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<p>Congenital Dyserythropoietic Anaemia type I (CDA-I) is a rare inherited disorder of erythropoiesis, in which erythroid cells display a unique nuclear phenotype referred to as ‘spongy’ heterochromatin. The molecular basis of CDA-I remains unknown, with most cases of CDA-I caused by mutations in <i>CDAN1</i>, encoding Codanin-1, or <i>CDIN1</i>, encoding for Codanin-1-interacting nuclease 1 (CDIN1). To date, very little is known about the function of CDA-I disease proteins and the mechanism by which their associated mutations cause disease. Here, we demonstrate that endogenous CDIN1 interacts with Codanin-1, to form a stable complex. Structural and functional analysis of this complex reveals that the CDIN1-Codanin-1 complex is an RNA nuclease. We shed light on the key mechanistic features of the complex using biochemical and biophysical approaches, complemented by all-atom molecular dynamics (MD) structural simulations. We identify various functional consequences of founder patient mutations on the RNA nuclease activity of CDIN1, providing a framework for understanding the pathophysiology and developing therapeutic strategies for CDA-I.</p>

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CDIN1-Codanin-1 complex defective in congenital dyserythropoietic anaemia type I is an RNA nuclease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月2日

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  • Sanja Brolih,
  • Hafiz Saqib Ali,
  • Caroline Scott,
  • Aude-Anais Olijnik,
  • Hazel Aitkenhead,
  • Gemma Moir-Meyer,
  • Angeline E. Gavard,
  • Yuliana Yosaatmadja,
  • Douglas R. Higgs,
  • Veronica Buckle,
  • Noemi Roy,
  • Opher Gileadi,
  • Joseph A. Newman,
  • Fernanda Duarte,
  • Christian Babbs,
  • Peter J. McHugh

摘要

Congenital Dyserythropoietic Anaemia type I (CDA-I) is a rare inherited disorder of erythropoiesis, in which erythroid cells display a unique nuclear phenotype referred to as ‘spongy’ heterochromatin. The molecular basis of CDA-I remains unknown, with most cases of CDA-I caused by mutations in CDAN1, encoding Codanin-1, or CDIN1, encoding for Codanin-1-interacting nuclease 1 (CDIN1). To date, very little is known about the function of CDA-I disease proteins and the mechanism by which their associated mutations cause disease. Here, we demonstrate that endogenous CDIN1 interacts with Codanin-1, to form a stable complex. Structural and functional analysis of this complex reveals that the CDIN1-Codanin-1 complex is an RNA nuclease. We shed light on the key mechanistic features of the complex using biochemical and biophysical approaches, complemented by all-atom molecular dynamics (MD) structural simulations. We identify various functional consequences of founder patient mutations on the RNA nuclease activity of CDIN1, providing a framework for understanding the pathophysiology and developing therapeutic strategies for CDA-I.