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PubMed1998

Constitutional and mosaic large NF1 gene deletions in neurofibromatosis type 1.

A set of neurofibromatosis type 1 (NF1) patients was screened for large NF1 gene deletions by comparing patient and parent genotypes at 10 intragenic polymorphic loci. Of 67 patient/parent sets (47 new mutation patients and 20 familial cases), five (7.5%) showed loss of heterozygosity (LOH), indicative of NF1 gene deletion. These five patients did not have severe NF1 manifestations, mental retardation, or dysmorphic features, in contrast to previous reports of large NF1 deletions. All five deletions were de novo and occurred on the maternal chromosome. However, two patients showed partial LOH, consistent with somatic mosaicism for the deletion, suggesting that mosaicism may be more frequent in NF1 than previously recognised (and may have bearing on clinical severity). We suggest that large NF1 deletions (1) are not always associated with unusual clinical features, (2) tend to occur more frequently on maternal alleles, and (3) are an important mechanism for constitutional and somatic mutations in NF1 patients.

Adult↗

PubMed2006

Cognitive dysfunction in NF1 knock-out mice may result from altered vesicular trafficking of APP/DRD3 complex.

BACKGROUND: It has been estimated that more than 50% of patients with Neurofibromatosis type 1 (NF1) have neurobehavioral impairments which include attention deficit/hyperactivity disorder, visual/spatial learning disabilities, and a myriad of other cognitive developmental problems. The biological mechanisms by which NF1 gene mutations lead to such cognitive deficits are not well understood, although excessive Ras signaling and increased GABA mediated inhibition have been implicated. It is proposed that the cognitive deficits in NF1 are the result of dysfunctional cellular trafficking and localization of molecules downstream of the primary gene defect. RESULTS: To elucidate genes involved in the pathogenic process, gene expression analysis was performed comparing the expression profiles in various brain regions for control and Nf1+/- heterozygous mice. Gene expression analysis was performed for hippocampal samples dissected from postnatal day 10, 15, and 20 mice utilizing the Affymetrix Mouse Genome chip (Murine 430 2.0). Analysis of expression profiles between Nf1+/- and wild-type animals was focused on the hippocampus because of previous studies demonstrating alterations in hippocampal LTP in the Nf1+/- mice, and the region's importance in visual/spatial learning. Network analysis identified links between neurofibromin and kinesin genes, which were down regulated in the Nf1+/- mice at postnatal days 15 and 20. CONCLUSION: Through this analysis, it is proposed that neurofibromin forms a binding complex with amyloid precursor protein (APP) and through filamin proteins interacts with a dopamine receptor (Drd3). Though the effects of these interactions are not yet known, this information may provide novel ideas about the pathogenesis of cognitive defects in NF1 and may facilitate the development of novel targeted therapeutic interventions.

Amyloid beta-Protein Precursor↗

PubMed1991

Differential expression of two types of the neurofibromatosis type 1 (NF1) gene transcripts related to neuronal differentiation.

A 360 residue region encoded by the neurofibromatosis type 1 (NF1) gene shows significant homology to the catalytic domains of both mammalian GTPase-activating proteins (GAP) and yeast IRA proteins. This GAP-related domain of the NF1 gene (NF1-GRD), like the GAP and IRA protein, has been reported to mediate hydrolysis of Ras-bound GTP to GDP, resulting in inactivation of Ras protein. In the present study, we identified two different types of NF1-GRD cDNA. One (type I) is identical to the previously reported sequence, and the other (type II) contained an additional 63 bp insertion that encodes for a region of 21 amino acids in the center of the NF1-GRD molecule. Alternative splicing is the most likely mechanism by which these two types of transcripts arise. Our observations reveal that the type I transcript is predominantly expressed in undifferentiated cells, whereas the type II transcript predominates in differentiated cells. Furthermore, the expression pattern of type I and type II NF1-GRD mRNA immediately changed in SH-SY5Y neuroblastoma cells when neuronal differentiation programs were induced by retinoic acid treatment. We propose that the differential expression of type I and type II NF1-GRD transcripts might be an 'on/off' switch that regulates the catalytic activity of the NF1 gene product, which plays an important role in the regulation of neuronal differentiation.

