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Biomedical subjects

M E Baser

Publications and source records attributed to M E Baser.

At least 37 records · Page 2Linked to original sources
PubMed2000

Neurofibromatosis 2 phenotypes and germ-line NF2 mutations determined by an RNA mismatch method and loss of heterozygosity analysis in NF2 schwannomas.

We used a novel RNase cleavage assay (NIRCA) to screen for neurofibromatosis 2 (NF2) mutations in NF2 schwannomas. Mutations were found in tumors in 16 of 20 patients. Eleven patients (55%) had loss of heterozygosity or loss of one allele, indicating that the mutation was a germ-line mutation. The phenotypes of these patients were consistent with previous NF2 genotype-phenotype correlation studies: patients with nonsense mutations had severe phenotypes, whereas those with splice-site or missense mutations had milder and variable phenotypes. These results confirm the utility of NIRCA as a rapid and convenient method for screening for germ-line NF2 mutations.

Adolescent↗
PubMed2000

Detection of novel NF2 mutations by an RNA mismatch cleavage method.

Mutations in the neurofibromatosis type 2 gene (NF2) cause benign nervous system tumors. Common methods for detecting NF2 mutations (such as single stranded conformational polymorphism analysis and denaturing gradient gel electrophoresis) are laborious and time-consuming. We adapted and improved a commercial assay, the Non-Isotopic RNase Cleavage Assay (NIRCAtrade mark, Ambion, Austin, TX) for rapid, non-isotopic, high-sensitivity screening for NF2 mutations in tumors. We improved the assay by: 1) extending the typical NIRCAtrade mark template size of < 500 bp to 1.3 kb without decreasing detection efficiency; 2) modifying the transcription step of the original protocol so that transcription of PCR products was increased by up to 50%; 3) optimizing the combination of cleavage enzymes and reaction time. With these modifications, mutations were found in 15 of 20 patients (75%) using NIRCAtrade mark. Seven of the point mutations detected (two nonsense, two missense, and three splice-site) are novel. All mutations were confirmed by direct sequencing and no mutations were found using direct sequencing in patients that were negative by NIRCAtrade mark. The 75% NF2 mutation detection rate using this design is similar to detection rates in tumors using other mutation detection methods.

Amino Acid Substitution↗
PubMed2000

Neurofibromatosis type 2.

Neurofibromatosis type 2 is an often devastating autosomal dominant disorder which, until relatively recently, was confused with its more common namesake neurofibromatosis type 1. Subjects who inherit a mutated allele of the NF2 gene inevitably develop schwannomas, affecting particularly the superior vestibular branch of the 8th cranial nerve, usually bilaterally. Meningiomas and other benign central nervous system tumours such as ependymomas are other common features. Much of the morbidity from these tumours results from their treatment. It is now possible to identify the NF2 mutation in most families, although about 20% of apparently sporadic cases are actually mosaic for their mutation. As a classical tumour suppressor, inactivation of the NF2 gene product, merlin/schwannomin, leads to the development of both NF2 associated and sporadic tumours. Merlin/schwannomin associates with proteins at the cell cytoskeleton near the plasma membrane and it inhibits cell proliferation, adhesion, and migration.

Humans↗
PubMed1997

The ocular presentation of neurofibromatosis 2.

Neurofibromatosis 2 (NF2) is an inherited disorder characterised primarily by bilateral vestibular schwannomas and other central nervous system tumours. Individuals with NF2 also have early onset cortical and posterior subcapsular or capsular cataract and other ocular abnormalities, such as retinal hamartomas. Although their diagnostic significance is rarely appreciated, the ocular manifestations are often the first sign of disease. We describe 5 cases that illustrate the diverse ocular manifestations of NF2.

Adolescent↗
PubMed1997

Immunohistochemical detection of schwannomin and neurofibromin in vestibular schwannomas, ependymomas and meningiomas.

In addition to schwannomas, patients with neurofibromatosis type 2 (NF2) frequently develop meningiomas and occasionally, ependymomas. Using DNA and protein analyses, we have shown NF2 gene mutations and lack of the gene product schwannomin in 29 schwannomas, 10 meningiomas, and in 7 ependymomas. We have raised antibodies (ABs) to peptides from the C-terminal (5990-AB) and N-terminal (5991-AB) domains of schwannomin. The ABs specifically detected a 65 kDa protein in a Schwann cell line and recognized schwannomin in the cytoplasm of Schwann cells (SCH), perineurial cells, and vestibular ganglion neurons. None of the 29 schwannomas were stained by the 5990-AB. Only 4 schwannomas were stained by the 5991-AB, indicating that most truncated schwannomins were unstable or not expressed in schwannomas. Seven of 10 meningiomas, including 3 tumors from NF2 patients, were not stained by either 5990-AB or 5991-AB. Only 2 of 7 ependymomas lacked schwannomin. Complete lack of schwannomin in these tumors supports a tumor suppressor function for schwannomin in some meningiomas and ependymomas. All tumors showed staining with an antibody to a C-terminal peptide of neurofibromin, confirming that full-length neurofibromin is present in these vestibular schwannomas, meningiomas, and ependymomas. The presence of schwannomin in some meningiomas and in the majority of ependymomas indicates that additional genes are likely to play a role in tumorigenesis of these tumors.

