title: Mutations in the Heme Exporter FLVCR1 Cause Sensory Neurodegeneration with Loss of Pain Perception.
abstract: Pain is necessary to alert us to actual or potential tissue damage. Specialized nerve cells in the body periphery, so called nociceptors, are fundamental to mediate pain perception and humans without pain perception are at permanent risk for injuries, burns and mutilations. Pain insensitivity can be caused by sensory neurodegeneration which is a hallmark of hereditary sensory and autonomic neuropathies (HSANs). Although mutations in several genes were previously associated with sensory neurodegeneration, the etiology of many cases remains unknown. Using next generation sequencing in patients with congenital loss of pain perception, we here identify bi-allelic mutations in the FLVCR1 (Feline Leukemia Virus subgroup C Receptor 1) gene, which encodes a broadly expressed heme exporter. Different FLVCR1 isoforms control the size of the cytosolic heme pool required to sustain metabolic activity of different cell types. Mutations in FLVCR1 have previously been linked to vision impairment and posterior column ataxia in humans, but not to HSAN. Using fibroblasts and lymphoblastoid cell lines from patients with sensory neurodegeneration, we here show that the FLVCR1-mutations reduce heme export activity, enhance oxidative stress and increase sensitivity to programmed cell death. Our data link heme metabolism to sensory neuron maintenance and suggest that intracellular heme overload causes early-onset degeneration of pain-sensing neurons in humans.
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.
authors.forename: Deborah
authors.initials: D
authors.lastname: Chiabrando
authors.affiliation: Unit of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Castori
authors.affiliation: Unit of Rare Diseases, Department of Pediatrics, Gaslini Institute, Genoa, Italy.
authors.forename: Maja
authors.initials: M
authors.lastname: di Rocco
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Ungelenk
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.|Institute of Human Genetics, Uniklinik RWTH Aachen, Aachen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Gießelmann
authors.affiliation: Unit of Neurophysiopathology, Department of Neuroscience, Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Di Capua
authors.affiliation: Unit of Rare Diseases, Department of Pediatrics, Gaslini Institute, Genoa, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Madeo
authors.affiliation: Unit of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Grammatico
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Sophie
authors.identifier: http://orcid.org/0000-0001-8080-9480
authors.initials: S
authors.lastname: Bartsch
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Altruda
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Silengo
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Tolosano
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.|Institute of Human Genetics, Uniklinik RWTH Aachen, Aachen, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Kurth
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D059472:Exome / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D016368:Frameshift Mutation / Q000235:genetics; D006418:Heme / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D009619:Nociceptors / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics*; D010146:Pain / Q000235:genetics* / Q000473:pathology; D061251:Primary Cell Culture; D011991:Receptors, Virus / Q000235:genetics*; D011984:Sensory Receptor Cells / Q000378:metabolism / Q000473:pathology
chemical_list: C492690:FLVCR1 protein, human; D026901:Membrane Transport Proteins; D011991:Receptors, Virus; D006418:Heme