Amino Acid Sequence↗

PubMed1989

A refined genetic map of the region of chromosome 17 surrounding the von Recklinghausen neurofibromatosis (NF1) gene.

The von Recklinghausen neurofibromatosis (NF1) gene has been mapped to the pericentromeric region of chromosome 17. We conducted linkage analyses of NF1 by using 10 polymorphic DNA markers from this chromosomal region. We ascertained 20 American Caucasian NF1 families (163 individuals, 98 NF1 affected) in Michigan and Ohio and also studied a large family ascertained primarily in North Carolina. The following markers were used in this study: HHH202, TH17.19, D17Z1, ERBA1, EW203, EW206, EW207, EW301, CRI-L581, and CRI-L946. NF1 did not recombine with either TH17.19 or HHH202 in any of the informative meioses surveyed (maximum lod scores of 17.04 and 7.21, respectively, at a recombination fraction of .00), indicating that these markers map very close to the NF1 gene. We also report evidence of three instances of recombination between NF1 and the centromeric marker D17Z1 (maximum lod score of 13.43 at a recombination fraction of .04), as well as two crossovers between pairs of marker loci. We find no evidence of locus heterogeneity, and our results support the localization of the NF1 gene to proximal chromosome 17q.

Chromosome Mapping↗

PubMed1993

The GTPase-activating NF1 fragment of 91 amino acids reverses v-Ha-Ras-induced malignant phenotype.

The human neurofibromatosis type 1 gene encodes a Ras GAP (GTPase-activating protein) of 2818 amino acids called NF1. This GAP contains a domain of 338 amino acids (residues 1194-1531) called NF1-GRD, which shares 26% sequence identity with the C-terminal domain (GAP1C, residues 709-1044) of another Ras GAP called GAP1. Both NF1-GRD and GAP1C activate normal Ras GTPases but not oncogenic mutants such as v-Ha-Ras. Any attempt to reverse the v-Ha-Ras-induced malignant transformation by the GAP1C has, so far, been unsuccessful. However, we have found that when the NF1-GRD is overexpressed in v-Ha-Ras-transformed NIH/3T3 cells, it greatly reduces their ability to form colonies in a soft agar, the property tightly associated with their malignancy. This is, so far, the first demonstration that a Ras-binding protein can act as a potent antagonist of the oncogenic Ras mutants in mammalian cells. In an attempt to further screen the smallest anti-oncogenic fragment derived from the NF1-GRD, we have prepared a series of its deletion mutants and examined their interaction with Ras first by monitoring their GAP activity (ability to activate the normal Ras GTPase). The deletion analysis has revealed that the N-terminal 247 amino acids (residues 1194-1440) of NF1-GRD are not required for its GAP activity, suggesting that its remaining domain of 91 amino acids (NF91, residues 1441-1531) is sufficient to bind the v-Ha-Ras, although its GAP activity is 20 times lower than the NF1-GRD. The NF91 is indeed able to reverse the v-Ha-Ras-induced malignant transformation as the NF1-GRD. The NF91 is, so far, the smallest among the tumor suppressor proteins that show the anti-v-Ha-Ras action in vivo. Thus, the NF91 appears to be a good starting material from which a smaller and more potent v-Ha-Ras antagonist could be devised to be used as a potential cure for the human cancers caused by the Ras mutants.

3T3 Cells↗

PubMed2000

Associations of clinical features in neurofibromatosis 1 (NF1).

