Precise single‐base editing mXenopus tropicalis would greatly expand the utility of this true diploid frog for modeling human genetic diseases caused by point mutations. Here, we report the efficient conversion of C‐to‐T or G‐to‐A in X. tropicalis using the rat apolipoprotein B mRNA editing enzyme catalytic subunit 1–XTEN‐clustered regularly interspaced short palindromic repeat‐associated protein 9 (Cas9) nickase‐uracil DNA glycosylase inhibitor‐nuclear localization sequence base editor [base editor 3 (BE3)]. Coinjection of guide RNA and the Cas9 mutant complex mRNA into 1‐cell stage X. tropicalis embryos caused precise C‐to‐T or G‐to‐A substitution in 14 out of 19 tested sites with efficiencies of 5–75%, which allowed for easy establishment of stable lines. Targeting the conserved T‐box 5 R237 and Tyr C28 residues in X. tropicalis with the BE3 system mimicked human Holt‐Oram syndrome and oculocutaneous albinism type 1A, respectively. Our data indicate that BE3 is an easy and efficient tool for precise base editing in X. tropicalis.—Shi, Z., Xin, H., Tian, D., Lian, J., Wang, J., Liu, G., Ran, R., Shi, S., Zhang, Z., Shi, Y., Deng, Y., Hou, C., Chen, Y. Modeling human point mutation diseases in Xenopus tropicalis with a modified CRISPR/Cas9 system. FASEB J. 33,6962–6968 (2019). http://www.fasebj.org

In humans, germline TP53 mutations predispose carriers to a wide spectrum of cancers, which is known as Li–Fraumeni syndrome (LFS). To date, the association of melanomas with LFS remains unestablished. No melanomas have been reported in any P53‐modified mouse models either. In this study, we show that targeted disruption of P53 at the DNA‐binding domain in Xenopus tropicalis recapitulates LFS, with the formation of soft‐tissue sarcomas and pancreatic ductal adenocarcinoma. Interestingly, 19% of the 14‐month‐old tp53Δ7/Δ7 homozygotes and 18% of tp53+/Δ7 heterozygotes spontaneously developed small nevi and non‐invasive melanomas. Large invasive melanomas were also observed in other older homozygous mutants, with about 7.9% penetrance. Our data suggest that more dermatologic investigation of LFS patients should be able to settle the association of melanoma with LFS in epidemiology. Our model is also valuable for further investigation of the molecular mechanism underlying melanoma progression upon germline alteration of the tp53 locus.