Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “NEUROFIBROMATOSIS”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,081 records · Page 60Linked to original sources
PubMed2004

Screening 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene.

A total of 500 unselected unrelated neurofibromatosis 1 (NF1) patients were screened for deletions of the NF1 gene. After excluding 67 patients with known intragenic NF1 mutations, the remaining 433 were genotyped using six intragenic and one distal microsatellite marker for the NF1 gene. A total of 28 patients were hemi- or homozygous for all seven markers and were thus considered as candidates for NF1 deletion with a calculated probability of 99.99%. Metaphase or interphase cells were available from 23 of these 28 individuals for molecular cytogenetics. Fluorescence in situ hybridization (FISH) confirmed an NF1 deletion in 22 (96%) of the 23 patients. Thus, a constitutional deletion of the NF1 gene is responsible for the disease phenotype in at least 4.4% of the 500 unselected NF1 patients. Genotyping using multiple microsatellite markers may provide a simple, inexpensive, and efficient strategy for screening deletions of the NF1 gene, and can as well be applied for other large genes.

Female↗
PubMed1995

Methods for rapid detection of a recurrent nonsense mutation and documentation of phenotypic features in neurofibromatosis type 1 patients.

We have developed a rapid screening method to detect a recurrent mutation in the neurofibromatosis type 1 gene. Using gene amplification and hybridization with allele-specific oligonucleotides, we screened 97 unrelated affected individuals for the recurrent C-->T substitution in codon 1947. The mutation was detected in 1 patient and found to cosegregate with the disease phenotype in the patient's family. Although the estimated prevalence of this mutation is low, rapid screening of different patient cohorts would identify multiple individuals carrying the same mutation. Such data would provide the first opportunity for examining correlations between phenotypic characteristics and molecular genotype and would allow clinicians to offer early diagnosis and prenatal screening to affected families. A format for the comparison of phenotypic features in other settings is presented.

Base Sequence↗
PubMed2005

Identification of genetic aberrations on chromosome 22 outside the NF2 locus in schwannomatosis and neurofibromatosis type 2.

Schwannomatosis is characterized by multiple peripheral and cranial nerve schwannomas that occur in the absence of bilateral 8th cranial nerve schwannomas. The latter is the main diagnostic criterion of neurofibromatosis type 2 (NF2), which is a related but distinct disorder. The genetic factors underlying the differences between schwannomatosis and NF2 are poorly understood, although available evidence implicates chromosome 22 as the primary location of the gene(s) of interest. To investigate this, we comprehensively profiled the DNA copy number in samples from sporadic and familial schwannomatosis, NF2, and a large cohort of normal controls. Using a tiling-path chromosome 22 genomic array, we identified two candidate regions of copy number variation, which were further characterized by a PCR-based array with higher resolution. The latter approach allows the detection of minute alterations in total genomic DNA, with as little as 1.5 kb per measurement point of nonredundant sequence on the array. In DNA derived from peripheral blood from a schwannomatosis patient and a sporadic schwannoma sample, we detected rearrangements of the immunoglobulin lambda (IGL) locus, which is unlikely to be due to a B-cell specific somatic recombination of IGL. Analysis of normal controls indicated that these IGL rearrangements were restricted to schwannomatosis/schwannoma samples. In the second candidate region spanning GSTT1 and CABIN1 genes, we observed a frequent copy number polymorphism at the GSTT1 locus. We further describe missense mutations in the CABIN1 gene that are specific to samples from schwannomatosis and NF2 and make this gene a plausible candidate for contributing to the pathogenesis of these disorders.

Adaptor Proteins, Signal Transducing↗
PubMed2002

NF1 mutations in neurofibromatosis 1 patients with plexiform neurofibromas.

Neurofibromatosis 1 (NF1) is an autosomal dominant disorder caused by genetic alterations of the NF1 gene on 17q11.2. About 30% of NF1 patients develop plexiform neurofibromas (PNFs), which often cause severe clinical deficits. To determine whether there is a certain genotype underlying PNFs or subtypes of PNFs, we screened 42 NF1 patients from 41 families with PNFs for mutations in the NF1 gene. In 33 out of the 41 (80%) unrelated patients NF1 mutations were found, 24 are novel while the other 9 have been described in previous studies. The 33 mutations included 23 nonsense and frameshift, six splice and four missense mutations. The tumors in these patients had various sizes and features/growth characteristics. No correlation was found between the type or location of the NF1 mutations and size, location or feature of the PNFs, suggesting that many types of NF1 mutations can lead to development of PNFs.