Brain Neoplasms↗
PubMed1997

Skin abnormalities in neurofibromatosis 2.

OBJECTIVE: To determine the prevalence, distribution, and histopathological conditions of skin abnormalities in neurofibromatosis 2 (NF2). DESIGN: Case series. SETTING: Hospital neurology department. PATIENTS: Consecutive sample of 88 patients with NF2 referred through workshops and publications, genetic counseling, and referral from neurosurgical departments; 81 patients met the National Institutes of Health, Bethesda, Md, NF2 diagnostic criteria and the diagnosis was established by mutation or segregation analyses in 7 patients. MAIN OUTCOME MEASURES: Prevalence, distribution, and type of skin abnormalities; histopathological features of 29 skin tumors selected primarily for medical indications. RESULTS: Fifty-two patients (59.1%) had 458 skin tumors, which were the first presenting sign in 27.3% of patients and usually appeared as flat dysplastic tumors or subcutaneous spherical nodular tumors of the peripheral nerves, on the limbs and trunk. Although 29 patients (33.0%) had café au lait spots, only 2 patients had as many as 6 spots. compared with patients with milder disease, patients with more severe disease had a significantly greater prevalence of skin tumors (24.0% and 71.0%, P < .001), more than 10 skin tumors (0.0% and 27.4%, P = .004), flat dysplastic skin tumors (8.0% and 54.8%, P < .001), and subcutaneous spherical nodular tumors (24.0% and 58.1%, P = .004). The histologically analyzed tumors were predominantly schwannomas, but 5 were neurofibromas and 2 were mixed tumors. CONCLUSIONS: The prevalence of some skin tumor types in NF2 is high and varies with disease severity, and schwannomas predominate in sampled tumors. The occurrence of neurofibromas is surprising, but could be explained by an interaction between neurofibromin and the NF2 gene product in regulating the ras proto-oncogene.

Adolescent↗
PubMed1996

Phenotypic variability in monozygotic twins with neurofibromatosis 2.

Mutations in the neurofibromatosis 2 (NF2) tumor suppressor gene on chromosome 22q12 cause a clinically variable autosomal dominant syndrome characterized by bilateral vestibular schwannomas (VSs), other nervous system tumors, and early onset lenticular cataracts. We studied three pairs of monozygotic (MZ) twins with NF2, all with bilateral VSs, to separate genetic from nongenetic causes of clinical variability. The evaluation included gadolinium-enhanced high-resolution magnetic resonance imaging of the head and spine, neuro-ophthalmic examination with slit lamp, physical examination, and zygosity testing with microsatellite markers. Each MZ pair was concordant for general phenotypic subtype (mild or severe) and often for the affected organ systems. However, the MZ pairs were discordant for some features of disease presentation or progression. For example, all three pairs were discordant for presence or type of associated cranial tumors. We hypothesize that phenotypic differences between NF2 MZ twins are at least partly due to stochastic processes, such as the loss of the second NF2 allele or alleles of other genes.

Adult↗
PubMed1996

Identification of three neurofibromatosis type 2 (NF2) gene mutations in vestibular schwannomas.

Vestibular schwannomas (VSs) are common benign tumors of Schwann cell origin and are frequently found in patients with neurofibromatosis type 2 (NF2). We analyzed 15 sporadic VSs for mutations in the tumors, two of which contained loss of heterozygosity (LOH). One of the tumors contained a novel mutation, a 19-bp deletion in exon 4. The two other tumors contained an identical mutation, a complete exon 4 deletion. The exon 4 deletion represents the second most frequently reported mutation of the NF2 gene in VSs.

Chromosome Deletion↗
PubMed1996

Phenotypic variability in two families with novel splice-site and frameshift NF2 mutations.

Neurofibromatosis 2 (NF2) is a clinically variable autosomal dominant disorder, caused by mutations in the NF2 tumor suppressor gene on chromosome 22q12, that predisposes to nervous system tumors and ocular abnormalities. To assess intrafamilial phenotypic variability, we performed mutation analysis and clinical assessment on two multigeneration NF2 families with five patients and seven asymptomatic first-degree relatives of patients. One family had a point mutation of agCC --> ggCC at position 1447-2 at the exon 13/14 boundary predicted to lead to an altered splice acceptor sequence and exon deletion. The other family had an insertion of 2 base pairs (TC) at position 761 in exon 8, leading to a frameshift. Both mild and severe phenotypes occurred in each family, indicating that phenotypic variability in NF2 can be caused by factors other than NF2 mutations. Genetic counseling of NF2 families should include the possibility that presymptomatic NF2 mutation carriers can develop a different phenotype than previously diagnosed patients.

Adolescent↗