Journal article
A porcine model of neurofibromatosis type 1 that mimics the human disease
JCI insight, Vol.3(12), e120402
06/21/2018
DOI: 10.1172/jci.insight.120402
PMCID: PMC6124439
PMID: 29925695
Abstract
Loss 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 café 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.
Details
- Title: Subtitle
- A porcine model of neurofibromatosis type 1 that mimics the human disease
- Creators
- Katherine A White - Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, South Dakota, USAVicki J Swier - Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, South Dakota, USAJacob T Cain - Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, South Dakota, USAJordan L Kohlmeyer - Molecular Medicine ProgramDavid K Meyerholz - Department of Pathology, andMunir R Tanas - Department of Pathology, andJohanna Uthoff - Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAEmily Hammond - Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAHua Li - Department of Molecular Genetics and Microbiology andFrank A Rohret - Exemplar Genetics, Coralville, Iowa, USAAdam Goeken - Department of Pathology, andChun-Hung Chan - Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, South Dakota, USAMariah R Leidinger - Department of Pathology, andShaikamjad Umesalma - Department of Pharmacology andMargaret R Wallace - Department of Molecular Genetics and Microbiology andRebecca D Dodd - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAKarin Panzer - Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAAmy H Tang - Department of Microbiology and Molecular Cell Biology, Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VirginiaBenjamin W Darbro - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USAAubin Moutal - Department of Pharmacology, University of Arizona, Tucson, Arizona, USASong Cai - Department of Pharmacology, University of Arizona, Tucson, Arizona, USAWennan Li - Department of Pharmacology, University of Arizona, Tucson, Arizona, USAShreya S Bellampalli - Department of Pharmacology, University of Arizona, Tucson, Arizona, USARajesh Khanna - Department of Pharmacology, University of Arizona, Tucson, Arizona, USAChristopher S Rogers - Exemplar Genetics, Coralville, Iowa, USAJessica C Sieren - Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USADawn E Quelle - Molecular Medicine ProgramJill M Weimer - Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, South Dakota, USA
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.3(12), e120402
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/jci.insight.120402
- PMID
- 29925695
- PMCID
- PMC6124439
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Grant note
- P30-CA086862 / National Cancer Institute Core Grant to the University of Iowa Holden Comprehensive Cancer Center Young Investigator’s Award / Children’s Tumor Foundation Synodos for NF1 / Children’s Tumor Foundation R01NS082283 / National Institutes of Health 2T32-GM0677954-14 / National Institutes of Health Pharmacological Sciences Training Grant 1R01NS098772 / National Institutes of Health Undergraduate Biology Research Program / University of Arizona 2015-04-009A / Children’s Tumor Foundation NF1000099 / U.S. Department of Defense Congressionally Directed Military Medical Research and Development Program 1R01DA042852 / National Institutes of Health
- Language
- English
- Date published
- 06/21/2018
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Hematology, Oncology, and Blood & Marrow Transplantation; Stead Family Department of Pediatrics; Pathology; Medical Genetics and Genomics; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984040013302771
Metrics
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