Neurofibromin Deficiency-Associated Transcriptional Dysregulation Suggests a Novel Therapy for Tibial Pseudoarthrosis in NF1

Paria, Nandina; Cho, Tae Joon; Choi, In Ho; Kamiya, Nobuhiro; Kayembe, Kay; Mao, Rong; Margraf, Rebecca L.; Obermosser, Gerlinde; Oxendine, Ila; Sant, David W.; Song, Mi Hyun; Stevenson, David A.; Viskochil, David; Wise, Carol A.; Kim, Harry K.W.; Rios, Jonathan J.

doi:10.1002/jbmr.2298

Cited by 24 publications

(34 citation statements)

References 25 publications

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“…Two of them were "de novo" mutations, and the others originated from their parents. Similar to previous studies [8,11,12,16], our results further confirmed that CPT always existed in the NF1 families and each patient with both NF1 and CPT was found harboring mutations in the NF1 gene, suggesting these mutations were closely associated with the complex phenotypes. In addition, the age of patients sustaining tibial fracture was found to be distinctly different.…”

Section: Discussionsupporting

confidence: 90%

Identification of One BOCR Mutation and Five NF1 Mutations in Male Patients with Neurofibromatosis Type 1 and Congenital Pseudarthrosis of the Tibia

Zhou¹,

Zeng

et al. 2016

Preprint

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Neurofibromatosis type1 (NF1) is an autosomal dominant disorder caused by mutations in the NF1gene. Although congenital pseudarthrosis of the tibia (CPT) has frequently been associated with NF1, the underlying molecular mechanism of CPT in these NF1 patients is yet ill-understood. The aim of the present study was to detect NF1 mutations from genomic DNA and to harbor variants associated with CPT in NF1 patients. Whole-exome sequencing was first carried out with samples from two patients with CPT in one NF1 family, and a novel mutation c.2324A>G (p.E775G) in NF1 gene was identified. Additionally, a missense variant c.455C>T (p.P152L) in BCOR gene completely co-segregated with the CPT phenotype within this family. Subsequently, NF1 and NF2 genes in four other unrelated patients with both NF1 and CPT were screened using targeted sequencing. Four mutations in NF1 gene, including two known mutations (c.2288T>C/p.L763P, c.574 C>T/p.R192*) and two novel mutations (c.768delT/p.F256Lfs*25, c.2229_2230delTG/ p.V744Qfs*23) were detected. Further study confirmed that CPT was present in NF1 families, and NF1 mutations were closely associated with these complex phenotypes. Moreover, the data from the current study indicated that male gender might be a susceptibility factor for CPT in NF1. Therefore, we speculated that BCOR variants might be related to CPT phenotype among male NF1 patients.

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Section: Discussionsupporting

confidence: 90%

Identification of One BOCR Mutation and Five NF1 Mutations in Male Patients with Neurofibromatosis Type 1 and Congenital Pseudarthrosis of the Tibia

Zhou¹,

Zeng

et al. 2016

Preprint

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“…The read coverage for the tibial pseudarthrosis sample (‘Mixed’) was 263x, where the NF1 somatic variant had 16% read frequency (41x variant containing reads which came from both directions). No reads in the blood sample contained the NF1 variant (91× coverage at this location) (previously reported in Paria et al 12). Data from 50 other exomes were analysed, and no other samples had reads containing this NF1 variant.…”

Section: Resultsmentioning

confidence: 56%

“…Even though pseudarthrosis tissue in individuals with NF1 has been shown to be caused by double inactivation of NF1,10 12 it is not known which specific cell type(s) is the originator of the somatic NF1 variant that drives the tibial dysplasia and pseudarthrosis. Once a somatic NF1 variant was identified in this patient's pseudarthrosis sample, further analysis by Sanger sequencing showed that this somatic variant was present in the soft tissue adjacent to the cortical bone at the fracture/pseudarthrosis site but was not present in the compact cortical bone.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, although a recent study showed that the large majority of NF1-associated tibial pseudathrosis samples show double inactivation of NF1 , a ‘second hit’ was not uniformly identified in all samples 12. We initially examined NF1 and 15 additional genes associated with the RAS/MAPK signalling pathway (see gene list in the Materials and methods section), but no mutations were detected in these genes except for the described NF1 and PTPN11 variants.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, not all individuals with tibial pseudarthrosis have NF1 and there is wide clinical variability of the tibial dysplasia in NF1, suggesting the possibility of additional genetic causes and/or modifiers. To elucidate the tissue of origin harbouring a somatic ‘second hit’ mutation associated with tibial pseudarthrosis, exome sequencing in one pseudarthrosis sample (c.3574 G>T, p.E1192*) (previously reported in Paria et al 12) was performed in different sections of tibial pseudarthrosis from an individual with NF1.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of somatic mutations in tibial pseudarthrosis samples in neurofibromatosis type 1

