title: CRISPR/Cas9-mediated mutation of PHEX in rabbit recapitulates human X-linked hypophosphatemia (XLH).
abstract: X-linked hypophosphatemia (XLH) is the most common cause of inheritable rickets, with an incidence of 1/20 000 in humans. Inactivation or mutation of the gene PHEX, a phosphate-regulating endopeptidase, leads to hypophosphatemia and defective bone mineralization in XLH patients. Presently, there is no adequate animal model for safety assessments of physiotherapies and drug screening for XLH rickets. In this study, an XLH model was generated via PHEX gene knockout (KO) through coinjection of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9)/sgRNA mRNA into rabbit zygotes. The typical phenotypes of growth retardation, hypophosphatemia, elevated serum FGF23 and bone mineralization were observed in the PHEX KO rabbits but not in normal controls. In summary, for the first time, we have successfully obtained PHEX KO rabbits and recapitulated human XLH using the CRISPR/Cas9 system. This novel XLH rabbit model could be utilized as a drug screening model for XLH prevention and preclinical therapy.
authors.affiliation: Jilin Provincial Key Laboratory of Animal Embryo Engineering, Institute of Zoonosis, Jilin University, Changchun 130062, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Sui
authors.affiliation: Jilin Provincial Key Laboratory of Animal Embryo Engineering, Institute of Zoonosis, Jilin University, Changchun 130062, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Jilin Provincial Key Laboratory of Animal Embryo Engineering, Institute of Zoonosis, Jilin University, Changchun 130062, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Jilin Provincial Key Laboratory of Animal Embryo Engineering, Institute of Zoonosis, Jilin University, Changchun 130062, China.
authors.forename: Mao
authors.initials: M
authors.lastname: Chen
authors.affiliation: Jilin Provincial Key Laboratory of Animal Embryo Engineering, Institute of Zoonosis, Jilin University, Changchun 130062, China.
authors.forename: Jichao
authors.initials: J
authors.lastname: Deng
authors.affiliation: Jilin Provincial Key Laboratory of Animal Embryo Engineering, Institute of Zoonosis, Jilin University, Changchun 130062, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Jilin Provincial Key Laboratory of Animal Embryo Engineering, Institute of Zoonosis, Jilin University, Changchun 130062, China lizj_1998@jlu.edu.cn lai_liangxue@gibh.ac.cn.
authors.forename: Zhanjun
authors.initials: Z
authors.lastname: Li
authors.affiliation: Jilin Provincial Key Laboratory of Animal Embryo Engineering, Institute of Zoonosis, Jilin University, Changchun 130062, China lizj_1998@jlu.edu.cn lai_liangxue@gibh.ac.cn.|CAS Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Liangxue
authors.initials: L
authors.lastname: Lai
mesh_terms: D000818:Animals; D002113:Calcification, Physiologic / Q000235:genetics; D004195:Disease Models, Animal; D053098:Familial Hypophosphatemic Rickets / Q000235:genetics* / Q000378:metabolism; D005260:Female; D000089703:Fibroblast Growth Factor-23; D055786:Gene Knockout Techniques / Q000379:methods / Q000662:veterinary; D040181:Genetic Diseases, X-Linked / Q000235:genetics; D006801:Humans; D017674:Hypophosphatemia / Q000209:etiology / Q000235:genetics; D009154:Mutation; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000235:genetics / Q000378:metabolism; D010710:Phosphates; D011817:Rabbits; D012279:Rickets / Q000209:etiology
chemical_list: C000717427:FGF23 protein, human; D010710:Phosphates; D000089703:Fibroblast Growth Factor-23; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human