Mitochondrial energetic failure underlies FLVCR1-related sensory neuropathy
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 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.
Authors
- Chiara Riganti (ORCID: https://orcid.org/0000-0001-9787-4836)
- Giorgia Ammirata
- Diletta Isabella Zanin Venturini
- Francesco De Giorgio (ORCID: https://orcid.org/0000-0002-6734-6722)
- Felix Kleefeld (ORCID: https://orcid.org/0000-0002-0643-7313)
- Veronica Fiorito (ORCID: https://orcid.org/0000-0001-9063-7918)
- Emily A. McCourt
- Luca Mignani (ORCID: https://orcid.org/0000-0002-9958-1225)
- Barbara Gnutti (ORCID: https://orcid.org/0000-0001-8583-2583)
- Anna Lucia Allocco (ORCID: https://orcid.org/0000-0001-5432-9280)
- Joanna Kopecka (ORCID: https://orcid.org/0000-0003-3612-3953)
- Francesca Giulia Magnani (ORCID: https://orcid.org/0000-0002-6503-3052)
- Deborah Chiabrando (ORCID: https://orcid.org/0000-0002-8968-8029)
- Francesca Bertino (ORCID: https://orcid.org/0000-0001-9137-6377)
- Boxun Zhao (ORCID: https://orcid.org/0000-0003-2337-5756)
- Eleonora Grasso (ORCID: https://orcid.org/0009-0009-0746-0193)
- Livia Metani
- Ram Manohar Basnet
- M. Di Rocco
- Raluca Elena Abalai
- Heike Kölbel
- Emanuela Tolosano
- Ettore Salsano
- Stefania Bellini
- Sara Petrillo
- Chiara Salio
- Andreas Hentschel
- Andreas Roos
- Davide Pareyson
- Rita Horvath
- Dario Finazzi
- Angela Abicht
Institutions
- Broad Institute (US)
- Boston Children's Hospital (US)
- Harvard University (US)
- University of Cambridge (GB)
- University of Pavia (IT)
- Children's Hospital of Eastern Ontario (CA)
- Istituto Giannina Gaslini (IT)
- The Medical Center of Aurora (US)
- Humboldt-Universität zu Berlin (DE)
- Düsseldorf University Hospital (DE)
- Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT)
- Medical Genetics Center (DE)
- Essen University Hospital (DE)
- Leibniz Institute for Analytical Sciences - ISAS (DE)
- Friedrich Baur Stiftung (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US)
- Heinrich Heine University Düsseldorf (DE)
- University of Turin (IT)
- Aurora University (US)
- University of Brescia (IT)
- Ludwig-Maximilians-Universität München (DE)
- University of Colorado Denver (US)
Publication Details
- Journal
- Communications Biology
- Published
- 2026-02-14
- DOI
- https://doi.org/10.1038/s42003-026-09691-y
- Primary Topic
- Glycogen Storage Diseases and Myoclonus
- Type
- article
- Field-Weighted Citation Impact
- 0.00