Neurofibromatosis 1 (NF1), an autosomal dominant disease, exhibits extreme clinical variability. This variability greatly increases the burden for affected families and impairs our ability to understand the pathogenesis of NF1. Recognition of heterogeneity within a disease may provide important pathogenic insights, therefore we tested clinical data from three large sets of NF1 patients for evidence that certain common features are more likely to occur in some NF1 patients than in others. Clinical information on 4,402 patients with NF1 was obtained from three independent databases. We examined associations between pairs of clinical features in individual affected probands. We also examined associations between the occurrence of individual features in affected relatives. Associations were summarized as odds ratios with 95% confidence intervals. We found associations between several pairs of features in affected probands: intertriginous freckling and Lisch nodules, discrete neurofibromas and plexiform neurofibromas, discrete neurofibromas and Lisch nodules, plexiform neurofibromas and scoliosis, learning disability or mental retardation and seizures. We also found associations between the occurrence of Lisch nodules, macrocephaly, short stature, and learning disability or mental retardation as individual features in parents and children with NF1. Our observations suggest that, contrary to established belief, some NF1 patients are more likely than others to develop particular manifestations of the disease. Genetic factors appear to determine the development of particular phenotypic features.

Adult↗

PubMed2004

Characterization of the somatic mutational spectrum of the neurofibromatosis type 1 (NF1) gene in neurofibromatosis patients with benign and malignant tumors.

One of the main features of neurofibromatosis type 1 (NF1) is benign neurofibromas, 10-20% of which become transformed into malignant peripheral nerve sheath tumors (MPNSTs). The molecular basis of NF1 tumorigenesis is, however, still unclear. Ninety-one tumors from 31 NF1 patients were screened for gross changes in the NF1 gene using microsatellite/restriction fragment length polymorphism (RFLP) markers; loss of heterozygosity (LOH) was found in 17 out of 91 (19%) tumors (including two out of seven MPNSTs). Denaturing high performance liquid chromatography (DHPLC) was then used to screen 43 LOH-negative and 10 LOH-positive tumors for NF1 microlesions at both RNA and DNA levels. Thirteen germline and 12 somatic mutations were identified, of which three germline (IVS7-2A>G, 3731delT, 6117delG) and eight somatic (1888delG, 4374-4375delCC, R2129S, 2088delG, 2341del18, IVS27b-5C>T, 4083insT, Q519P) were novel. A mosaic mutation (R2429X) was also identified in a neurofibroma by DHPLC analysis and cloning/sequencing. The observed somatic and germline mutational spectra were similar in terms of mutation type, relative frequency of occurrence, and putative underlying mechanisms of mutagenesis. Tumors lacking mutations were screened for NF1 gene promoter hypermethylation but none were found. Microsatellite instability (MSI) analysis revealed MSI in five out of 11 MPNSTs as compared to none out of 70 neurofibromas (p=1.8 x 10(-5)). The screening of seven MPNSTs for subtle mutations in the CDKN2A and TP53 genes proved negative, although the screening of 11 MPNSTs detected LOH involving either the TP53 or the CDKN2A gene in a total of four tumors. These findings are consistent with the view that NF1 tumorigenesis is a complex multistep process involving a variety of different types of genetic defect at multiple loci.

Alleles↗

PubMed1999

Distribution and high frequency of novel alleles at NF1 polymorphic markers in the Italian population.

Segregation analysis of Neurofibromatosis type 1 (NF1) intragenic polymorphisms is a useful diagnostic tool for linkage analysis in familial cases and for the exclusion/detection of deletion in sporadic patients. We performed a segregation analysis of intragenic NF1 polymorphic markers in an Italian NF1 population consisting of 17 familial and 41 sporadic cases, for a total of 79 affected and 105 unaffected individuals. The haplotype in linkage with the mutation could be identified in all of the familial cases. Furthermore, an intragenic deletion was found in one sporadic case and confirmed by means of FISH using an NF1 IVS27 specific probe generated by a novel PCR procedure. In order to determine the allele frequencies at four NF1 polymorphisms in the Italian population, the unaffected family members and 25 unrelated Italian individuals were genotyped. Allele frequencies were found to be statistically different from those in the literature for markers IVS27AC28.4 and IVS38GT53.0. In addition four novel alleles were found in four unrelated subjects, and we observed a mutation during paternal gametogenesis in one case. These data suggest that NF1 polymorphic intragenic loci are unstable. It is unclear whether or not their marked instability may enhance the high mutation rate of the NF1 gene.

