CRISPR/Cas9-mediated mutation ofPHEXin rabbit recapitulates human X-linked hypophosphatemia (XLH)

作者：Tingting Sui, Lin Yuan, Huan Liu, Mao Chen, Jichao Deng, Yong Wang, Zhanjun Li, Liangxue Lai · 发表于：Human Molecular Genetics · 年份：2016 · DOI：10.1093/hmg/ddw125 · 被引用次数：46 · 研究领域：Parathyroid Disorders and Treatments、Renal and related cancers、Genetic Syndromes and Imprinting

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.