A porcine model of neurofibromatosis type 1 that mimics the human disease
AuthorWhite, Katherine A
Swier, Vicki J
Cain, Jacob T
Kohlmeyer, Jordan L
Meyerholz, David K
Tanas, Munir R
Rohret, Frank A
Leidinger, Mariah R
Wallace, Margaret R
Dodd, Rebecca D
Tang, Amy H
Darbro, Benjamin W
Bellampalli, Shreya S
Rogers, Christopher S
Sieren, Jessica C
Quelle, Dawn E
Weimer, Jill M
AffiliationUniv Arizona, Dept Pharmacol
MetadataShow full item record
PublisherAMER SOC CLINICAL INVESTIGATION INC
CitationJCI Insight. 2018;3(12):e120402. https://doi.org/10.1172/jci.insight.120402.
RightsCopyright © 2018, American Society for Clinical Investigation
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractLoss of the NF1 tumor suppressor gene causes the autosomal dominant condition, neurofibromatosis type 1 (NF1). Children and adults with NF1 suffer from pathologies including benign and malignant tumors to cognitive deficits, seizures, growth abnormalities, and peripheral neuropathies. NF1 encodes neurofibromin, a Ras-GTPase activating protein, and NF1 mutations result in hyperactivated Ras signaling in patients. Existing NF1 mutant mice mimic individual aspects of NF1, but none comprehensively models the disease. We describe a potentially novel Yucatan miniswine model bearing a heterozygotic mutation in NF1 (exon 42 deletion) orthologous to a mutation found in NF1 patients. NF1(+/ex42del) miniswine phenocopy the wide range of manifestations seen in NF1 patients, including cafe au lait spots, neurofibromas, axillary freckling, and neurological defects in learning and memory. Molecular analyses verified reduced neurofibromin expression in swine NF1(+/ex42del) fibroblasts, as well as hyperactivation of Ras, as measured by increased expression of its downstream effectors, phosphorylated ERK1/2, SIAH, and the checkpoint regulators p53 and p21. Consistent with altered pain signaling in NF1, dysregulation of calcium and sodium channels was observed in dorsal root ganglia expressing mutant NF1. Thus, these NF1(+/ex42del) miniswine recapitulate the disease and provide a unique, much-needed tool to advance the study and treatment of NF1.
VersionFinal published version
SponsorsSynodos for NF1 program at the Children's Tumor Foundation; Children's Tumor Foundation [2015-04-009A]; NIH [R01NS082283, 1R01NS098772, 1R01DA042852]; US Department of Defense Congressionally Directed Military Medical Research and Development Program [NF1000099]; NCI [P30-CA086862]; NIH shared instrumentation award [1S10OD02502501]; Pharmacological Sciences Training grant [2T32-GM0677954-14]; Children's Tumor Foundation
- Neurofibromin in neurofibromatosis type 1 - mutations in NF1gene as a cause of disease.
- Authors: Abramowicz A, Gos M
- Issue date: 2014 Jul-Sep
- Legius syndrome, an Update. Molecular pathology of mutations in SPRED1.
- Authors: Brems H, Legius E
- Issue date: 2013
- A novel NF1 mutation in a Chinese patient with giant café-au-lait macule in neurofibromatosis type 1 associated with a malignant peripheral nerve sheath tumor and bone abnormality.
- Authors: Tong HX, Li M, Zhang Y, Zhu J, Lu WQ
- Issue date: 2012 Aug 29
- Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1.
- Authors: Hirata Y, Brems H, Suzuki M, Kanamori M, Okada M, Morita R, Llano-Rivas I, Ose T, Messiaen L, Legius E, Yoshimura A
- Issue date: 2016 Feb 12
- Neurofibromatosis type 1 (NF1) gene: Beyond café au lait spots and dermal neurofibromas.
- Authors: Peltonen S, Kallionpää RA, Peltonen J
- Issue date: 2017 Jul