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<p>Genetic pain loss disorders represent a heterogeneous group of rare diseases mainly characterized by defective nociception. Understanding the underlying molecular mechanism is fundamental to improve the treatment of patients affected by these rare disorders. Feline Leukemia Virus Subgroup C Receptor 1 (<i>FLVCR1</i>) is one of the genes previously associated with sensory neuropathy that requires further investigation. Here, we report on two additional patients with novel disease-causing variants in <i>FLVCR1</i> and introduce a zebrafish model of the disease. The analyses of patient-derived fibroblasts show that distinct <i>FLVCR1</i> variants compromised all the known functions associated with FLVCR1, thus affecting choline levels, heme biosynthesis and mitochondrial Ca<sup>2+</sup> handling. Furthermore, we provide evidence that the alteration of these processes impairs the TCA cycle and OXPHOS, and induces lipid peroxidation. Our data points to the alterations of energetic metabolism as a potential driving pathomechanism in FLVCR1-associated sensory neuropathy.</p>

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Mitochondrial energetic failure underlies FLVCR1-related sensory neuropathy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月14日

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  • Francesca Bertino,
  • Diletta Isabella Zanin Venturini,
  • Eleonora Grasso,
  • Joanna Kopecka,
  • Chiara Salio,
  • Barbara Gnutti,
  • Ram Manohar Basnet,
  • Stefania Bellini,
  • Luca Mignani,
  • Boxun Zhao,
  • Felix Kleefeld,
  • Andreas Hentschel,
  • Francesca Magnani,
  • Veronica Fiorito,
  • Raluca Elena Abalai,
  • Livia Metani,
  • Anna Lucia Allocco,
  • Sara Petrillo,
  • Francesco De Giorgio,
  • Giorgia Ammirata,
  • Ettore Salsano,
  • Davide Pareyson,
  • Maja di Rocco,
  • Angela Abicht,
  • Emily McCourt,
  • Rita Horvath,
  • Heike Kölbel,
  • Austin Larson,
  • Andreas Roos,
  • Timothy W. Yu,
  • Dario Finazzi,
  • Chiara Riganti,
  • Emanuela Tolosano,
  • Deborah Chiabrando

摘要

Genetic pain loss disorders represent a heterogeneous group of rare diseases mainly characterized by defective nociception. Understanding the underlying molecular mechanism is fundamental to improve the treatment of patients affected by these rare disorders. Feline Leukemia Virus Subgroup C Receptor 1 (FLVCR1) is one of the genes previously associated with sensory neuropathy that requires further investigation. Here, we report on two additional patients with novel disease-causing variants in FLVCR1 and introduce a zebrafish model of the disease. The analyses of patient-derived fibroblasts show that distinct FLVCR1 variants compromised all the known functions associated with FLVCR1, thus affecting choline levels, heme biosynthesis and mitochondrial Ca2+ handling. Furthermore, we provide evidence that the alteration of these processes impairs the TCA cycle and OXPHOS, and induces lipid peroxidation. Our data points to the alterations of energetic metabolism as a potential driving pathomechanism in FLVCR1-associated sensory neuropathy.