دورية أكاديمية
The pathogenic mechanism of syndactyly type V identified in a Hoxd13Q50R knock-in mice.
| العنوان: | The pathogenic mechanism of syndactyly type V identified in a Hoxd13Q50R knock-in mice. |
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| المؤلفون: | Wang H; 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.; 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., Chen X; 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., Meng X; 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., Cao Y; 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., Han S; 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., Liu K; 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., Zhao X; 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., Zhao X; 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. xiulizhao@ibms.pumc.edu.cn., Zhang X; 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. xuezhang@pumc.edu.cn. |
| المصدر: | Bone research [Bone Res] 2024 Apr 01; Vol. 12 (1), pp. 21. Date of Electronic Publication: 2024 Apr 01. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: West China School of Stomatology, Sichuan University Country of Publication: China NLM ID: 101608652 Publication Model: Electronic Cited Medium: Print ISSN: 2095-4700 (Print) Linking ISSN: 20954700 NLM ISO Abbreviation: Bone Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2014- : Chengdu, Sichuan, P. R. China : [New York] : West China School of Stomatology, Sichuan University ; co-published by Nature Publishing Group Original Publication: Chengdu, Sichuan, P. R. China : Sichuan University Press |
| مواضيع طبية MeSH: | Brachydactyly* , Syndactyly*/genetics , Limb Deformities, Congenital*, Mice ; Humans ; Animals ; Hedgehog Proteins/genetics ; Transcription Factors/genetics |
| مستخلص: | Syndactyly type V (SDTY5) is an autosomal dominant extremity malformation characterized by fusion of the fourth and fifth metacarpals. In the previous publication, we first identified a heterozygous missense mutation Q50R in homeobox domain (HD) of HOXD13 in a large Chinese family with SDTY5. In order to substantiate the pathogenicity of the variant and elucidate the underlying pathogenic mechanism causing limb malformation, transcription-activator-like effector nucleases (TALEN) was employed to generate a Hoxd13Q50R mutant mouse. The mutant mice exhibited obvious limb malformations including slight brachydactyly and partial 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 limb development, we found the ectopically expressed Shh, Grem1 and Fgf8 and down-regulated Bmp2 in the embryonic limb bud at E10.5 to E12.5. A transcriptome sequencing analysis was conducted on limb buds (LBs) at E11.5, revealing 31 genes that exhibited notable disparities in mRNA level between the Hoxd13Q50R homozygotes and the wild-type. These genes are known to be involved in various processes such as limb development, cell proliferation, migration, and apoptosis. Our findings indicate that the ectopic expression of Shh and Fgf8, in conjunction with the down-regulation of Bmp2, results in a failure of patterning along both the anterior-posterior and proximal-distal axes, as well as a decrease in interdigital programmed cell death (PCD). This cascade ultimately leads to the development of syndactyly and brachydactyly in heterozygous mice, and severe limb malformations in homozygous mice. These findings suggest that abnormal expression of SHH, FGF8, and BMP2 induced by HOXD13Q50R may be responsible for the manifestation of human SDTY5. (© 2024. The Author(s).) |
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| معلومات مُعتمدة: | 30871367 National Natural Science Foundation of China (National Science Foundation of China); 2022YFC2703700 National Science Foundation of China | National Natural Science Foundation of China-Yunnan Joint Fund (NSFC-Yunnan Joint Fund); 2021-I2M-1-051 Chinese Academy of Medical Sciences (CAMS) |
| المشرفين على المادة: | 0 (Hedgehog Proteins) 0 (Transcription Factors) |
| SCR Disease Name: | Syndactyly, type v |
| تواريخ الأحداث: | Date Created: 20240401 Date Completed: 20240403 Latest Revision: 20240404 |
| رمز التحديث: | 20240404 |
| مُعرف محوري في PubMed: | PMC10984994 |
| DOI: | 10.1038/s41413-024-00322-y |
| PMID: | 38561387 |
| قاعدة البيانات: | MEDLINE |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 2095-4700 |
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| DOI: | 10.1038/s41413-024-00322-y |