scholarly journals The Role of Co-Deleted Genes in Neurofibromatosis Type 1 Microdeletions: An Evolutive Approach

Genes ◽  
2019 ◽  
Vol 10 (11) ◽  
pp. 839
Author(s):  
Larissa Brussa Reis ◽  
Andreia Carina Turchetto-Zolet ◽  
Maievi Fonini ◽  
Patricia Ashton-Prolla ◽  
Clévia Rosset
Keyword(s):  
Positive Selection ◽  
Neurofibromatosis Type 1 ◽  
Mammalian Species ◽  
Ring Finger ◽  
Purifying Selection ◽  
Neurofibromatosis Type ◽  
Evolutionary Constraint ◽  
Loss Of Function ◽  
Cancer Predisposition Syndrome

Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome that results from dominant loss-of-function mutations mainly in the NF1 gene. Large rearrangements are present in 5–10% of affected patients, generally encompass NF1 neighboring genes, and are correlated with a more severe NF1 phenotype. Evident genotype–phenotype correlations and the importance of the co-deleted genes are difficult to establish. In our study we employed an evolutionary approach to provide further insights into the understanding of the fundamental function of genes that are co-deleted in subjects with NF1 microdeletions. Our goal was to access the ortholog and paralog relationship of these genes in primates and verify if purifying or positive selection are acting on these genes. Fourteen genes were analyzed in twelve mammalian species. Of these, four and ten genes showed positive selection and purifying selection, respectively. The protein, RNF135, showed three sites under positive selection at the RING finger domain, which may have been selected to increase efficiency in ubiquitination routes in primates. The phylogenetic analysis suggests distinct evolutionary constraint between the analyzed genes. With these analyses, we hope to help clarify the correlation of the co-deletion of these genes and the more severe phenotype of NF1.

Mosaic Neurofibromatosis Type 1 in Children: A Single-Institution Experience

2017 ◽  
Vol 21 (5) ◽  
pp. 379-382 ◽  
Author(s):  
Irene Lara-Corrales ◽  
Mitra Moazzami ◽  
Maria Teresa García-Romero ◽  
Elena Pope ◽  
Patricia Parkin ◽  
...  
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Cross Sectional Study ◽  
Clinical Findings ◽  
Loss Of Function ◽  
Cross Sectional ◽  
Uncommon Presentation ◽  
Sick Children

Background: Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder caused by loss-of-function mutation in the NF1 gene. Segmental or mosaic NF1 (MNF) is an uncommon presentation of the NF1 result of postzygotic mutations that present with subtle localised clinical findings. Objectives: Our study’s objectives were to describe the clinical characteristics of children with MNF. Methods: We conducted a cross-sectional study of children diagnosed with MNF at the Hospital for Sick Children in Toronto, Canada, from January 1992 to September 2012. Data were abstracted from health records and analysed using a standardised data collection form approved by our hospital Research Ethics Board. Results: We identified 60 patients with MNF; 32 of 60 (53.3%) were female. Mean ± SD age at first assessment was 10.6 ± 4.6 years. The most common initial physical manifestation in 39 of 60 (65.0%) patients was localised pigmentary changes only, followed by plexiform neurofibromas only in 10 of 60 (16.7%) and neurofibromas only in 9 of 60 (15.0%). Unilateral findings were seen in 46 of 60 (76.7%) patients. Most common associations identified included learning disabilities (7/60; 12%) and bony abnormalities (6/60; 10.0%). Conclusions: MNF is an underrecognised condition with potential implications for patients. Children mostly present with pigmentary anomalies only. Most patients do not develop associated findings or complications before adulthood, but long-term follow-up will help determine outcomes and possible associations. Recognition and confirmation of the diagnosis is important to provide follow-up and genetic counselling to patients.

scholarly journals Neurofibromin regulates metabolic rate via neuronal mechanisms in Drosophila

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Valentina Botero ◽  
Bethany A. Stanhope ◽  
Elizabeth B. Brown ◽  
Eliza C. Grenci ◽  
Tamara Boto ◽  
...  
Keyword(s):  
Metabolic Rate ◽  
Neurofibromatosis Type 1 ◽  
Genetic Disorder ◽  
Neurofibromatosis Type ◽  
Pathophysiological Mechanism ◽  
Metabolic Homeostasis ◽  
Loss Of Function ◽  
Dynamic Activity ◽  
Neuronal Mechanisms

AbstractNeurofibromatosis type 1 is a chronic multisystemic genetic disorder that results from loss of function in the neurofibromin protein. Neurofibromin may regulate metabolism, though the underlying mechanisms remain largely unknown. Here we show that neurofibromin regulates metabolic homeostasis in Drosophila via a discrete neuronal circuit. Loss of neurofibromin increases metabolic rate via a Ras GAP-related domain-dependent mechanism, increases feeding homeostatically, and alters lipid stores and turnover kinetics. The increase in metabolic rate is independent of locomotor activity, and maps to a sparse subset of neurons. Stimulating these neurons increases metabolic rate, linking their dynamic activity state to metabolism over short time scales. Our results indicate that neurofibromin regulates metabolic rate via neuronal mechanisms, suggest that cellular and systemic metabolic alterations may represent a pathophysiological mechanism in neurofibromatosis type 1, and provide a platform for investigating the cellular role of neurofibromin in metabolic homeostasis.