Adolescent↗
PubMed2003

Constitutional NF1 mutations in neurofibromatosis 1 patients with malignant peripheral nerve sheath tumors.

Neurofibromatosis type 1 (NF1) patients have 10% of lifetime risk for developing malignant peripheral nerve sheath tumors (MPNST), one of the most aggressive cancers. We examined the spectrum of constitutional NF1 mutations among 24 NF1 patients with MPNST. We found mutations in 18 patients: four megabase deletions involving the NF1 gene, 13 truncating mutations, and only one missense mutation. One deletion included both exonic and intronic sequences. No typical splicing mutation was found. Five of these mutations were novel: c.3686delA, c.197_204+9del17, c.3044T>C (p.Leu1015Pro), c.2497delT, and c.6020_6027dup. The proportion of megabase deletions of the NF1 gene found in patients with MPNST (17%=4/24) was higher than that in a group of unselected NF1 patients (5.4%=27/500).

Adolescent↗
PubMed2006

Functional splicing assay shows a pathogenic intronic mutation in neurofibromatosis type 1 (NF1) due to intronic sequence exonization.

Genomic variations with no apparent effect ("neutral polymorphisms") may have a significant effect on splicing. The effect of this type of mutation is difficult to spot, unless a functional assay is undertaken. In our study, DNA sequencing of a patient with clinically defined neurofibromatosis type 1 (NF1) showed only a single polymorphism in intron 30 due to an A>G transition 279 nucleotides from the 3' splice site. Using a minigene splicing assay we conclusively show that this change produces a cryptic exon with a 3' SS defined by the nucleotide change and the unexpected activation of a very weak 5'SS. Further site directed mutagenesis studies aimed at identifying the signals involved in the cryptic exon inclusion were carried out. Interestingly we find that particular characteristics of the cryptic 5' SS are essential for its inclusion. Significantly an additional single nucleotide change disrupting the cryptic 5'ss consensus sequence rescues the effect of the pathogenetic mutation resulting in normal splicing.

Base Sequence↗
PubMed2006

Identification of forty-five novel and twenty-three known NF1 mutations in Chinese patients with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1), characterized by skin neurofibromas and an excess of café-au-lait spots, is due to mutations in the neurofibromin (NF1) gene. Identifying the genetic defect in individuals with the disease represents a significant challenge because the gene is extremely large with a high incidence of sporadic mutations across the entire gene ranging from single nucleotide substitutes to large deletions. In the present study, we have used a combination of techniques (heteroduplex analysis, sequencing, loss of heterozygosity and quantification of gene dosage) to define the genetic defect in 68 individuals from a cohort of 107 NF1 Taiwanese patients of Chinese origin. Fifty-eight were initially identified using heteroduplex analytical techniques and confirmed by sequence analysis. A further five were identified by direct sequence analysis alone. The reminders were shown to carry large deletions in the NF1 gene by demonstrating loss of heterozygosity that was confirmed by gene dosage measurements using quantitative-PCR techniques. Mis-sense, non-sense, frame-shift or splice-site mutations were identified across the entire gene of which the majority (45/68) were novel in nature. The detection rate with the various analytical techniques and the types of mutation detected are consistent with published data involving both individuals and large cohort studies from other ethnic backgrounds.

Adolescent↗
PubMed2002

Loss of heterozygosity for the NF2 gene in retinal and optic nerve lesions of patients with neurofibromatosis 2.

Individuals affected with the neurofibromatosis 2 (NF2) cancer predisposition syndrome develop specific ocular lesions. To determine whether these lesions result from altered NF2 gene expression, microdissection and PCR were used to investigate 40 ocular lesions from seven eyes of four NF2 patients for LOH, with markers that flank the NF2 gene on chromosome 22q. NF2 protein (merlin) expression was also evaluated in these lesions, using immunohistochemistry. Retinal hamartoma was observed in all seven eyes, including one with combined pigment epithelial and retinal hamartoma (CPERH). Retinal tufts were present in four eyes (three patients), retinal dysplasia in two eyes (two patients), optic nerve neurofibroma in one eye, iris naevoid hyperplasia in two eyes (two patients) and pseudophakia in all eyes. Markers were informative in three patients (six eyes from three unrelated families). One patient was non-informative due to prolonged decalcification. All retinal and optic nerve, but not iris lesions, demonstrated consistent LOH for the NF2 gene. Merlin was not expressed in the retina, optic nerve, or iris lesions. These results suggest that inactivation of the NF2 gene is associated with the formation of a variety of retinal and optic nerve lesions in NF2 patients.

Adolescent↗
PubMed2004

Absence of c-kit gene mutations in gastrointestinal stromal tumours from neurofibromatosis type 1 patients.

