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A porcine model of neurofibromatosis type 1 that mimics the human disease.

A porcine model of neurofibromatosis type 1 that mimics the human disease.

Authors :
White KA
Swier VJ
Cain JT
Kohlmeyer JL
Meyerholz DK
Tanas MR
Uthoff J
Hammond E
Li H
Rohret FA
Goeken A
Chan CH
Leidinger MR
Umesalma S
Wallace MR
Dodd RD
Panzer K
Tang AH
Darbro BW
Moutal A
Cai S
Li W
Bellampalli SS
Khanna R
Rogers CS
Sieren JC
Quelle DE
Weimer JM
Source :
JCI insight [JCI Insight] 2018 Jun 21; Vol. 3 (12). Date of Electronic Publication: 2018 Jun 21 (Print Publication: 2018).
Publication Year :
2018

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

Language :
English
ISSN :
2379-3708
Volume :
3
Issue :
12
Database :
MEDLINE
Journal :
JCI insight
Publication Type :
Academic Journal
Accession number :
29925695
Full Text :
https://doi.org/10.1172/jci.insight.120402