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.
Highlights
Neurodegenerative disorders affecting peripheral sensory neurons lead to loss of pain perception as disease hallmark
Hereditary Sensory and Autonomic Neuropathy (HSAN) is a genetic disorder mainly characterized by the impairment of sensory neurons, which transmit information about
We studied trios with an affected child and healthy parents with the diagnosis of hereditary sensory and autonomic neuropathy (HSAN) (Fig 1 and Table 1)
Summary
Neurodegenerative disorders affecting peripheral sensory neurons lead to loss of pain perception as disease hallmark. The absence of protective behaviors towards noxious stimuli causes unintentional self-injuries and chronic ulcerations. Autonomic dysfunction and motor deficits may be additional features of sensory and autonomic neuropathies (HSANs). Prominent loss of large and small myelinated fibers distinguishes sensory neuropathies from clinically presenting channelopathy-associated pain insensitivity (CIP)[3]. Proteins which are involved in sensory neurodegeneration affect distinct molecular pathways: sphingolipid-metabolism, membrane-shaping of organelles, regulation of ion channels, endoplasmic reticulum turnover and axonal trafficking[1, 4,5,6,7,8]. The molecular mechanisms underlying sensory neurodegeneration are still incompletely understood and disease-causing mutations remain to be identified in a substantial number of patients
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