Molecular genetic analyses in neurofibromatosis type 1 patients with tumors (original) (raw)
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Confirmation of a Double-Hit Model for the NF1Gene in Benign Neurofibromas
The American Journal of Human Genetics, 1997
Neurofibroma is a benign tumor that arises from small or large nerves. This neoplastic lesion is a common feature of neurofibromatosis type 1 (NF1), one of the most common autosomal dominant disorders. The NF1 gene codes for a protein called "neurofibromin." It possesses a region that shares a high homology with the family of GTPase-activating proteins, which are negative regulators of RAS function and thereby control cell growth and differentiation. The evidence points to the NF1 gene being a tumor-suppressor gene. NF1 patients also have an increased incidence of certain malignant tumors that are believed to follow the "two hit" hypothesis, with one allele constitutionally inactivated and the other somatically mutated. Recently, somatic loss of heterozygosity (LOH) has been described for neurofibromas, and mutations in both copies of the NF1 gene have been reported for a dermal neurofibroma. The aim of our study was the analysis of the NFl locus in benign neurofibromas in NF1 patients. We performed LOH analysis on 60 neurofibromas belonging to 17 patients, 9 of them with family history of the disease and 8 of them sporadic. We have analyzed five intragenic NFl markers and six extragenic markers, and we have found LOH in 25% of the neurofibromas (corresponding to 53% of the patients). In addition, we found that in the neurofibromas of patients from familial cases the deletions occurred in the allele that is not transmitted with the disease, indicating that both copies of the NFl gene were inactivated in these tumors. Therefore, the recent reports mentioned above, together with our findings, strongly support the double inactivation of the NF1 gene in benign neurofibromas.
Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas
European Journal of Human Genetics, 2012
Neurofibromatosis type-1 (NF1), caused by heterozygous inactivation of the NF1 tumour suppressor gene, is associated with the development of benign and malignant peripheral nerve sheath tumours (MPNSTs). Although numerous germline NF1 mutations have been identified, relatively few somatic NF1 mutations have been described in neurofibromas. Here we have screened 109 cutaneous neurofibromas, excised from 46 unrelated NF1 patients, for somatic NF1 mutations. NF1 mutation screening (involving loss-of-heterozygosity (LOH) analysis, multiplex ligation-dependent probe amplification and DNA sequencing) identified 77 somatic NF1 point mutations, of which 53 were novel. LOH spanning the NF1 gene region was evident in 25 neurofibromas, but in contrast to previous data from MPNSTs, it was absent at the TP53, CDKN2A and RB1 gene loci. Analysis of DNA/RNA from neurofibroma-derived Schwann cell cultures revealed NF1 mutations in four tumours whose presence had been overlooked in the tumour DNA. Bioinformatics analysis suggested that four of seven novel somatic NF1 missense mutations (p.A330T, p.Q519P, p.A776T, p.S1463F) could be of functional/clinical significance. Functional analysis confirmed this prediction for p.S1463F, located within the GTPase-activating protein-related domain, as this mutation resulted in a 150-fold increase in activated GTP-bound Ras. Comparison of the relative frequencies of the different types of somatic NF1 mutation observed with those of their previously reported germline counterparts revealed significant (P¼0.001) differences. Although non-identical somatic mutations involving either the same or adjacent nucleotides were identified in three pairs of tumours from the same patients (Po0.0002), no association was noted between the type of germline and somatic NF1 lesion within the same individual.