Alleles↗

PubMed1996

Nf1 gene targeting: toward models and mechanisms.

Patients with neurofibromatosis type I develop multiple benign nerve sheath tumors and are predisposed to a number of malignancies. Since loss-of-function mutations in the NF1 gene appear to be responsible for the disease, NF1 has been classified as a tumor suppressor. Several strategies involving the targeted disruption of the murine homologue have been used in an attempt to establish an animal model for the disease and four types of animals have been generated: (1) Nf1 +/- animals, (2) NF1 -/- embryos, (3) Nf1 -/- chimeras, and (4) mice transplanted with Nf1 -/- hematopoietic stem cells. In addition to yielding mice which mimic various aspects of the human disease, each of these approaches has contributed to a better understanding of the normal function of Nf1.

Animals↗

PubMed1993

Identification and characterization of sporadic and inherited mutations in exon 31 of the neurofibromatosis (NF1) gene.

Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders in humans, and presents with a variety of clinical symptoms, which are highly variable in expression. The mutation rate for NF1 is high, with as many as half of all cases resulting from new mutations. Although the NF1 gene has been cloned and its cDNA sequence determined, the specific role of the NF1 gene product in contributing to the NF1 mutations is one of the first steps in correlating genotype with clinical symptoms of the disease. In this paper we describe two independent mutations in exon 31 of the NF1 gene identified following polymerase chain reaction (PCR) amplification, heteroduplexing, and single strand conformational polymorphism (SSCP) analysis. One is a novel insertion that segregates with the disease phenotype in that particular family (5852insTT), while the other is a further example of the sporadic, recurrent C-->T mutation previously described in the literature (C5842T). The relationship between these mutations and clinical features of NF1 presented by the patients will be discussed.

Adolescent↗

PubMed2002

RT-PCR splicing analysis of the NF1 open reading frame.

Neurofibromatosis 1 (NF1) is an autosomal dominant condition whose molecular diagnosis is challenging because of the large size of the gene and the vast number of unique NF1 gene mutations. Some splicing and nonsense mutations have been shown to cause exon skipping. Recently, temperature-induced abnormal splicing has been found in NF1 in ex-vivo tissues. This prompted us to investigate the entire NF1 transcript for such aberrant splicing. We found several novel exon skips that appeared de novo or were present initially and increased in aged/cooled blood: exon 20, exons 20 and 21 combined, exon 33, exon 34, exon 37, exon 40, exon 45, exons 43 and 45 combined, part of exon 43, and the first codon of exon 12b. Some aberrant splice forms were undetectable when blood was drawn into Qiagen PAXgene tubes, rather than EDTA vacutainers, and we demonstrate how these aberrant splicing events are a potential pitfall for RNA-based NF1 mutation characterization. The same reverse transcription/polymerase chain reaction strategy was used to screen for novel NF1 alternative splicing in Schwann cells and seven other tissues. Even though no Schwann-specific alternative exons were identified, we found minor novel splicing isoforms differentially expressed such as skips of exon 37 and exon 40. Skipping of exon 43, part of exon 43, and the first codon of exon 12b were found in all tissues analyzed. These forms suggest greater tissue-based variability in the NF1 message than was previously thought and may indicate minor amounts of heterogeneity at the protein level.

Alternative Splicing↗

PubMed2002

Molecular characterisation of t(17;22)(q11.2;q11.2) is not consistent with NF1 gene duplication.

