Neurofibromatosis type 2 appears to be a genetically homogeneous disease (original) (raw)
Related papers
Clinical and genetic patterns of neurofibromatosis 1 and 2
British Journal of Ophthalmology, 1993
General introduction to the neurofibromatoses The diseases traditionally known as neurofibromatosis have now been formally separated into two types: neurofibromatosis type 1 or NFl (the type described by von Recklinghausen) and neurofibromatosis type 2 or NF2 (a much rarer form).' It is now recognised that although they have overlapping features, including an inherited propensity to neurofibromas and tumours of the central nervous system, they are indeed separate diseases and map to different chromosomes-17 for 662 on June 13, 2020 by guest. Protected by copyright.
The parental origin of new mutations in neurofibromatosis 2
neurogenetics, 2000
from new mutations at the NF2 locus. Loss of heterozygosity (LOH) in tumor specimens due to deletions covering the normal NF2 allele can be used to infer the haplotypes surrounding underlying mutations and determine the allelic origin of new mutations. We studied 71 sporadic NF2 patients using both LOH and pedigree analysis and compared the parental origin of the new mutation with the underlying molecular change. In the 45 informative individuals, 31 mutations (69%) were of paternal and 14 (31%) were of maternal origin (Pp0.016). Comparison with corresponding constitutional mutations revealed no correlation between parental origin and the type or location of the mutations. However, in 4 of 6 patients with somatic mosaicism the NF2 mutation was of maternal origin. A slight parent of origin effect on severity of disease was found. Further clinical and molecular studies are needed to determine the basis of these unexpected observations.
Further genotype â phenotype correlations in neurofibromatosis 2
Clinical Genetics, 2010
Neurofibromatosis 2 (NF2) is caused by mutations in the NF2 gene predisposing carriers to develop nervous system tumours. Different NF2 mutations result in either loss/reduced protein function or gain of protein function (abnormally behaving mutant allele i.e. truncated protein potentially causing dominant negative effect). We present a comparison between the clinical presentations of patients with mutations that are predicted to produce truncated protein (nonsense/frameshift mutations) to those that results in loss of protein expression (large deletions) to elucidate further genotype-phenotype correlations in NF2. Patients with nonsense/frameshift mutations have a younger age of diagnosis and a higher prevalence/proportion of meningiomas (p = 0.002, p = 0.014), spinal tumours (p = 0.004, p = 0.004) and non-VIII cranial nerve tumours (p = 0.006, p = 0.003). We also found younger age of diagnosis of vestibular schwannomas (p = 0.007), higher mean numbers of cutaneous lesions (p = 0.003) and spinal tumours (p = 0.006) in these patients. With respect to NF2 symptoms, we found younger age of onset of hearing loss (p = 0.010), tinnitus (p = 0.002), paraesthesiae (p = 0.073), wasting and weakness (p = 0.001) and headaches (p = 0.049) in patients with nonsense/frameshift mutations. Our comparison shows, additional, new correlations between mutations in the NF2 gene and the NF2 disease phenotype, and this further confirms that nonsense/frameshift mutations are associated with more severe NF2 symptoms. Therefore patients with this class of NF2 mutation should be followed up closely.
Genetic Diagnosis of Neurofibromatosis Type 2.
2011
Introduction Neurofibromatosis type 2 is an autosomal dominant disease caused by mutations in the NF2 gene on 22q12.2. Its protein product, merlin, supposedly plays an important role in connecting membrane proteins with the cytoskeleton by coordinating growth-factor signalling. The most common mutations are truncating and splice site mutations, showing a genotype-phenotype correlation. A high rate of somatic mosaicism may account for the difficulty of molecular genetic diagnosis. The main clinical feature is bilateral vestibular schwannomas and multiple neural tumours. Furthermore patients present tinnitus, hearing loss and dysequilibrium, subcapsular cataracts and cutaneous manifestations. The management of the disease includes surgical removal and radiological staging. Objectives It was intended to develop a genetic testing protocol for patients with clinical criteria for this condition comprising sequence analysis and exon dosage study, allowing the observation of genotypephenotype correlations. Methodology Primers were designed to cover the entire coding region, flanking intronic sequences and 5' and 3' UTR. The obtained sequences were aligned with the reference sequence and checked against SNPs and documented mutations. Multiplex Ligation-dependent Probe Amplification was also performed covering the 17 exons and the gene promoter. Two newly diagnosed cases and one individual with an identified mutation along with his mother were studied. Results It was possible to validate our mutation screening procedure through the detection of a documented mutation in exon 11, although his mother had no identifiable mutations. In a patient with bilateral schwannomas was detected a novel mutation, being a nonsense frameshift insertion in exon 5. In another patient with several neural tumours it was impossible to identify any mutation. Conclusions The main purpose of this study was fulfilled despite the impossibility of drawing conclusions on genotype-phenotype correlation due to sample shortage. The importance of genetic testing in both lymphocyte and tumour DNA with sequencing and Multiplex Ligation-dependent Probe Amplification should not to be neglected.
