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Mutations in the Heme Exporter FLVCR1 Cause Sensory Neurodegeneration with Loss of Pain Perception
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نویسنده
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chiabrando d. ,castori m. ,di rocco m. ,ungelenk m. ,gießelmann s. ,di capua m. ,madeo a. ,grammatico p. ,bartsch s. ,hübner c.a. ,altruda f. ,silengo l. ,tolosano e. ,kurth i.
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منبع
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plos genetics - 2016 - دوره : 12 - شماره : 12
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چکیده
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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. © 2016 chiabrando et al.
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آدرس
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department of molecular biotechnology and health sciences,molecular biotechnology center,university of torino,torino, Italy, unit of medical genetics,department of molecular medicine,sapienza university,san camillo-forlanini hospital,rome, Italy, unit of rare diseases,department of pediatrics,gaslini institute,genoa, Italy, institute of human genetics,jena university hospital,friedrich-schiller-university jena,jena, Germany, institute of human genetics,jena university hospital,friedrich-schiller-university jena,jena,germany,institute of human genetics,uniklinik rwth aachen,aachen, Germany, unit of neurophysiopathology,department of neuroscience,bambino gesù children's hospital,rome, Italy, unit of rare diseases,department of pediatrics,gaslini institute,genoa, Italy, unit of medical genetics,department of molecular medicine,sapienza university,san camillo-forlanini hospital,rome, Italy, institute of human genetics,jena university hospital,friedrich-schiller-university jena,jena, Germany, institute of human genetics,jena university hospital,friedrich-schiller-university jena,jena, Germany, department of molecular biotechnology and health sciences,molecular biotechnology center,university of torino,torino, Italy, department of molecular biotechnology and health sciences,molecular biotechnology center,university of torino,torino, Italy, department of molecular biotechnology and health sciences,molecular biotechnology center,university of torino,torino, Italy, institute of human genetics,jena university hospital,friedrich-schiller-university jena,jena,germany,institute of human genetics,uniklinik rwth aachen,aachen, Germany
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Authors
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