GENERATION AND CHARACTERIZATION OF A KNOCK-IN MOUSE MODEL FOR FLVCR1-RELATED SENSORY NEUROPATHY

Abalai RE¹, Marvaldi L², Ferrini F³, Riganti C¹, Zanin Venturini DI¹, Metani L¹, Tolosano E¹ and Chiabrando D¹ | ¹Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center “Guido Tarone”, University of Torino, Turin, Italy; ²Neuroscience Institute Cavalieri Ottolenghi, Orbassano (TO), Italy; ³Dipartimento di Morfofisiologia Veterinaria and Rita Levi Montalcini Center for Brain Repair, Grugliasco (TO), Italy

FLVCR1 (Feline-Leukemia-Virus-subgroup-C-Receptor-1) encodes a plasma membrane choline/ethanolamine importer involved in intracellular heme homeostasis and mitochondrial calcium handling. Mutations in FLVCR1 cause complex sensory neuropathies featuring retinitis pigmentosa, sensory ataxia, pain insensitivity, and motor deficits, but the mechanisms underlying neuronal dysfunction remain elusive. To address this, we generated mouse models carrying the pathogenic FLVCR1-P221S mutation in homozygosity (FLVCR1P221S/P221S) and compound heterozygosity (FLVCR1P221S/del), and established primary cultures of dorsal root ganglia (DRG) sensory neurons. Behavioral testing revealed preserved motor coordination up to 15 months, although some animals developed late-onset motor symptoms. In nociceptive assays, FLVCR1P221S/P221S mice displayed delayed thermal responses, whereas FLVCR1P221S/del mutants showed reduced mechanical sensitivity and thermal hypersensitivity. Morphological analysis of DRG neurons revealed reduced soma area and axon length in both genotypes, indicating intrinsic structural vulnerability. However, metabolic profiling of DRG, brain, liver, and muscle showed no major alterations, suggesting compensatory adaptations in vivo. These findings establish a reliable model for FLVCR1-linked sensory neuropathies, highlighting the morphological and functional consequences of FLVCR1 dysfunction in sensory neurons. This model provides a valuable tool to investigate both in vivo and in vitro on primary sensory neurons coltures how impaired choline transport and calcium signaling contribute to neuronal vulnerability and to develop targeted therapeutic strategies to preserve sensory neuron integrity.