PubMed, 2006
Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with a prevalence of about 1/3000. The clinical diagnosis of NF1 is based on the presence of two or more of the following criteria: six or more café au lait spots, >2 neurofibromas of any type or 1 plexiform neurofibroma, freckling in the axillary or inguinal region, optic glioma, a distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex with or without pseudoarthrosis, and a first degree relative with NF1. The disease has numerous complications. The pathogenesis is not clarified. The NF1 gene is a megagene (length of app. 350 kilobases of genomic DNA), localised on the long arm of the 17th chromosome at the position 17q11.2. The mutation rate for NF1-gene is high. The half of all cases of NF1 are from new mutations. The gene protein product - neurofibromin plays an important role in the tumorogenesis as a tumor-suppressor gene. Molecular genetic evaluation for the identification of disease-causing mutations is possible in cca 20% patients. The patient care is best done in specialised neurofibromatosis centers.
Genetic Linkage Analysis of Neurofibromatosis
Annals of the New York Academy of Sciences, 1986
This study represents a collaborative effort primarily between the National Cancer Institute and the University of California, Los Angeles. The goal of the study has been to map the gene or genes responsible for the classical form of neurofibromatosis (NF) using the standard gene markers. Samples have been obtained from many of the families for DNA polymorphism analysis, and those results are discussed elsewhere in this volume.' Key members of the families in the study have had physical examinations as well as blood drawn for the laboratory studies. The original data set consisted of 11 multigenerational families and 108 subjects? We are reporting 8 additional families
Neurofibromatosis type 2: Molecular and clinical analyses in Argentine sporadic and familial cases
Neuroscience Letters, 2010
Neurofibromatosis 2 is a familial syndrome characterized by the development of schwannomas, meningiomas and ependymomas. Most of them are benign however, their location in the nervous system has harmful effects on important cranial and spinal structures. These tumors are developed as the outcome of NF2 gene (22q12) inactivation. The NF2 protein, merlin or schwannomin belongs to the Ezrin, Radixin, Moesin (ERM) family involved in the cytoskeletal network and has a tumor suppressor function. Inactivating mutations occur as "de novo" (more frequently) or as inherited, and most of them are frameshift or nonsense. Our aim is to study NF2 gene alterations in Argentine patients and relate them to clinical features. 10 families and 29 single patients were analyzed for: 1) at-risk haplotype by STRsegregation analysis and 2) NF2 gene mutations by SSCP/heteroduplex/sequencing. The at-risk haplotype was uncovered in 8 families and mutations were identified in 5 patients. The molecular data are in full agreement with the clinical features supporting previous reports. The obtained results were important for the detection of mutation-carrying relatives and exclusion of other individuals from risk.
NF2 gene in neurofibromatosis type 2 patients
Human Molecular Genetics, 1998
Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder that predisposes to nervous system tumors. The schwannomin (also termed merlin) protein encoded by the NF2 gene shows a close relationship to the family of cytoskeleton-to-membrane proteins linkers ERM (ezrin-radixin-moesin proteins). Even though penetrance of the disease is >95% and no genetic heterogeneity has been described, point mutations in the NF2 gene have been observed in only 34-66% of the screened NF2 patients, depending on the series. In order to generate tools that would enable an exhaustive alteration screening for the NF2 gene, we have deduced its entire genomic sequence. This knowledge has provided the delineation of a mutation screening strategy which, when applied to a series of 19 NF2 patients, has revealed a high recurrence of large deletions in the gene and has raised the efficiency of mutation detection in NF2 patients to 84% of the cases in this series. The remaining three patients who express two functional NF2 alleles are all sporadic cases, an observation compatible with the presence of mosaicism for NF2 mutation.
A point mutation associated with a severe phenotype of neurofibromatosis 2
Annals of Neurology, 1996
Neurofibromatosis 2 (NF2) is an autosomal dominant disease characterized by bilateral vestibular schwannomas and other nonmalignant tumors of the brain, spinal cord, and peripheral nerves. Although the average age of onset of NF2 is 20 years, some individuals may become symptomatic in childhood. We studied 5 unrelated NF2 patients who became symptomatic before age 13. All 5 had multiple tumors in addition to vestibular schwannoma, and none had a positive family history. Sequence analysis of the NF2 gene revealed identical nonsense mutation of exon 6 in 3 patients. Because this mutation destroys a restriction enzyme recognition site, genomic DNA from the 2 other children was directly tested for this change and identical alterations were detected. Although the work of our laboratory and others has not, in general, detected identical mutations in unrelated patients, this mutation seems to occur particularly frequently in the pediatric population and thus may be associated with an especially severe phenotype. Restriction analysis in children with NF2 may be a cost effective way of identifying their mutation. Further work is needed to characterize the effects of this change on the NF2 protein product and its relationship to this severe phenotype.