Proceedings of the National Academy of Sciences, 1993
The NFI gene, which is altered in patients with type 1 neurofibromatosis, encodes neurofibromin, a protein whose GTPase-activating function can negatively regulate GTP Ras by accelerating its conversion to inactive GDPRas. In schwannoma cell lines from patients with neuroffbromatosis, loss of neurofibromin was previously shown to be associated with impaired regulation of GTP Ras. Our analysis of other neural crest-derived tumor cell lines has shown that some melanoma and neuroblastoma cell lines established from tumors occurring in patients without neurofibromatosis contain reduced or undetectable levels of neurofibromin, with concomitant genetic abnormalities of the NFI locus. In contrast to the schwannoma cell lines, GTP Ras was appropriately regulated in the melanoma and neuroblastoma lines that were deficient in neuroflbromin, even when c-H-ras was overexpressed in the lines. These results demonstrate that some neural crest tumors not associated with neurofibromatosis have acquired somatically inactivated NFI genes and suggest a tumor-suppressor function for neurofibromin that is independent of Ras GTPase activation.
Genome Research, 2013
Neurofibromatosis type 1 (NF1) (MIM#162200) is a relatively frequent genetic condition that predisposes to tumor formation. The main types of tumors occurring in NF1 patients are cutaneous and subcutaneous neurofibromas, plexiform neurofibromas, optic pathway gliomas, and malignant peripheral nerve sheath tumors. To search for somatic mutations in cutaneous (dermal) neurofibromas, whole-exome sequencing (WES) was performed on seven spatially separated tumors and two reference tissues (blood and unaffected skin) from a single NF1 patient. Validation of WES findings was done using routine Sanger sequencing or Sequenom IPlex SNP genotyping. Exome sequencing confirmed the existence of a known familial splice-site mutation NM_000267.3:c.3113+1G4A in exon 23 of NF1 gene (HGMD ID CS951480) in blood, unaffected skin, and all tumor samples. In five out of seven analyzed tumors, we additionally detected second-hit mutations in the NF1 gene. Four of them were novel and one was previously observed. Each mutation was distinct, demonstrating the independent origin of each tumor. Only in two of seven tumors we detected an additional somatic mutation that was not associated with NF1. Our study demonstrated that somatic mutations of NF1 are likely the main drivers of cutaneous tumor formation. The study provides evidence for the rareness of single base pair level alterations in the exomes of benign NF1 cutaneous tumors.
The mutational spectrum of the NF1 gene in neurofibromatosis type I patients from UAE
Child's Nervous System, 2014
Introduction Germline heterozygous mutations in the tumor suppresser NF1 gene cause a cancer predisposition syndrome known as neurofibromatosis type 1 (NF1). This disease is one of the most common multisystem disorders with an estimated incidence of 1 in 3,000 to 1 in 4,000 births. Clinically, NF1 patients are prone to develop "café au lait" spots, neurofibromas, Lisch nodules, freckling of the axillary, or inguinal region and optic nerve gliomas. Materials and methods In the present study, we report clinical and molecular findings of five unrelated patients and seven cases from four families with NF1 from UAE. To reveal the genetic defects underlying NF1 in our cohort of patients, we screened the whole coding and splice site regions of the NF1
Molecular genetics of neurofibromatosis type 1 (NF1)
Journal of Medical Genetics, 1996
Neurofibromatosis type 1 (NF1), also called von Recklinghausen disease or peripheral neurofibromatosis, is a common autosomal dominant disorder characterised by multiple neurofibromas, cafe au lait spots, and Lisch nodules of the iris, with a variable clinical expression. The gene responsible for this condition, NF1, has been isolated by positional cloning. It spans over 350kb of genomic DNA in chromosomal region 17qll.2 and encodes an mRNA of 11-13 kb containing at least 59 exons. NFI is widely expressed in a variety of human and rat tissues. Four alternatively spliced NFI transcripts have been identified. Three of these transcript isoforms (each with an extra exon: 9br, 23a, and 48a, respectively) show differential expression to some extent in various tissues, while the fourth isoform (2-9kb in length) remains to be examined. The protein encoded by NFI, neurofibromin, has a domain homologous to the GTPase activating protein (GAP) family, and downregulates ras activity. The identification of somatic mutations in NFI from tumour tissues strongly supports the speculation that NFl is a member of the tumour suppressor gene family. Although the search for mutations in the gene has proved difficult, germline mutation analysis has shown that around 82% of all the fully characterised NF1 specific mutations so far predict severe truncation of neurofibromin. Further extensive studies are required to elucidate the gene function and the mutation spectrum. This should then facilitate the molecular diagnosis and the development of new therapy for the disease.
