Abstract
Neurofibromatosis type 1 (NF1) is a rare, autosomal dominant disease with variable clinical presentations. Large animal models are useful to help dissect molecular mechanisms, determine relevant biomarkers, and develop effective therapeutics. Here, we studied a NF1 minipig model (NF1+/ex42del) for the first 12 months of life to evaluate phenotype development, track disease progression, and provide a comparison to human subjects. Through systematic evaluation, we have shown that compared to littermate controls, the NF1 model develops phenotypic characteristics of human NF1: [1] café-au-lait macules, [2] axillary/inguinal freckling, [3] shortened stature, [4] tibial bone curvature, and [5] neurofibroma. At 4 months, full body computed tomography imaging detected significantly smaller long bones in NF1+/ex42del minipigs compared to controls, indicative of shorter stature. We found quantitative evidence of tibial bowing in a subpopulation of NF1 minipigs. By 8 months, an NF1+/ex42del boar developed a large diffuse shoulder neurofibroma, visualized on magnetic resonance imaging, which subsequently grew in size and depth as the animal aged up to 20 months. The NF1+/ex42del minipig model progressively demonstrates signature attributes that parallel clinical manifestations seen in humans and provides a viable tool for future translational NF1 research.
Highlights
Neurofibromatosis type 1 (NF1) is a rare, autosomal dominant disease with variable clinical presentations
Our previous work with minipigs has shown that a deletion of exon 42 (NF1+/ex42del), a mutation observed in NF1 patients, mimics early in life, a wide range of phenotypes exhibited by the human population including café-au-lait macules (CALMs), cutaneous and/or plexiform neurofibromas, axillary and inguinal freckling, unidentified bright objects, decreased cognitive abilities[22], and increased pain and sleep disturbances[34]
All eight NF1+/ex42del subjects presented with multiple CALMs at the first imaging timepoint (TP1, 4 months of age), while no CALMs were present on the four wildtype subjects (Fig. 1, Fig. S2)
Summary
Neurofibromatosis type 1 (NF1) is a rare, autosomal dominant disease with variable clinical presentations. We studied a NF1 minipig model (NF1+/ex42del) for the first 12 months of life to evaluate phenotype development, track disease progression, and provide a comparison to human subjects. Our previous work with minipigs has shown that a deletion of exon 42 (NF1+/ex42del), a mutation observed in NF1 patients, mimics early in life, a wide range of phenotypes exhibited by the human population including CALMs, cutaneous and/or plexiform neurofibromas, axillary and inguinal freckling, unidentified bright objects, decreased cognitive abilities[22], and increased pain and sleep disturbances[34]. This study provided a unique opportunity for systematic evaluation to capture the natural penetrance of phenotypical presentation and track progression of disease manifestation of NF1+/ex42del minipigs compared to sibling wildtype controls
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