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A new mouse model of Ehlers-Danlos syndrome generated using CRISPR/Cas9-mediated genomic editing

2021; The Company of Biologists; Volume: 14; Issue: 12 Linguagem: Inglês

10.1242/dmm.048963

1754-8411

Yuko Nitahara‐Kasahara, Shuji Mizumoto, Yukiko Inoue, Shota Saka, Guillermo Posadas-Herrera, Aki Nakamura-Takahashi, Yuki Takahashi, Ayana Hashimoto, Kohei Konishi, Shinji Miyata, Chiaki Masuda, Emi Matsumoto, Yasunobu Maruoka, Takahiro Yoshizawa, Toshiki Tanase, Takayoshi Inoue, Shuhei Yamada, Y. Nomura, Shin’ichi Takeda, Atsushi Watanabe, Tomoki Kosho, Takashi Okada,

Glycosylation and Glycoproteins Research

ABSTRACT 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.