A new mouse model of Ehlers-Danlos syndrome generated using CRISPR/Cas9-mediated genomic editing
| Autor: | Chiaki Masuda, Yuki Takahashi, Atsushi Watanabe, Shota Saka, Yukiko U. Inoue, Shuji Mizumoto, Takashi Okada, Kohei Konishi, Toshiki Tanase, Shinji Miyata, Aki Nakamura-Takahashi, Yuko Nitahara-Kasahara, Takahiro Yoshizawa, Shuhei Yamada, Takayoshi Inoue, Yasunobu Maruoka, Guillermo Posadas-Herrera, Emi Matsumoto, Tomoki Kosho, Yoshihiro Nomura, Takeda Shin'ichi, Ayana Hashimoto |
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| Rok vydání: | 2021 |
| Předmět: |
Neuromuscular Disease Models
Decorin Myopathy Mutant Neuroscience (miscellaneous) Medicine (miscellaneous) Biology General Biochemistry Genetics and Molecular Biology Dermatan sulfate Mouse model Mice chemistry.chemical_compound Immunology and Microbiology (miscellaneous) Pregnancy Pathology medicine RB1-214 Animals CRISPR CRISPR/Cas9 Mice Knockout Perimysium Musculocontractural Ehlers-Danlos syndrome Skeletal muscle Genomics Molecular biology medicine.anatomical_structure chemistry Knockout mouse Medicine Ehlers-Danlos Syndrome Female CRISPR-Cas Systems Sulfotransferases medicine.symptom Research Article |
| Zdroj: | Disease Models & Mechanisms article-version (VoR) Version of Record Disease Models & Mechanisms, Vol 14, Iss 12 (2021) |
| ISSN: | 1754-8411 1754-8403 |
| DOI: | 10.1242/dmm.048963 |
| Popis: | Musculocontractural Ehlers-Danlos syndrome (mcEDS) is caused by generalized depletion of dermatan sulfate (DS) due to biallelic pathogenic variants in CHST14 encoding dermatan 4-O-sulfotransferase 1 (D4ST1) (mcEDS-CHST14). Here, we generated mouse models for mcEDS-CHST14 carrying homozygous mutations (1 bp deletion or 6 bp insertion/10 bp deletion) in Chst14 through CRISPR/Cas9 genome engineering to overcome perinatal lethality in conventional Chst14-deleted knockout mice. DS depletion was detected in the skeletal muscle of these genome-edited mutant mice, consistent with loss of D4ST1 activity. The mutant mice showed common pathophysiological features, regardless of the variant, including growth impairment and skin fragility. Notably, we identified myopathy-related phenotypes. Muscle histopathology showed variation in fiber size and spread of the muscle interstitium. Decorin localized diffusely in the spread endomysium and perimysium of skeletal muscle, unlike in wild-type mice. The mutant mice showed lower grip strength and decreased exercise capacity compared to wild type, and morphometric evaluation demonstrated thoracic kyphosis in mutant mice. The established CRISPR/Cas9-engineered Chst14 mutant mice could be a useful model to further our understanding of mcEDS pathophysiology and aid in the development of novel treatment strategies. Summary: CRISPR/Cas9 genome-engineered Chst14−/− mouse models of musculocontractural Ehlers-Danlos syndrome (mcEDS) display similar myopathic features (particularly those caused by the loss of D4ST1) to mcEDS patients and may facilitate further understanding of mcEDS. |
| Databáze: | OpenAIRE |
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