scholarly journals Impacts of NF1 Gene Mutations and Genetic Modifiers in Neurofibromatosis Type 1

2021 ◽  
Vol 12 ◽  
Author(s):  
Wei Wang ◽  
Cheng-Jiang Wei ◽  
Xi-Wei Cui ◽  
Yue-Hua Li ◽  
Yi-Hui Gu ◽  
...  
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Clinical Symptoms ◽  
Genetic Disorder ◽  
Gene Mutations ◽  
Neurofibromatosis Type ◽  
Genetic Modifiers ◽  
Complete Penetrance ◽  
Nf1 Gene ◽  
Underlying Mechanisms

Neurofibromatosis type 1 (NF1) is a tumor predisposition genetic disorder that directly affects more than 1 in 3,000 individuals worldwide. It results from mutations of the NF1 gene and shows almost complete penetrance. NF1 patients show high phenotypic variabilities, including cafe-au-lait macules, freckling, or other neoplastic or non-neoplastic features. Understanding the underlying mechanisms of the diversities of clinical symptoms might contribute to the development of personalized healthcare for NF1 patients. Currently, studies have shown that the different types of mutations in the NF1 gene might correlate with this phenomenon. In addition, genetic modifiers are responsible for the different clinical features. In this review, we summarize different genetic mutations of the NF1 gene and related genetic modifiers. More importantly, we focus on the genotype–phenotype correlation. This review suggests a novel aspect to explain the underlying mechanisms of phenotypic heterogeneity of NF1 and provides suggestions for possible novel therapeutic targets to prevent or delay the onset and development of different manifestations of NF1.

scholarly journals The impact of host immune cells on the development of neurofibromatosis type 1: The abnormal immune system provides an immune microenvironment for tumorigenesis

2019 ◽  
Vol 2 (Supplement_1) ◽  
pp. i33-i39
Author(s):  
Cheng-Jiang Wei ◽  
Shu-Chen Gu ◽  
Jie-Yi Ren ◽  
Yi-Hui Gu ◽  
Xiang-Wen Xu ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Cells ◽  
Neurofibromatosis Type 1 ◽  
Immune Escape ◽  
Genetic Disorder ◽  
Neurofibromatosis Type ◽  
Complex Interactions ◽  
Nf1 Gene ◽  
The Impact

Abstract AbstractThe immune system plays an essential role in the development of tumors, which has been demonstrated in multiple types of cancers. Consistent with this, immunotherapies with targets that disrupt these mechanisms and turn the immune system against developing cancers have been proven effective. In neurofibromatosis type 1 (NF1), an autosomal dominant genetic disorder, the understanding of the complex interactions of the immune system is incomplete despite the discovery of the pivotal role of immune cells in the tumor microenvironment. Individuals with NF1 show a loss of the NF1 gene in nonneoplastic cells, including immune cells, and the aberrant immune system exhibits intriguing interactions with NF1. This review aims to provide an update on recent studies showing the bilateral influences of NF1 mutations on immune cells and how the abnormal immune system promotes the development of NF1 and NF1-related tumors. We then discuss the immune receptors major histocompatibility complex class I and II and the PD-L1 mechanism that shield NF1 from immunosurveillance and enable the immune escape of tumor tissues. Clarification of the latest understanding of the mechanisms underlying the effects of the abnormal immune system on promoting the development of NF1 will indicate potential future directions for further studies and new immunotherapies.

scholarly journals Familial Lymphoproliferative Malignancies and Tandem Duplication of NF1 Gene

2014 ◽  
Vol 2014 ◽  
pp. 1-4
Author(s):  
Gustavo Fernandes ◽  
Mirela Souto ◽  
Frederico Costa ◽  
Edite Oliveira ◽  
Bernardo Garicochea
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Tandem Duplication ◽  
Cancer Susceptibility ◽  
Direct Sequencing ◽  
Genetic Disorder ◽  
Clinical Signs ◽  
Neurofibromatosis Type ◽  
Genetic Alterations ◽  
Nf1 Gene

