Sex Is a major determinant of neuronal dysfunction in neurofibromatosis type 1

Diggs-Andrews, Kelly A.; Brown, Jacquelyn A.; Gianino, Scott M.; Rubin, Joshua B.; Wozniak, David F.; Gutmann, David H.

doi:10.1002/ana.24093

Cited by 125 publications

(107 citation statements)

References 33 publications

(45 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our study also found an increased risk for need for therapy in females with NF1 and OPG, confirming recent studies suggesting that sex plays a role in the development of gliomas and neuronal dysfunction in patients with NF1. 21,22 A recent large multicenter study of visual outcomes in children with NF1 and OPG showed that at completion of chemotherapy, visual acuity improved in 32% of subjects, remained stable in 40%, and declined in 28%. 23 There are a number of limitations to this study.…”

Section: Discussionmentioning

confidence: 99%

The Use of Magnetic Resonance Imaging Screening for Optic Pathway Gliomas in Children with Neurofibromatosis Type 1

Prada

Hufnagel

Hummel

et al. 2015

The Journal of Pediatrics

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

The Use of Magnetic Resonance Imaging Screening for Optic Pathway Gliomas in Children with Neurofibromatosis Type 1

Prada

Hufnagel

Hummel

et al. 2015

The Journal of Pediatrics

View full text Add to dashboard Cite

“…Additionally, multiple studies have suggested a role of sex on the severity of defects in individuals with RASopathies. For example, studies of RASopathy mouse models associated with Neurofibromatosis 1 (NF1) showed that females have more severe neuronal dysfunction than males (44).…”

Section: Resultsmentioning

confidence: 99%

In vivo severity ranking of Ras pathway mutations associated with developmental disorders

Jindal

Goyal

Yamaya

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Germ-line mutations in components of the Ras/MAPK pathway result in developmental disorders called RASopathies, affecting about 1/1,000 human births. Rapid advances in genome sequencing make it possible to identify multiple disease-related mutations, but there is currently no systematic framework for translating this information into patient-specific predictions of disease progression. As a first step toward addressing this issue, we developed a quantitative, inexpensive, and rapid framework that relies on the early zebrafish embryo to assess mutational effects on a common scale. Using this assay, we assessed 16 mutations reported in MEK1, a MAPK kinase, and provide a robust ranking of these mutations. We find that mutations found in cancer are more severe than those found in both RASopathies and cancer, which, in turn, are generally more severe than those found only in RASopathies. Moreover, this rank is conserved in other zebrafish embryonic assays and Drosophila-specific embryonic and adult assays, suggesting that our ranking reflects the intrinsic property of the mutant molecule. Furthermore, this rank is predictive of the drug dose needed to correct the defects. This assay can be readily used to test the strengths of existing and newly found mutations in MEK1 and other pathway components, providing the first step in the development of rational guidelines for patient-specific diagnostics and treatment of RASopathies.T he Ras/MAPK (rat sarcoma/mitogen-activated protein kinase) signaling pathway is involved in essentially all aspects of organismal development, from the first cell divisions in the early embryo to postnatal development and growth (1-3). Given its critical function, it is not surprising that deregulated Ras/ MAPK signaling, resulting from either genetic or environmental perturbations, can lead to developmental abnormalities. A large class of such abnormalities, known as RASopathies, is associated with activating germ-line mutations in many components of the Ras pathway (4). Estimated to affect 1/1,000 human births, these abnormalities are characterized by a broad spectrum of phenotypes, including cardiac defects, craniofacial dysmorphisms, and neurocognitive delays (4). Although the origins of these phenotypes are still poorly understood, studies of model organisms show that many of the observed structural and functional defects can indeed be mimicked by targeted introduction of mutations found in RASopathies (5). Hundreds of such mutations have already been identified, and many more are likely to be discovered by the sequencing of affected individuals (6).Importantly, these studies identify new mutations in the very same components that are mutated in cancer and have been extensively studied both in vitro and in vivo (7-9). In particular, multiple new mutations were identified in MEK1, a MAPK kinase (10) and an important target for anticancer therapeutics (11)(12)(13)(14)(15)(16)(17)(18)(19). Because it is commonly believed that cancer mutations would be embryonic lethal when inherited through t...

show abstract

“…In Nf1 optic glioma mice, reduced cAMP levels and higher levels of RGC apoptosis are observed in females, leading to reduced visual acuity in female mice only. 53 Moreover, while the frequency of OPG development is similar in girls and boys with NF1, 3 times more females with NF1-OPG require treatment for visual decline. 53 These findings support a role for sex as a critical factor that underlies clinical outcomes in children with NF1-OPG.…”