RAS and beyond: the many faces of the neurofibromatosis type 1 protein
Disease Models & Mechanisms, 2022
Neurofibromatosis type 1 is a rare neurogenetic syndrome, characterized by pigmentary abnormalities, learning and social deficits, and a predisposition for benign and malignant tumor formation caused by germline mutations in the NF1 gene. With the cloning of the NF1 gene and the recognition that the encoded protein, neurofibromin, largely functions as a negative regulator of RAS activity, attention has mainly focused on RAS and canonical RAS effector pathway signaling relevant to disease pathogenesis and treatment. However, as neurofibromin is a large cytoplasmic protein the RAS regulatory domain of which occupies only 10% of its entire coding sequence, both canonical and non-canonical RAS pathway modulation, as well as the existence of potential non-RAS functions, are becoming apparent. In this Special article, we discuss our current understanding of neurofibromin function.
Journal of Investigative Dermatology, 2000
suppressor gene product, neurofibromin, functions in part as a Ras-GAP, a negative regulator of Ras. Neurofibromin is implicated in the neuronal abnormality of NF1 patients; however, the precise cellular function of neurofibromin has yet to be clarified. Using proteomic strategies, we identified a set of neurofibromin-associating cellular proteins, including axon regulator Collapsin response mediator protein-2 (CRMP-2). CRMP-2 directly bound to the C-terminal domain of neurofibromin, and this association was regulated by the manner of CRMP-2 phosphorylation. In nerve growth factor (NGF)-stimulated PC12 cells, neurofibromin and CRMP-2 co-localized particularly on the distal tips and branches of extended neurites. Suppression of neurofibromin using NF1 siRNA significantly inhibited this neurite outgrowth and upregulated a series of CRMP-2 phosphorylations by kinases identified as CDK5, GSK-3b and Rho-kinase (RhoK).
2019
Neurofibromatosis type 1 (NF1) is an autosomal predominant, mucocutaneous and inclination disorder. They include it in the development of benign and malignant tumors. Hereditary change in NF1 prompts changes in the outflow of cytoplasmic protein. 90% of all cases represent NF1 in neurofibromatosis. children tainted with NF1, they distinguish them inside a year.NF1 Patients ordinarily experience the ill effects of the café au laitt, freckling, and skeletal dysplasia. The GTPase actuating protein goes about as the principal job in NF1 quality, which fills in as a negative controlled by authoritative with the RAS protein. The neurofibromatosis type 1 quality is a 287-kilo premise of chromosome 17q11.2. In NF1 patients, the dermatologists distinguished the basic cutaneous highlights. Cutaneous neurofibroma has a variable pace of development during life expectancy. The threatening fringe nerve sheath tumor is plexiform neurofibromas. Palpebral plexiform neurofibroma is mono-sidelong. We ...
Neurofibromatosis Type 1: Genetic and Cellular Mechanisms of Peripheral Nerve Tumor Formation
The Neuroscientist, 1997
Neurofibromatosis type 1 (NF1) is among the most common inherited human diseases. The NF1 protein is a Ras-GTPase activating protein, positioning NF1 in important intracellular signaling pathways. Patients with mutations in the NF1 gene can develop benign peripheral nerve tumors (neurofibromas), learning disabilities, and/or benign optic nerve gliomas, in addition to abnormalities unassociated with the nervous system. The NF1 gene is believed to act as a tumor suppressor. How NF1 mutations relate to benign features of NF1 is the subject of active investigation. Studies using transgenic mice with NF1 mutations and cells derived from these mice have yielded exciting new data, implicating multiple cell types mutant at NF1 and possibly factors in the environment in the pathogenesis of benign neurofibromas. NEUROSCIENTIST 3:412-420, 1997