Background. Neurofibromatosis type 1 is a genetic disorder caused by loss-of-function mutations in a tumor suppressor gene (NF1) which codifies the protein neurofibromin. The frequent genetic alterations that modify neurofibromin function are deletions and insertions. Duplications are rare and phenotype in patients bearing duplication of NF1 gene is thought to be restricted to developmental abnormalities, with no reference to cancer susceptibility in these patients. We evaluated a patient who presented with few clinical signs of neurofibromatosis type 1 and a conspicuous personal and familiar history of different types of cancer, especially lymphoproliferative malignancies. The coding region of the NF-1 gene was analyzed by real-time polymerase chain reaction and direct sequencing. Multiplex ligation-dependent probe amplification was performed to detect the number of mutant copies. The NF1 gene analysis showed the following alterations: mosaic duplication of NF1, TRAF4, and MYO1D. Fluorescence in situ hybridization using probes (RP5-1002G3 and RP5-92689) flanking NF1 gene in 17q11.2 and CEP17 for 17q11.11.1 was performed. There were three signals (RP5-1002G3conRP5-92689) in the interphases analyzed and two signals (RP5-1002G3conRP5-92689) in 93% of cells. These findings show a tandem duplication of 17q11.2.Conclusion. The case suggests the possibility that NF1 gene duplication may be associated with a phenotype characterized by lymphoproliferative disorders.

scholarly journals Neurofibromatosis Type 1 Gene Alterations Define Specific Features of a Subset of Glioblastomas

2021 ◽  
Vol 23 (1) ◽  
pp. 352
Author(s):  
Maximilian Scheer ◽  
Sandra Leisz ◽  
Eberhard Sorge ◽  
Olha Storozhuk ◽  
Julian Prell ◽  
...  
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Gene Mutations ◽  
Neurofibromatosis Type ◽  
Loss Of Function ◽  
Malignant Tumours ◽  
Cellular Mechanisms ◽  
Rich Domain ◽  
Nf1 Gene ◽  
Gene Alterations

Neurofibromatosis type 1 (NF1) gene mutations or alterations occur within neurofibromatosis type 1 as well as in many different malignant tumours on the somatic level. In glioblastoma, NF1 loss of function plays a major role in inducing the mesenchymal (MES) subtype and, therefore defining the most aggressive glioblastoma. This is associated with an immune signature and mediated via the NF1–MAPK–FOSL1 axis. Specifically, increased invasion seems to be regulated via mutations in the leucine-rich domain (LRD) of the NF1 gene product neurofibromin. Novel targets for therapy may arise from neurofibromin deficiency-associated cellular mechanisms that are summarised in this review.

scholarly journals Pulmonary Hypertension and Neurofibromatosis Type 1: A Case Report with the Revision of Literature

2019 ◽  
Vol 14 (5) ◽  
Author(s):  
Walter Serra
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Molecular Mechanisms ◽  
Autosomal Dominant ◽  
Genetic Disorder ◽  
Neurofibromatosis Type ◽  
Nerve Sheath ◽  
Nf1 Gene ◽  
Pulmonary Arterial ◽  
Group 5

Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic disorder caused by mutations of the NF1 gene that can lead to the development of benign neurofibroma-like tumours and Malignant Peripheral Nerve Sheath Tumours (MPNST). Pulmonary Arterial Hypertension (PAH) is a rare but severe complication associated with NF1 (PAH-NF). PH-NF1 is classified as group 5 PH, defined as “PH with unclear and/or multifactorial mechanisms”, because the mechanisms of PH remain poorly understood. A better understanding of the genetic and molecular mechanisms underlying the disease may require new ways to develop specific therapies. We present the clinical outcomes of a 51-year old female previously diagnosed with NF1, who presented with progressively worsening dyspnea.

scholarly journals Application of Combined Long Amplicon Sequencing (CoLAS) for Genetic Analysis of Neurofibromatosis Type 1: A Pilot Study

