TY - JOUR
T1 - Longitudinal phenotype development in a minipig model of neurofibromatosis type 1
AU - Uthoff, Johanna
AU - Larson, Jared
AU - Sato, Takashi S.
AU - Hammond, Emily
AU - Schroeder, Kimberly E.
AU - Rohret, Frank
AU - Rogers, Christopher S.
AU - Quelle, Dawn E.
AU - Darbro, Benjamin W.
AU - Khanna, Rajesh
AU - Weimer, Jill M.
AU - Meyerholz, David K.
AU - Sieren, Jessica C.
N1 - Funding Information:
The authors would like to acknowledge the following individuals for technical assistance: Judy Rohret, Jason Struzynski, Kelly Stark, Melissa Saylor, Jarron Atha, Dan Thedens, Marla Kleingartner, Autumn Craig, Kori Rich, Adam Goeken, Mariah Leidinger, Susan Walsh, Michael Acevedo, Tony Smith, and Kevin Knoernschild. This work was supported by funding from the Synodos for NF1 program at the Children’s Tumor Foundation to DKM, BWD, CSR, JCS, DEQ, and JMW and an NCI Core grant (P30CA086862) to the University of Iowa Holden Comprehensive Cancer Center. NIH shared instrumentation awards were used to purchase both the CT (S10OD018526) and the MR (S10OD02502501) scanners utilized in this study.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85082028930&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85082028930&partnerID=8YFLogxK
U2 - 10.1038/s41598-020-61251-4
DO - 10.1038/s41598-020-61251-4
M3 - Article
C2 - 32193437
AN - SCOPUS:85082028930
SN - 2045-2322
VL - 10
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 5046
ER -