The Neurofibromatosis Institute, 5415 Briggs Avenue, La Crescenta, CA 91214, USAUnited States
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Persons with ordinary, prototypical Neurofibromatosis 1 (NF1) are born with a germinal/zygotic mutation at the NF1 locus on the long arm of chromosome 17 (17q) present in all of their cells. An NF1 germinal mutation is the “first hit,” accounting for haploinsufficiency at the NF1 locus. The NF1 somatic mutation is the “second hit,” accounting for diploinsufficiency (deranged or lost function of both alleles) at the NF1 locus. The NF1 somatic mutation occurs in a variety of somatic (i.e., non-germinal) cells, including, and especially the schwann cells (SC). I suggest that NF1 haploinsufficiency provides the conditions for the SC (and other cells) to develop NF1 diploinsufficiency rather than NF1 diploinsufficiency developing independently of the conditions in which it originates. In either case, imagine a viral analogue with an apoptosis trigger held in abeyance unless an NF1 somatic mutation occurs in the presence of an NF1 germinal mutation or whole gene deletion. That is, instead of altering the feature, for example, decreasing neurofibroma size and symptoms with MEK inhibitors, I herein suggest an approach to preventing certain NF1 features, keying off the fact that almost NF1 features involve somatic mutation of the cell’s NF1 wild type (WT) allele.
Keywords: neurofibroma; diploinsufficiency
OpenJournal PUBLISHERS Editorial To stop the progression of neurofibromatosis 1, a somatic mutation causes cellular apoptosis * Vincent M. Riccardi, MD, MBA* The Neurofibromatosis Institute, 5415 Briggs Avenue, La Crescenta, CA 91214, USA * *Corresponding author Vincent M. Riccardi, MD, MBA The Neurofibromatosis Institute, 5415 Briggs Avenue, La Crescenta, CA 91214, USA; E-mail: riccardi@medconsumer.com Article information th th Accepted: July 4th, 2025; Published: July 12th, 2025 Cite this article Riccardi VM.To stop the progression of neurofibromatosis 1,a somatic mutation causes cellular apoptosis. Neuro Open J. 2025; 11(1): e1-e2. ersons with ordinary, prototypical Neurofibromatosis 1 (NF1) article raises is the presence or timing of the NF1 somatic mutation are born with a germinal/zygotic mutation at the NF1 locus with regard to the development of the NF1 feature. Does the NF1 P on the long arm of chromosome 17 (17q) present in all of their somatic mutation derive the precursor or does the NF1 somatic cells. An NF1 germinal mutation is the “first hit,” accounting for mutation account for the conversion of the precursor to the haploinsufficiency at the NF1 locus. The NF1 somatic mutation feature? I expect that often it is the latter. Respecting this general is the “second hit,” accounting for diploinsufficiency (deranged or type of reasoning, perhaps the NF1 syndrome progression could lost function of both alleles) at the NF1 locus. The NF1 somatic be reversed or stopped early on through genetic manipulation mutation occurs in a variety of somatic (i.e., non-germinal) cells, before elements of the disorder compromised the person. For including, and especially the schwann cells (SC). I suggest that example, we could modify the zygote’s NF1 mutation, amplify NF1 haploinsufficiency provides the conditions for the SC (and expression of wildtype allele or use the occurrence of an NF1 other cells) to develop NF1 diploinsufficiency rather than NF1 somatic mutation as a trigger to remove the affected cell through diploinsufficiency developing independently of the conditions in induced apoptosis.
which it originates. In either case, imagine a viral analogue with an apoptosis trigger held in abeyance unless an NF1 somatic mutation Many factors other than the NF1 locus or the latter’s occurs in the presence of an NF1 germinal mutation or whole protein product, Neurofibromin (Nfn), might or can influence Cnf 3 4 gene deletion. That is, instead of altering the feature, for example, development, such as mast cells,3 collagen deposition4 and skin 5 2 decreasing neurofibroma size and symptoms with MEK inhibitors, adnexae.5 Rice, et al2 makes a clear case for cell-cell cooperativity I herein suggest an approach to preventing certain NF1 features, in NF1 syndrome skin potentially contributing to the development keying off the fact that almost NF1 features involve somatic of NF1 diploinsufficiency. Terminal sensory axons in the skin mutation of the cell’s NF1 wild type (WT) allele. are not always associated with other skin components (sweat glands, sebaceous glands, sweat ducts, vascular bundles, etc.). But, The NF1 phenotype, that is, the NF1 syndrome, has when they are, SCs may be dislodged from the involved nerve many elements, not all with the same “causal relationship” to NF1 and proliferate according to new schedules. Such cell divisions genotype. NF1 features are elements closest in causal proximity to afford new opportunities for the occurrence of SC NF1 somatic the genomic disturbance, for example, neurofibromas or vertebral mutations, ultimately affording both NF1 haploinsufficient SC dysplasia.1 NF1 consequences, derived from NF1 features, include and NF1 diploinsufficient SC accumulations, in turn providing a atypical neurofibromas and spinal scoliosis.1 NF1 complications, cellular and intercellular conglomeration that either anticipates or derived from NF1 consequences, include neurofibrosarcoma represents an early-stage cNF. The overall point is that something and spinal cord compression.1 Respecting the publication of F.L. about NF1 haploinsufficient cellular cooperativity affords the 6,7 Rice and colleagues,2 there is also the matter of the precursor opportunity for, or actually triggers, NF1 somatic mutations.6,7 of the NF1 feature. Their article emphasizes the importance of NF1 syndrome elements that are precursors to the syndrome’s As one peruses the natural history of the NF1 characteristic features. Specifically, they describe a precursor to the syndrome at the cellular level, recurrent NF1 diploinsufficiency, NF1 cutaneous neurofibroma (cNF). One important question the that is, recurrent NF1 somatic mutation, occurs very frequently cc Copyright 2025 by Riccardi VM. This is an open-access article distributed under Creative Commons Attribution 4.0 International License (CC BY 4.0), which Neuro Open J. 2025; 11(1): e1-e2.
in multiple types of tissue, including that of the central nervous change from NF1 haploinsufficiency to NF1 diploinsufficiency. system, the peripheral nervous system, the skin, the skeleton, stem cells, endocrine glands, the vascular system, the pulmonary