1 region may affect tumor initiation or development.

Adolescent↗
PubMed1993

An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes.

Neurofibromatosis (NF) type 1 (NF1) is notable for its variable expression. To determine whether variation in expression has an inherited component, we examined 175 individuals in 48 NF families, including six MZ twin pairs. Three quantitative traits were scored--number of café-au-lait patches, number of cutaneous neurofibromas, and head circumference; and five binary traits were scored--the presence or absence of plexiform neurofibromas, optic gliomas, scoliosis, epilepsy, and referral for remedial education. For café-au-lait patches and neurofibromas, correlation was highest between MZ twins, less high between first-degree relatives, and lower still between more distant relatives. The high correlation between MZ twins suggests a strong genetic component in variation of expression, but the low correlation between distant relatives suggests that the type of mutation at the NF1 locus itself plays only a minor role. All of the five binary traits, with the exception of plexiform neurofibromas, also showed significant familial clustering. The familial effects for these traits were consistent with polygenic effects, but there were insufficient data to rule out other models, including a significant effect of different NF1 mutations. There was no evidence of any association between the different traits in affected individuals. We conclude that the phenotypic expression of NF1 is to a large extent determined by the genotype at other "modifying" loci and that these modifying genes are trait specific.

Adolescent↗
PubMed1993

[Ophthalmologic differentiation of various forms of neurofibromatosis].

Neurofibromatosis (NF) is one of the most frequent autosomal-dominant hereditary disorders. The molecular-genetic differentiation of NF 1 and NF 2 has important implications for the ophthalmologist. Among 80 patients with NF 1, Lisch nodules were diagnosed in 83% as typical criteria for the disease. In 6 patients who did not meet the NIH criteria for NF 1 and NF 2, the ophthalmological investigation showed no cataracts or Lisch nodules; thus, the ophthalmological examination can help to confirm a subtype of NF. In 8 out of 22 NF 2 patients a juvenile posterior subcapsular cataract was diagnosed. Our examination demonstrates that the diagnostic value of lens opacities in NF 2 patients--especially for early detection of the disease--must be clarified, especially with regard to the fact that there were no patients with incipient cataract and no neuroradiological criteria for the disease.

Adolescent↗
PubMed1993

[Molecular genetics of neurofibromatosis type 1].

The gene responsible for neurofibromatosis type 1 (NF1) encodes a protein similar to GTPase-activating protein (GAP) for the products of ras protooncogenes. Since NF1 protein possesses GAP-like activity, it is suggested that NF1 protein plays a role in the regulation of ras-mediated signal transduction. Impaired function of NF1 protein could therefore, lead to abnormal growth or differentiation of neural crest-derived cells in NF1 patients. Mutations of NF1 gene are also found in sporadic tumors not associated with NF1, supporting the hypothesis that NF1 gene acts as a tumor suppressor gene.

GTPase-Activating Proteins↗
PubMed1993

[Molecular biological analysis of neurofibromatosis type 2 gene].

Neurofibromatosis type 2 is a hereditary disorder characterized by bilateral vestibular and other schwannomas as well as various other central nervous system neoplasms such as gliomas, meningiomas, and neurofibromas. The region containing the NF2 gene has been localized to 22q12 both by linkage analysis and deletion mapping of NF2-related tumors. Recently a candidate gene, named Merlin, was cloned by means of defining a constitutional interstitial deletion in an NF2 patient. The Merlin gene product belongs to a family of proteins which include moesin, ezrin and radixin, involved in linking the cytoskeleton to the cell membrane. Merlin thus forms a novel class of tumor suppressor genes, and an analysis of its function in vivo and the clinical implications of its loss in schwannoma cells remains to be explored.

Cell Line↗
PubMed1993

[Local immune response in neurofibromatosis type 1 and type 2].

Neurofibromatosis, in all its variant forms, is a hereditary disease characterized by dysplasia, neoplasia, and the tendency to expand and undergo malignant transformation. We underline the presence of chronic inflammation and of immunologic interdependency. The immune reactions against the non-self have been investigated histologically in light of the concepts of immunosurveillance and immunotolerance. Such investigations would ameliorate subsequent studies and favour the employment of immunomodulatory treatments.

Adolescent↗
PubMed1996

Somatic mosaicism in a patient with neurofibromatosis type 1.

Using loss of heterozygosity analysis, a method designed to detect moderate to large gene deletions, we have identified a new-mutation neurofibromatosis type 1 (NF1) patient who is somatically mosaic for a large maternally derived deletion in the NF1 gene region. The deletion extends at least from exon 4 near the 5' end of the gene to intron 39 near the 3' end. The gene-coding region is, therefore, mostly or entirely deleted, encompassing a loss of > or = 100 kb. We hypothesize that the deletion occurred at a relatively early developmental timepoint, since signs of NF1 in this patient are not confined to a specific body region, as seen in "segmental" NF, and since both mesodermally and ectodermally derived cells are affected. This report provides the first molecular evidence of somatic mosaicism in NF1 and, taken together with a recent report of germ-line mosaicism in NF1, adds credence to the concept that mosaicism plays an important role in phenotypic and genetic aspects of NF1 and may even be a relatively common phenomenon.

Adult↗
PubMed1995

The neurofibromatosis 2 (NF2) tumour suppressor gene: implications beyond the hereditary tumour syndrome?

The cloning of the gene that causes neurofibromatosis type 2 (NF2), a hereditary tumour syndrome typically associated with brain tumours such as vestibular schwannomas and meningiomas, represents another successful application of the "positional cloning" approach--that is, the isolation of a hereditary disease gene of unknown function, based on the determination of its chromosomal location in the human genome. The NF2 gene is homologous to a family of genes whose products, including moesin, ezrin, radixin and protein 4.1, appear to have an important role in bridging the cell membrane and the intracellular cytoskeletion. Mutation analyses have revealed that the NF2 tumour suppressor gene is frequently mutated not only in vestibular schwannomas and meningiomas from NF2 patients, but also in their sporadic counterparts, which represent approximately one third of all human brain tumours. Furthermore, malignant human tumours seemingly unrelated to the NF2 syndrome, such as malignant melanomas (derived from the neural crest) and malignant mesotheliomas (derived from pleural mesoderm), also frequently have mutations or deletions at the NF2 locus, suggesting a broader role of the NF2 gene in the initiation and progression of human neoplasms.

Chromosome Mapping↗