期刊
DISEASE MODELS & MECHANISMS
卷 14, 期 12, 页码 -出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dmm.048963
关键词
Musculocontractural Ehlers-Danlos syndrome; Dermatan sulfate; Mouse model; CRISPR/Cas9; Myopathy
资金
- Health Sciences Research Grants for Research on Human Genome and Gene Therapy from the Ministry of Health, Labor and Welfare of Japan
- Japan Society for the Promotion of Science (JSPS KAKENHI) [19K07054JP, 19H03616JP]
- Practical Research Project for Rare/Intractable Diseases, Japan Agency for Medical Research and Development [17ek0109105h0003]
- Research Institute of Meijo University
Researchers generated mouse models for musculocontractural Ehlers-Danlos syndrome (mcEDS) through CRISPR/Cas9 genome editing, revealing pathophysiological features such as growth impairment, skin fragility, and muscle-related phenotypes caused by depletion of dermatan sulfate (DS). This study provides insights into the pathophysiology of mcEDS and may contribute to the development of novel treatment strategies.
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.
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