2021 ◽  
Vol 43 (2) ◽  
pp. 782-801
Author(s):  
Sumihito Togi ◽  
Hiroki Ura ◽  
Yo Niida
Keyword(s):  
Genetic Analysis ◽  
Neurofibromatosis Type 1 ◽  
Gene Mutations ◽  
Neurofibromatosis Type ◽  
Amplicon Sequencing ◽  
Causative Mutation ◽  
Coding Region ◽  
Causative Gene ◽  
Nf1 Gene

Elaborate analyses of the status of gene mutations in neurofibromatosis type 1 (NF1) are still difficult nowadays due to the large gene sizes, broad mutation spectrum, and the various effects of mutations on mRNA splicing. These problems cannot be solved simply by sequencing the entire coding region using next-generation sequencing (NGS). We recently developed a new strategy, named combined long amplicon sequencing (CoLAS), which is a method for simultaneously analysing the whole genomic DNA region and, also, the full-length cDNA of the disease-causative gene with long-range PCR-based NGS. In this study, CoLAS was specifically arranged for NF1 genetic analysis, then applied to 20 patients (five previously reported and 15 newly recruited patients, including suspicious cases) for optimising the method and to verify its efficacy and benefits. Among new cases, CoLAS detected not only 10 mutations, including three unreported mutations and one mosaic mutation, but also various splicing abnormalities and allelic expression ratios quantitatively. In addition, heterozygous mapping by polymorphisms, including introns, showed copy number monitoring of the entire NF1 gene region was possible in the majority of patients tested. Moreover, it was shown that, when a chromosomal level microdeletion was suspected from heterozygous mapping, it could be detected directly by breakpoint-specific long PCR. In conclusion, CoLAS not simply detect the causative mutation but accurately elucidated the entire structure of the NF1 gene, its mRNA expression, and also the splicing status, which reinforces its high usefulness in the gene analysis of NF1.

Isolated premature menarche in two siblings with Neurofibromatosis type 1

2020 ◽  
Vol 33 (6) ◽  
pp. 813-816
Author(s):  
James Blackburn ◽  
Mohammed Didi ◽  
Shivaram Avula ◽  
Senthil Senniappan
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Pubertal Timing ◽  
Genetic Disorder ◽  
Pubertal Development ◽  
Neurofibromatosis Type ◽  
Malignant Tumours ◽  
Peripheral Tissues ◽  
Paediatric Endocrinology ◽  
The Central Nervous System

AbstractObjectivesNeurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder, caused by mutation in NF1. The condition is typified by the development of benign and malignant tumours in both the central nervous system and peripheral tissues. Isolated menarche is a sub-classification of incomplete isosexual precocious puberty typified by menarche in girls with no other features of pubertal development. The effects of NF1 on pubertal timing are poorly understood, we report two siblings with NF1 and apparent abnormal pubertal development.Case PresentationTwo siblings were referred to the tertiary paediatric endocrinology clinic at 6 and 7 years of age with recurrent, cyclical vaginal bleeding. There was a strong family history of NF1, the mother of the siblings and two brothers were also diagnosed at a young age. On examination both patients were prepubertal at presentation. Both siblings underwent a gonadotrophin releasing hormone test, which revealed a follicle-stimulating hormone dominant (prepubertal) response. The features were suggestive of isolated premature menarche as no other cause was identified. The elder sibling established menarche and developed signs of consonant pubertal development at 12 years of age. The younger sibling remains under regular follow-up.ConclusionsNF1 has previously been associated with alterations in pubertal timing. We report, for the first time, two siblings with NF1 who presented with isolated menarche.

A highly informative CA/GT repeat polymorphism in intron 38 of the human neurofibromatosis type 1 (NF1) gene

1993 ◽  
Vol 92 (4) ◽  
pp. 429-430 ◽  
Author(s):  
Conxi L�zaro ◽  
Antonia Gaona ◽  
Ganfeng Xu ◽  
Robert Weiss ◽  
Xavier Estivill
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Repeat Polymorphism ◽  
Nf1 Gene
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