Most sporadic gastrointestinal stromal tumours (GISTs) have somatic c-kit gene mutations that are considered to be causal. Neurofibromatosis type 1 (NF1) is caused by mutations of the NF1 gene and NF1 patients have an increased risk of developing GISTs. Since most neoplasms are considered to develop as a result of the combination of several gene mutations, these findings suggest that GISTs from NF1 patients might have somatic c-kit gene mutations and that sporadic GISTs from non-NF1 patients might have somatic NF1 gene mutations. The present study analysed 29 GISTs from seven NF1 patients for c-kit gene mutations and ten sporadic GISTs from ten non-NF1 patients for NF1 mutations. Exons 9, 11, 13, and 17 of the c-kit gene were amplified and directly sequenced after the extraction of genomic DNA from wax-embedded tissues from 26 GISTs from five NF1 patients. The whole coding region of the c-kit cDNA and the whole coding region of the NF1 cDNA were amplified and directly sequenced after RNA extraction and cDNA synthesis in three fresh GIST tissues from two NF1 patients and ten fresh GIST tissues from ten non-NF1 patients. Of the ten sporadic GISTs, eight had heterozygous mutations at exon 11, and one at exon 9, of c-kit. Heterozygous NF1 gene mutations were detected in GISTs from the two NF1 patients from whom fresh tissues were available. None of the 29 GISTs derived from NF1 patients had detectable c-kit gene mutations and none of the ten GISTs derived from non-NF1 patients had detectable NF1 mutations. These results suggest that the pathogenesis of GISTs in NF1 patients is different from that in non-NF1 patients.

Base Sequence↗
PubMed2002

First application of preimplantation genetic diagnosis to neurofibromatosis type 2 (NF2).

Neurofibromatosis type 2 (NF2) is a dominantly inherited cancer predisposition syndrome that is caused bymutations in the NF2 gene. We report here the first clinical preimplantation genetic diagnosis (PGD) forNF2. A protocol was developed to simultaneously amplify the mutation and a single nucleotide polymorphism (SNP) located within the gene. The mutation and polymorphism were analysed by simultaneous fluorescent single-strand conformation polymorphism (SSCP) on an automated DNA sequencer. The mutation, carried by the male partner, was a single base pair substitution affecting a splice site in intron 4 of the gene. The female partner was infertile due to polycystic ovary syndrome and would require IVF to conceive. The couple was found to be informative at a linked intragenic SNP situated in the 5' untranslated region of the gene. The SNP was included in the assay to reduce the risk of misdiagnosis due to allele dropout (ADO). The couple underwent three cycles of treatment during which a total of 43 blastomeres were biopsied from 31 embryos. Amplification at both loci was obtained in 35 cells (81%). A total of five embryos were transferred, two in the first cycle, two in the second and one in the third. No pregnancy ensued. The results of the diagnoses indicated that, in this couple, the inheritance of the mutation may be non-Mendelian. Out of a total of 32 embryos tested only four were found not to carry the mutation. The reasons for this apparent skew remain unknown.

Adult↗
PubMed1993

Neurofibromatosis 1 mRNA expression in blood vessels.

Vascular hypertrophic lesions occur in neurofibromatosis type 1 (NF1). The role of the gene which causes NF1 in the growth and development of blood vessels is not known. mRNA expression of the NF1 gene was studied in blood vessels in the transition between intact and culture and in quiescent and proliferative conditions. The expression and alternative splicing pattern of the catalytic domain of NF1 consistently changed in proliferating cells, supporting a role for this gene in the regulation of growth of vascular smooth muscle and the vascular pathology in NF1.

Animals↗
PubMed1995

Reduced neurofibromin content but normal GAP activity in a patient with neurofibromatosis type 1 caused by a five base pair duplication in exon 12b of the NF1 gene.

We screened a total of 87 unrelated patients with neurofibromatosis type 1 (NF1) for mutations in exons 11, 12a, and 12b of the NF1 gene using temperature gradient gel electrophoresis (TGGE). A novel mutation (1998insCCTCT) was found in exon 12b. The 5-bp duplication comprising nucleotides 1994 to 1998 is predicted to lead to a truncated protein product lacking three quarters of its C-terminal sequence including the entire GTPase-activating protein-(GAP)-related domain. This mutation is associated with a reduction by 50% of the detectable amount of neurofibromin found in this patient. Despite the reduced level of neurofibromin cellular GAP activity was normal, which suggests that defects in other functions of the neurofibromin molecule may be important in the pathogenesis of NF1.

