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A Murine Model for Human ECO Syndrome Reveals a Critical Role of Intestinal Cell Kinase in Skeletal Development

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Abstract

An autosomal-recessive inactivating mutation R272Q in the human intestinal cell kinase (ICK) gene caused profound multiplex developmental defects in human endocrine-cerebro-osteodysplasia (ECO) syndrome. ECO patients exhibited a wide variety of skeletal abnormalities, yet the underlying mechanisms by which ICK regulates skeletal development remained largely unknown. The goal of this study was to understand the structural and mechanistic basis underlying skeletal anomalies caused by ICK dysfunction. Ick R272Q knock-in transgenic mouse model not only recapitulated major ECO skeletal defects such as short limbs and polydactyly but also revealed a deformed spine with defective intervertebral disk. Loss of ICK function markedly reduced mineralization in the spinal column, ribs, and long bones. Ick mutants showed a significant decrease in the proliferation zone of long bones and the number of type X collagen-expressing hypertrophic chondrocytes in the spinal column and the growth plate of long bones. These results implicate that ICK plays an important role in bone and cartilage development by promoting chondrocyte proliferation and maturation. Our findings provided new mechanistic insights into the skeletal phenotype of human ECO and ECO-like syndromes.

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Acknowledgements

We are grateful for the partial financial support from NIH R01AR064792 (XL), DK082614 (ZF), and CA195273 (ZF). We appreciate the technical assistance of the Research Histology Core at University of Virginia. The funders have no role in the study.

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, University of Virginia, 135 Hospital Dr., Charlottesville, VA, 22908, USA

    Mengmeng Ding, Li Jin, Lin Xie, A. Bobby Chhabra & Xudong Li

  2. Department of Pharmacology, University of Virginia, PO Box 800735, 1340 Jefferson Park Avenue, Charlottesville, VA, 22908, USA

    So Hyun Park, Yixin Tong, Di Wu & Zheng Fu

  3. Department of Orthopaedic Surgery, Wuhan Orthopaedic Hospital, Huazhong University of Science & Technology, Hubei, 430030, China

    Lin Xie

  4. The Gastrointestinal Surgery Center, Tongji Hospital, Huazhong University of Science & Technology, Hubei, 430030, China

    Yixin Tong

  5. Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China

    Mengmeng Ding

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  1. Mengmeng Ding
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  2. Li Jin
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  4. So Hyun Park
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  8. Zheng Fu
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  9. Xudong Li
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Correspondence to Zheng Fu or Xudong Li.

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Conflict of interest

Mengmeng Ding, Li Jin, Lin Xie, So Hyun Park, Yixin Tong, Di Wu, A. Bobby Chhabra, Zheng Fu, Xudong Li declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

All procedures involving animals were performed in accordance with ethical standards in an animal protocol that was approved by the Institutional Animal Care and Use Committee.

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Ding, M., Jin, L., Xie, L. et al. A Murine Model for Human ECO Syndrome Reveals a Critical Role of Intestinal Cell Kinase in Skeletal Development. Calcif Tissue Int 102, 348–357 (2018). https://doi.org/10.1007/s00223-017-0355-3

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  • DOI: https://doi.org/10.1007/s00223-017-0355-3

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