PHALANGES DEFORMITY ASSOCIATED WITH NEUROFIBROMATOSIS-1: A CASE REPORT

Hand Surgery ◽  
2012 ◽  
Vol 17 (03) ◽  
pp. 379-381
Author(s):  
Hiroyoshi Hagiwara ◽  
Suguru Hagiwara ◽  
Takashi Ajiki ◽  
Yuichi Hoshino
Keyword(s):  
Case Report ◽  
Neurofibromatosis Type 1 ◽  
Ring Finger ◽  
Neurofibromatosis Type ◽  
Neurofibromatosis 1

We present a case of phalangeal deformity in a 17-year-old boy. The deformity was caused by a neurofibroma associated with neurofibromatosis type 1, affecting the left ring finger. The mass was surgically resected. Recurrence had not occurred at three-year follow-up.

scholarly journals Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations?

2014 ◽  
Vol 23 (5) ◽  
pp. 596-601 ◽  
Author(s):  
Eric Pasmant ◽  
Béatrice Parfait ◽  
Armelle Luscan ◽  
Philippe Goussard ◽  
Audrey Briand-Suleau ◽  
...  
Keyword(s):  
Molecular Diagnosis ◽  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Loss Of Function ◽  
Large Gene

scholarly journals Genetic disruption of the small GTPase RAC1 prevents plexiform neurofibroma formation in mice with neurofibromatosis type 1

2020 ◽  
Vol 295 (29) ◽  
pp. 9948-9958
Author(s):  
Julie A. Mund ◽  
SuJung Park ◽  
Abbi E. Smith ◽  
Yongzheng He ◽  
Li Jiang ◽  
...  
Keyword(s):  
Schwann Cells ◽  
Neurofibromatosis Type 1 ◽  
Plexiform Neurofibroma ◽  
Neurofibromatosis Type ◽  
Tumor Formation ◽  
Genetically Engineered ◽  
Small Gtpase ◽  
Cancer Predisposition Syndrome

Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome caused by mutations in the NF1 tumor suppressor gene. NF1 encodes neurofibromin, a GTPase-activating protein for RAS proto-oncogene GTPase (RAS). Plexiform neurofibromas are a hallmark of NF1 and result from loss of heterozygosity of NF1 in Schwann cells, leading to constitutively activated p21RAS. Given the inability to target p21RAS directly, here we performed an shRNA library screen of all human kinases and Rho-GTPases in a patient-derived NF1−/− Schwann cell line to identify novel therapeutic targets to disrupt PN formation and progression. Rho family members, including Rac family small GTPase 1 (RAC1), were identified as candidates. Corroborating these findings, we observed that shRNA-mediated knockdown of RAC1 reduces cell proliferation and phosphorylation of extracellular signal–regulated kinase (ERK) in NF1−/− Schwann cells. Genetically engineered Nf1flox/flox;PostnCre+ mice, which develop multiple PNs, also exhibited increased RAC1-GTP and phospho-ERK levels compared with Nf1flox/flox;PostnCre– littermates. Notably, mice in which both Nf1 and Rac1 loci were disrupted (Nf1flox/floxRac1flox/flox;PostnCre+) were completely free of tumors and had normal phospho-ERK activity compared with Nf1flox/flox;PostnCre+ mice. We conclude that the RAC1-GTPase is a key downstream node of RAS and that genetic disruption of the Rac1 allele completely prevents PN tumor formation in vivo in mice.

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 Current Aspects on the Pathophysiology of Bone Metabolic Defects during Progression of Scoliosis in Neurofibromatosis Type 1

2022 ◽  
Vol 11 (2) ◽  
pp. 444
Author(s):  
Angelos Kaspiris ◽  
Olga D. Savvidou ◽  
Elias S. Vasiliadis ◽  
Argyris C. Hadjimichael ◽  
Dimitra Melissaridou ◽  
...  
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Transforming Growth Factor ◽  
Neurofibromatosis Type ◽  
Loss Of Function ◽  
Mineral Density ◽  
Autosomal Dominant Disorder ◽  
Trabecular Microarchitecture ◽  
Osteoblastic Activity ◽  
Metabolic Defects

