Longitudinal phenotype development in a minipig model of neurofibromatosis type 1

• Published in: Scientific reports Vol. 10; no. 1; p. 5046
• Main Authors: Uthoff, Johanna, Larson, Jared, Sato, Takashi S., Hammond, Emily, Schroeder, Kimberly E., Rohret, Frank, Rogers, Christopher S., Quelle, Dawn E., Darbro, Benjamin W., Khanna, Rajesh, Weimer, Jill M., Meyerholz, David K., Sieren, Jessica C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.03.2020; Nature Publishing Group
• Subjects: 692/308/1426; 692/308/575; 692/699/375/365; Animal models; Animals; Bones; Computed tomography; Disease; Disease Models, Animal; Disease Progression; Genetic disorders; Genotype & phenotype; Human subjects; Humanities and Social Sciences; Humans; Magnetic Resonance Imaging; Medical imaging; Molecular modelling; multidisciplinary; Mutation; Neurofibroma - diagnostic imaging; Neurofibroma - pathology; Neurofibromatosis; Neurofibromatosis 1 - diagnostic imaging; Neurofibromatosis 1 - pathology; Neurological disorders; Phenotype; Phenotypes; Recklinghausen's disease; Science; Science (multidisciplinary); Standard deviation; Swine; Swine, Miniature; Tibia - diagnostic imaging; Tibia - pathology; Time Factors; Tomography, X-Ray Computed; Translational Research, Biomedical; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-61251-4

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.