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

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.

Download Full-text

Analysis of NF1 Gene Mutations in Neurofibromatosis Type 1 Patients in Japan

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.1994.1215 ◽

1994 ◽

Vol 199 (1) ◽

pp. 207-212 ◽

Cited By ~ 6

Author(s):

N. Hatta ◽

T. Horiuchi ◽

S. Fujita

Keyword(s):

Neurofibromatosis Type 1 ◽

Gene Mutations ◽

Neurofibromatosis Type ◽

Nf1 Gene

Download Full-text

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

Frontiers in Neurology ◽

10.3389/fneur.2021.704639 ◽

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.

Download Full-text

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

Current Issues in Molecular Biology ◽

10.3390/cimb43020057 ◽

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.

Download Full-text

Isolated premature menarche in two siblings with Neurofibromatosis type 1

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2019-0494 ◽

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.

Download Full-text