Neurofibromatosis type 1 (NF1), which is the most common phacomatoses, is an autosomal dominant disorder characterized by clinical presentations in various tissues and organs, such as the skin, eyes and nervous and skeletal systems. The musculoskeletal implications of NF1 include a variety of deformities, including scoliosis, kyphoscoliosis, spondylolistheses, congenital bony bowing, pseudarthrosis and bone dysplasia. Scoliosis is the most common skeletal problem, affecting 10–30% of NF1 patients. Although the pathophysiology of spinal deformities has not been elucidated yet, defects in bone metabolism have been implicated in the progression of scoliotic curves. Measurements of Bone Mineral Density (BMD) in the lumbar spine by using dual energy absorptiometry (DXA) and quantitative computer tomography (QCT) have demonstrated a marked reduction in Z-score and osteoporosis. Additionally, serum bone metabolic markers, such as vitamin D, calcium, phosphorus, osteocalcin and alkaline phosphatase, have been found to be abnormal. Intraoperative and histological vertebral analysis confirmed that alterations of the trabecular microarchitecture are associated with inadequate bone turnover, indicating generalized bone metabolic defects. At the molecular level, loss of function of neurofibromin dysregulates Ras and Transforming Growth factor-β1 (TGF-β1) signaling and leads to altered osteoclastic proliferation, osteoblastic activity and collagen production. Correlation between clinical characteristics and molecular pathways may provide targets for novel therapeutic approaches in NF1.

scholarly journals Pathogenic Neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq

2021 ◽  
Author(s):  
R. Koster ◽  
R.D. Brandão ◽  
D. Tserpelis ◽  
C.E.P. van Roozendaal ◽  
C.N. van Oosterhoud ◽  
...  
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Rna Splicing ◽  
Splice Variants ◽  
Neurofibromatosis Type ◽  
Enrichment Score ◽  
Loss Of Function ◽  
Splicing Variants ◽  
Reference Transcript ◽  
Splice Junctions

AbstractPurposeNeurofibromatosis type 1 (NF1) is caused by loss-of-function variants in the NF1 gene. Approximately 10% of these variants affect RNA splicing and are either missed by conventional DNA diagnostics or are misinterpreted by in silico splicing predictions. A targeted RNAseq-based approach was designed to detect pathogenic RNA splicing and associated pathogenic DNA variants.MethodsRNA was extracted from lymphocytes, followed by targeted NF1 RNAseq. An in-house developed tool (QURNAS) was used to calculate the enrichment score (ERS) for each splicing event.ResultsThis method was thoroughly tested using two different patient cohorts with known pathogenic splice-variants. In both cohorts all 56 normal reference transcript exon splice junctions, 24 previously described and 45 novel non-reference splicing events were detected. Additionally, all expected pathogenic splice-variants were detected. Eleven patients with NF1 symptoms were subsequently tested, three of which have a known NF1 DNA variant with a putative effect on RNA splicing. This effect could be confirmed for all 3. The other eight patients were previously without any molecular confirmation of their NF1-diagnosis. A deep-intronic pathogenic splice variant could now be identified for two of them (25%).ConclusionTargeted NF1 RNAseq can be successfully used to detect pathogenic RNA splicing variants, complementary to DNA based diagnostics.

scholarly journals Pathogenic neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
R. Koster ◽  
R. D. Brandão ◽  
D. Tserpelis ◽  
C. E. P. van Roozendaal ◽  
C. N. van Oosterhoud ◽  
...  
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Rna Splicing ◽  
Splice Variants ◽  
Neurofibromatosis Type ◽  
Enrichment Score ◽  
Loss Of Function ◽  
Splicing Variants ◽  
Reference Transcript ◽  
Splice Junctions

AbstractNeurofibromatosis type 1 (NF1) is caused by loss-of-function variants in the NF1 gene. Approximately 10% of these variants affect RNA splicing and are either missed by conventional DNA diagnostics or are misinterpreted by in silico splicing predictions. Therefore, a targeted RNAseq-based approach was designed to detect pathogenic RNA splicing and associated pathogenic DNA variants. For this method RNA was extracted from lymphocytes, followed by targeted RNAseq. Next, an in-house developed tool (QURNAs) was used to calculate the enrichment score (ERS) for each splicing event. This method was thoroughly tested using two different patient cohorts with known pathogenic splice-variants in NF1. In both cohorts all 56 normal reference transcript exon splice junctions, 24 previously described and 45 novel non-reference splicing events were detected. Additionally, all expected pathogenic splice-variants were detected. Eleven patients with NF1 symptoms were subsequently tested, three of which have a known NF1 DNA variant with a putative effect on RNA splicing. This effect could be confirmed for all 3. The other eight patients were previously without any molecular confirmation of their NF1-diagnosis. A deep-intronic pathogenic splice variant could now be identified for two of them (25%). These results suggest that targeted RNAseq can be successfully used to detect pathogenic RNA splicing variants in NF1.

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