The pathogenic mechanism of syndactyly type V identified in aHoxd13Q50R knock-in mice  

作　　者：Han Wang Xiumin Chen Xiaolu Meng Yixuan Cao Shirui Han Keqiang Liu Ximeng Zhao Xiuli Zhao Xue Zhang 

机构地区：[1]McKusick-Zhang Center for Genetic Medicine,State Key Laboratory of Complex Severe and Rare Diseases,Department of Medical Genetics,Institute of Basic Medical Sciences Chinese Academy of Medical Sciences,School of Basic Medicine Peking Union Medical College,Beijing 100005,China [2]Department of Orthopedics,State Key Laboratory of Complex Severe and Rare Diseases,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100730,China

出　　处：《Bone Research》2024年第2期349-360,共12页骨研究（英文版）

基　　金：supported by grants from the National Key Research and Development Program of China(2022YFC2703700 and 2022YFC2703900);National Natural Science Foundation of China(30871367);CAMS Innovation Fund for Medical Sciences(CIFMS 2021-I2M-1-018 and CIFMS 2021-I2M-1-051).

摘　　要：Syndactyly type V (SDTY5) is an autosomal dominant extremity malformation characterized by fusion of the fourth and fifthmetacarpals. In the previous publication, we first identified a heterozygous missense mutation Q50R in homeobox domain (HD) ofHOXD13 in a large Chinese family with SDTY5. In order to substantiate the pathogenicity of the variant and elucidate the underlyingpathogenic mechanism causing limb malformation, transcription-activator-like effector nucleases (TALEN) was employed togenerate a Hoxd13Q50R mutant mouse. The mutant mice exhibited obvious limb malformations including slight brachydactyly andpartial syndactyly between digits 2-4 in the heterozygotes, and severe syndactyly, brachydactyly and polydactyly in homozygotes.Focusing on BMP2 and SHH/GREM1/AER-FGF epithelial mesenchymal (e-m) feedback, a crucial signal pathway for limbdevelopment, we found the ectopically expressed Shh, Grem1 and Fgf8 and down-regulated Bmp2 in the embryonic limb bud atE10.5 to E12.5. A transcriptome sequencing analysis was conducted on limb buds (LBs) at E11.5, revealing 31 genes that exhibitednotable disparities in mRNA level between the Hoxd13Q50R homozygotes and the wild-type. These genes are known to be involvedin various processes such as limb development, cell proliferation, migration, and apoptosis. Our findings indicate that the ectopicexpression of Shh and Fgf8, in conjunction with the down-regulation of Bmp2, results in a failure of patterning along both theanterior-posterior and proximal-distal axes, as well as a decrease in interdigital programmed cell death (PCD). This cascadeultimately leads to the development of syndactyly and brachydactyly in heterozygous mice, and severe limb malformations inhomozygous mice. These findings suggest that abnormal expression of SHH, FGF8, and BMP2 induced by HOXD13Q50R may beresponsible for the manifestation of human SDTY5.

关 键 词：BMP2 MECHANISM finding 

分 类 号：R682.1[医药卫生—骨科学]