A tandem duplication of the NF1 gene in 17q11.2 has recently been detected by high-resolution fluorescence in situ hybridisation (FISH) on stretched chromosomes and DNA fibres. These findings suggest not only that, in the 17q11.2 region, the NF1 gene is surrounded by NF1 low-copy repeats on each side of the gene, but also that the NF1 gene and its directly flanking regions are duplicated structures. However, if the NF1 gene is duplicated at 17q11.2, this should be observed by FISH analysis on metaphase chromosomes of relevant translocation carriers with the probes originally used to identify the duplication, since hybridisation signals of some of the probes would be expected on both derivative chromosomes, the der(17) and the der(22). We have only been able to obtain signals on the one or the other derivative of a female translocation carrier. Therefore, our results do not support the hypothesis of a duplication of the NF1 gene and its immediately flanking regions at 17q11.2 as had been previously postulated. Rather, our findings suggest that there is one NF1 gene in the 17q11.2 region.

Chromosomes, Human, Pair 17↗

PubMed1996

Characterization of a cytogenetic 17q11.2 deletion in an NF1 patient with a contiguous gene syndrome.

We report on a rare patient screened as a putative carrier of a contiguous gene syndrome on the basis of a complex phenotype characterized by sporadic neurofibromatosis type 1 (NF1), dysmorphism, mental retardation and severe skeletal anomalies. A cytogenetically visible 17q11.2 deletion was detected in the patient's karyotype by high-resolution banding and confirmed by fluorescence in situ hybridization with yeast artificial chromosomes targeting the NF1 region. Analysis of the segregation from parents to proband of 13 polymorphic DNA markers, either contiguous or contained within the NF1 gene, showed that the patient is hemizygous at sites within the NF1 gene-the AAAT-Alu repeat in the 5' region of intron 27b, the CA/GT microsatellite in the 3' region of intron 27b, and the CA/GT microsatellite in intron 38- and at the extragenic D17S798 locus, distal to the 3' end of NF1. The patient may be an important resource in the identification of genes downstream of NF1 that may contribute to some of his extra-NF1 clinical signs.

Adult↗

PubMed1997

Somatic mosaicism for deletion of the entire NF1 gene identified by FISH.

We report a young child with a large congenital cervical plexiform neurofibroma and multiple café-aul-ait spots in a generalized distribution who has mosaicism for complete deletion of the NF1 gene. The deletion was demonstrated with intragenic cosmid probes as well as YACs spanning a 700-kb contig including NF1, by two-color FISH with an NF1 and a control probe. Using different intragenic probes, deletion was found in 77-84% of cultured peripheral blood lymphocytes but not in cultured skin fibroblasts. Neither parent has signs of neurofibromatosis type 1 (NF1) or a gene deletion. This is the first report of mosaicism for complete deletion of the NF1 gene. The child did not have typical NF1 or display segmental features of NF1.

Cells, Cultured↗

PubMed1997

A third neurofibromatosis type 1 (NF1) pseudogene at chromosome 15q11.2.

Sequences related to the neurofibromatosis type 1 (NF1) gene have been identified on several human chromosomes. In the centromeric region of chromosomes 14 and 15, two NF1 pseudogenes have been described. Sequence comparison between NF1-related exons amplified from two yeast artificial chromosome clones hybridizing to chromosomal region 15q11.2 and published NF1-related sequences localized at 15q11.2 suggested that a third NF1 pseudogene resides in this chromosomal region. The previous localization of an NF1-related locus to the telomeric part of chromosome 15 could not be confirmed by us. Our findings further support pericentromeric spreading of partial NF1 gene copies at chromosome 15q11.2 during evolution.

Base Sequence↗

PubMed2006

Diagnostic delay of NF1 in hemifacial hypertrophy due to plexiform neurofibromas.