Base Composition↗
PubMed1997

Evidence for the presence of the second allele of the neurofibromatosis type 1 gene in melanocytes derived from café au laitmacules of NF1 patients.

Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited disorder caused by mutations in the NF1 gene on 17q11.2. Melanocytes cultured from cafe au lait macules (CALM) of patients with NF1 were analysed for loss of heterozygosity (LOH) at the NF1 locus using a 3'-flanking and four intragenic markers. None of the informative samples showed LOH. In addition, the X-inactivation pattern of melanocytes from CALM (n = 4) and from the unaffected skin of the patients (n = 3) suggests a monoclonal origin of the cells isolated from skin biopsies up to 2 cm2 in size.

Cells, Cultured↗
PubMed1993

Detection of a neurofibromatosis type I (NF1) homologous sequence by PCR: implications for the diagnosis and screening of genetic diseases.

The neurofibromatosis type I (NF1) gene was extensively screened for mutations using single strand conformation polymorphism (SSCP) technology. During the analysis of the NF1 GAP-related domain, electrophoretically abnormal fragments were detected. Direct sequencing of these fragments allowed us to identify the presence of a NF1 highly homologous sequence (NF1HHS). A detailed analysis of a hybrid panel located this sequence on chromosome 15q24-->qter. An accurate search through several data banks demonstrated that this sequence is a new NF1 homologue. This report shows how it is possible to find homologous sequences at random, and subsequently to make wrong interpretations.

Animals↗
PubMed1995

Single-cell PCR performed with neurofibroma Schwann cells reveals the presence of both alleles of the neurofibromatosis type 1 (NF1) gene.

It is commonly held that Schwann cells (SC) are the progenitor cells of benign neurofibromas. To test for loss of heterozygosity (LOH) at the neurofibromatosis 1 (NF1) gene locus, three intragenic polymorphic markers were analyzed after polymerase chain reaction amplification, starting from 98 single SC isolated from primary cultures of neurofibromas, of five informative NF1 patients. The patterns obtained did not provide evidence for LOH at the NF1 gene. LOH by nondisjunction, large deletions, or somatic recombination in SC seems not to be the mechanism of generation of neurofibromas.

Alleles↗
PubMed1991

Recurrence of a nonsense mutation in the NF1 gene causing classical neurofibromatosis type 1.

The gene responsible for von Recklinghausen neurofibromatosis (NF1) has recently been identified, and several point mutations and deletions have been described. The availability of intron-exon boundaries of several exons of the NF1 gene facilitates the search for mutations in affected patients. We have analysed 38 patients for mutations in exon 4 of the NF1 gene, and found one patient with a C----T transition at base position 1087 of the cDNA, changing an arginine codon to a stop codon, at amino acid position 365. Sequencing of other members of the family, including both parents, did not show the mutation, confirming that this mutation is responsible for this sporadic NF1 case. As the mutation described here was previously identified in an independent case by others, this case represents a recurrence of this mutation and suggests that codon 365 might be a hot spot for mutations in the NF1 gene. Thus, a specific search for this mutation should be performed when studying NF1 sporadic or familiar cases for genetic analysis.

Amino Acid Sequence↗
PubMed1995

A 163-bp deletion in the neurofibromatosis 2 (NF2) gene associated with variant phenotypes [corrected].

We have analyzed cDNA from a 46-year-old atypical neurofibromatosis type 2 (NF2) patient who had lumbar tumors, cataract and schwannomas of peripheral nerves but no vestibular schwannomas, and have identified a 163-bp deletion in the NF2 transcript. The deletion is predicted to remove 54, alter 15 and add four extra amino acids at the C-terminus of the NF2-gene product. The same deletion was found in her two daughters and in a 3-year-old grandson. Bilateral vestibular schwannomas were detected in the two asymptomatic daughters, whereas no abnormality was found in the grandson.

Adult↗
PubMed1992

Analysis of segregation and expression of an identified mutation at the neurofibromatosis type 1 locus.

A previously identified complex mutation, affecting exon 28 of the neurofibromatosis type 1 gene, was employed for the analysis of the expression pattern in primary cultures of neurofibroma cells and melanocytes from a café-au-lait macule of the patient, respectively. Reverse transcription and subsequent polymerase chain reaction amplification of the segment carrying the mutation revealed that both alleles were expressed in both cell types analysed, thus excluding loss of heterozygosity in this particular instance. Segregation of the alleles of the intragenic Alu sequence length-polymorphism disclosed the paternal origin of the mutated allele. Detection of this mutation was also used for presymptomatic direct DNA diagnosis in the younger child of the patient.

Adult↗