et al. 2015

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Background Tibial pseudarthrosis is associated with neurofibromatosis type 1 (NF1) and there is wide clinical variability of the tibial dysplasia in NF1, suggesting the possibility of genetic modifiers. Double inactivation of NF1 is postulated to be necessary for the development of tibial pseudarthrosis, but tissue or cell of origin of the ‘second hit’ mutation remains unclear. Methods Exome sequencing of different sections of surgically resected NF1 tibial pseudarthrosis tissue was performed and compared to germline (peripheral blood). Results A germline NF1 splice site mutation (c.61-2A>T, p.L21 M68del) was identified from DNA extracted from peripheral blood. Exome sequencing of DNA extracted from tissue removed during surgery of the tibial pseudarthrosis showed a somatic mutation of NF1 (c.3574G>T, p.E1192*) in the normal germline allele. Further analysis of different regions of the tibial pseudarthrosis sample showed enrichment of the somatic mutation in the soft tissue within the pseudarthrosis site and absence of the somatic mutation in cortical bone. In addition, a germline variant in PTPN11 (c.1658C>T, p.T553M), a gene involved in the RAS signal transduction pathway was identified, although the clinical significance is unknown. Conclusions Given that the NF1 somatic mutation was primarily detected in the proliferative soft tissue at the pseudarthrosis site, it is likely that the second hit occurred in mesenchymal progenitors from the periosteum. These results are consistent with a defect of differentiation, which may explain why the mutation is found in proliferative cells and not within cortical bone tissue, as the latter by definition contains mostly mature differentiated osteoblasts and osteocytes.

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2016 Children's Tumor Foundation conference on neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis

Fisher

Belzberg

Blank

et al. 2018

American J of Med Genetics Pt A

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Organized and hosted by the Children's Tumor Foundation (CTF), the Neurofibromatosis (NF) conference is the premier annual gathering for clinicians and researchers interested in neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). The 2016 edition constituted a blend of clinical and basic aspects of NF research that helped in clarifying different advances in the field. The incorporation of next generation sequencing is changing the way genetic diagnostics is performed for NF and related disorders, providing solutions to problems like genetic heterogeneity, overlapping clinical manifestations, or the presence of mosaicism. The transformation from plexiform neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) is being clarified, along with new management and treatments for benign and premalignant tumors. Promising new cellular and in vivo models for understanding the musculoskeletal abnormalities in NF1, the development of NF2 or SWN associated schwannomas, and clarifying the cells that give rise to NF1-associated optic pathway glioma were presented. The interaction of neurofibromin and SPRED1 was described comprehensively, providing functional insight that will help in the interpretation of pathogenicity of certain missense variants identified in NF1 and Legius syndrome patients. Novel promising imaging techniques are being developed, as well as new integrative and holistic management models for patients that take into account psychological, social, and biological factors. Importantly, new therapeutic approaches for schwannomas, meningiomas, ependymomas, PNF, and MPNST are being pursued. This report highlights the major advances that were presented at the 2016 CTF NF conference.

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Neurofibromin Deficiency-Associated Transcriptional Dysregulation Suggests a Novel Therapy for Tibial Pseudoarthrosis in NF1

Cited by 24 publications

References 25 publications

Identification of One <em>BOCR</em> Mutation and Five <em>NF1</em> Mutations in Male Patients with Neurofibromatosis Type 1 and Congenital Pseudarthrosis of the Tibia

Identification of One <em>BOCR</em> Mutation and Five <em>NF1</em> Mutations in Male Patients with Neurofibromatosis Type 1 and Congenital Pseudarthrosis of the Tibia

Evaluation of somatic mutations in tibial pseudarthrosis samples in neurofibromatosis type 1

2016 Children's Tumor Foundation conference on neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis

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