Section: Use Of Nf1 Gem Strains To Understandmentioning

confidence: 99%

“…As mentioned above, female mice as well as female humans with NF1-OPG are more likely to experience visual decline and require treatment than their male counterparts. 53 These observations raise the possibility that females have different epigenetic programming due to X-chromosome influences, which change the intracellular context in which changes in neurofibromin expression affect biological outcomes. Identifying these epigenetic determinants may reveal new genes for risk stratification and therapeutic targeting.…”

Section: Translating Basic Science Discoveries Tomentioning

confidence: 99%

“…55 Moreover, this effect is independent of sex, suggesting that it reflects the primary biology of these tumors. 53 As more diverse GEM models of NF1-OPG are developed, it might be possible to mechanistically determine why tumors in this location have such different outcomes relevant to the design of targeted therapies.…”

Section: Translating Basic Science Discoveries Tomentioning

confidence: 99%

See 1 more Smart Citation

Eliminating barriers to personalized medicine

Gutmann

2014

Neurology

View full text Add to dashboard Cite

With the emergence of high-throughput discovery platforms, robust preclinical small-animal models, and efficient clinical trial pipelines, it is becoming possible to envision a time when the treatment of human neurologic diseases will become personalized. The emergence of precision medicine will require the identification of subgroups of patients most likely to respond to specific biologically based therapies. This stratification only becomes possible when the determinants that contribute to disease heterogeneity become more fully elucidated. This review discusses the defining factors that underlie disease heterogeneity relevant to the potential for individualized brain tumor (optic pathway glioma) treatments arising in the common single-gene cancer predisposition syndrome, neurofibromatosis type 1 (NF1). In this regard, NF1 is posited as a model genetic condition to establish a workable paradigm for actualizing precision therapeutics for other neurologic disorders. Neurology ® 2014;83:463-471 GLOSSARY cAMP 5 cyclic adenosine monophosphate; GEM 5 genetically engineered mouse; GWAS 5 genome-wide association studies; mTOR 5 mammalian target of rapamycin; NF1 5 neurofibromatosis type 1; NSC 5 neural stem cell; OPG 5 optic pathway glioma; PA 5 pilocytic astrocytoma; RGC 5 retinal ganglion cell.Neurofibromatosis type 1 (NF1) is one of the most common monogenic disorders in which affected individuals develop benign and malignant tumors.1 NF1 impacts 1:2,500 people worldwide, and individuals with NF1 are prone to the development of peripheral (neurofibromas, malignant peripheral nerve sheath tumors) and central (optic pathway glioma, malignant glioma) nervous system tumors.2,3 Similar to other autosomal dominant cancer predisposition syndromes, 4,5 people with NF1 start life with a germline mutation in one copy of the NF1 tumor suppressor gene; however, tumors require somatic (acquired) inactivation of the remaining functional NF1 allele, leading to complete loss of NF1 expression in specific cell types.6,7 For example, complete Nf1 gene inactivation in neuroglial 8,9 or Schwann cell 10,11 progenitors is required for murine optic glioma or neurofibroma formation, respectively.With the development of numerous accurate small-animal (genetically engineered mouse; GEM) models of NF1-associated nervous system tumors ( the stage has been set for the discovery and validation of promising therapeutic strategies and their translation to people affected with NF1. However, despite these advances, there are currently no effective therapies, which likely reflects the striking biological and clinical heterogeneity inherent to this condition. This review uses NF1-associated brain tumors (optic glioma) as an illustrative platform to discuss the barriers and challenges to developing and implementing effective targeted therapies.NF1-ASSOCIATED OPTIC PATHWAY GLIOMA NF1-associated optic pathway gliomas (NF1-OPGs) are largely pediatric tumors typically arising in children younger than 7 years of age. 21,22 As such, 15%-20% of child...

show abstract

Sex Is a major determinant of neuronal dysfunction in neurofibromatosis type 1

Cited by 125 publications

References 33 publications

The Use of Magnetic Resonance Imaging Screening for Optic Pathway Gliomas in Children with Neurofibromatosis Type 1

The Use of Magnetic Resonance Imaging Screening for Optic Pathway Gliomas in Children with Neurofibromatosis Type 1

In vivo severity ranking of Ras pathway mutations associated with developmental disorders

Eliminating barriers to personalized medicine

Contact Info

Product

Resources

About