Benign tumors of the peripheral nerve sheath, termed neurofibromas, are the hallmark feature of neurofibromatosis type 1 (NF1). These tumors can result in hypertrophy of a limb or another anatomic region. Hemifacial hypertrophy due to an underlying neurofibroma is a typical manifestation of NF1 in young children although the overall frequency of facial involvement is low. We retrospectively studied all patients, which were referred to our outpatient clinic because of hemihypertrophy or swelling of the face for initially unknown reason with a final diagnosis of NF1. A total number of six patients were identified. Clinical and radiological characteristics of these patients were analyzed. In all patients, diagnosis of NF1 could be established based on the typical clinical criteria. However, despite other typical NF1-associated features (e.g. multiple café-au-lait spots) diagnosis of a plexiform neurofibroma as underlying cause for the hemifacial hypertrophy was significantly delayed in all patients. MRI scans were misinterpreted in all of the cases as lymphangioma because plexiform neurofibromas can resemble mesenchymal tumors or lymphangiomas. NF1 has to be considered in the differential diagnosis of hemifacial hypertrophy. A thorough clinical examination of affected patients should focus on typical disease-defining features. Early diagnosis of NF1 can prevent unnecessary treatment at least in some patients.

Cheek↗

PubMed2005

Analysis of somatic NF1 promoter methylation in plexiform neurofibromas and Schwann cells.

Neurofibromatosis 1 (NF1) is an autosomal dominant disorder with the characteristic feature being the neurofibroma. It is believed that both NF1 alleles must be inactivated as the first step in tumorigenesis. However, often the somatic mutations are not identified, suggesting that epigenetic changes such as methylation could account for the "second hit" in some tumors. The literature reports that the region of the NF1 promoter surrounding the transcription start site is completely unmethylated in several normal tissues and some NF1-related dermal and plexiform neurofibromas. We analyzed the methylation state of the NF1 promoter in normal Schwann cells (the cell type clonally expanded in neurofibromas) and in NF1-related plexiform tumor samples with unidentified somatic mutations. In a region of 451 bp surrounding the transcription start site, a low level of methylation was found at several specific cytosines in 12 of 18 tumor samples. Overall, epigenetic silencing through methylation does not appear to be a major mechanism for the second hit. However, this study, which analyzed the largest number of NF1-related plexiform tumors and is the first to include Schwann cell-enriched tumor cultures, detected greater methylation than in any previous reports. This suggests that methylation, especially at potential transcription factor binding sites, is moderately perturbed in some plexiform neurofibromas and should be investigated further.

Cells, Cultured↗

PubMed2005

Distinct roles of enhancer nuclear factor 1 (NF1) sites in plasmacytoma and osteopetrosis induction by Akv1-99 murine leukemia virus.

Murine leukemia viruses (MLVs) can be lymphomagenic and bone pathogenic. In this work, the possible roles of two distinct proviral enhancer nuclear factor 1 (NF1) binding sites in osteopetrosis and tumor induction by B-lymphomagenic Akv1-99 MLV were investigated. Akv1-99 and mutants either with NF1 site 1, NF1 site 2 or both sites disrupted induced tumors (plasma cell proliferations by histopathology) with remarkably similar incidence and mean latency in inbred NMRI mice. Clonal immunoglobulin gene rearrangement detection, by Southern analysis, confirmed approximately half of the tumors induced by each virus to be plasmacytomas while the remaining lacked detectable clonally rearranged Ig genes and were considered polyclonal; a demonstration that enhancer NF1 sites are dispensable for plasmacytoma induction by Akv1-99. In contrast, X-ray analysis revealed significant differences in osteopetrosis induction by the four viruses strongly indicating that NF1 site 2 is critical for viral bone pathogenicity, whereas NF1 site 1 is neutral or moderately inhibitory. In conclusion, enhancer NF1 sites are major determinants of osteopetrosis induction by Akv1-99 without significant influence on viral oncogenicity.

Animals↗