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<p>Wolfram syndrome (WS) is marked by juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing loss. The causative genes, <i>WFS1</i> and <i>CISD2</i>, correspond to WS types 1 and 2, respectively. Here, we establish their mutual indispensability for inositol 1,4,5-triphosphate receptor (IP<sub>3</sub>R) activity, demonstrating their ability to restore reduced IP<sub>3</sub>R activity in WFS1- or CISD2-deficient mammalian cells. Additionally, our <i>Drosophila</i> WS models lacking <i>dWFS1</i> or <i>dCISD</i> exhibit diabetes-like phenotypes analogous to WS patients, and overexpression of <i>dWFS1</i> and <i>dCISD</i> in the flies alleviates their phenotypes. We have engineered a peptide containing the CDGSH domain of CISD2, critical for its interaction with IP<sub>3</sub>R. Overexpression of our CISD2 peptide or treatment with its cell-penetrating peptide (CPP)-conjugated form restores calcium homeostasis in WFS1- or CISD2-deficient cells, and overexpressing the homologous dCISD peptide suppresses diabetes-like phenotypes in WS model flies. These findings underscore the intricate involvements of WFS1 and CISD2 in ER calcium regulation and provide potential therapeutic prospects for WS-related diabetes.</p>

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Reciprocal rescue of Wolfram syndrome by two causative genes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月3日

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  • Su Jin Ham,
  • Eunju Yoon,
  • Da Hyun Lee,
  • Sehyeon Kim,
  • Heesuk Yoo,
  • Jongkyeong Chung

摘要

Wolfram syndrome (WS) is marked by juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing loss. The causative genes, WFS1 and CISD2, correspond to WS types 1 and 2, respectively. Here, we establish their mutual indispensability for inositol 1,4,5-triphosphate receptor (IP3R) activity, demonstrating their ability to restore reduced IP3R activity in WFS1- or CISD2-deficient mammalian cells. Additionally, our Drosophila WS models lacking dWFS1 or dCISD exhibit diabetes-like phenotypes analogous to WS patients, and overexpression of dWFS1 and dCISD in the flies alleviates their phenotypes. We have engineered a peptide containing the CDGSH domain of CISD2, critical for its interaction with IP3R. Overexpression of our CISD2 peptide or treatment with its cell-penetrating peptide (CPP)-conjugated form restores calcium homeostasis in WFS1- or CISD2-deficient cells, and overexpressing the homologous dCISD peptide suppresses diabetes-like phenotypes in WS model flies. These findings underscore the intricate involvements of WFS1 and CISD2 in ER calcium regulation and provide potential therapeutic prospects for WS-related diabetes.