Hereditary sensory and autonomic neuropathies (HSANs) are a group of clinically and genetically heterogeneous disorders of the peripheral nervous system mainly characterized by impaired nociception and autonomic dysfunction. We previously identified heme metabolism as a novel pathway contributing to sensory neurons maintenance and nociception. Indeed, we reported mutations in the feline leukemia virus subgroup C receptor 1 (FLVCR1) gene in individuals affected by HSAN. FLVCR1 gene encodes for 2 heme export proteins, FLVCR1a (plasma membrane) and FLVCR1b (mitochondria), crucially involved in the regulation of cellular heme homeostasis. Here, we report on 2 additional patients carrying novel biallelic mutations in FLVCR1 translation initiation codon (c.2T>C; p.(Met1Thr) and c.3G>T; p.(Met1Ile)). We overexpressed the c.2T>C; p.(Met1Thr) mutant in human cell lines and we describe its impact on protein structure and function in comparison with other HSAN-related mutations. We found that the mutation interferes with translation in 2 different ways: by lowering levels of translation of wild-type protein and by inducing translation initiation from a downstream in-frame ATG, leading to the production of an N-terminal truncated protein that is retained in the endoplasmic reticulum. The impact of different kinds of mutations on FLVCR1a localization and structure was also described. The identification of novel FLVCR1 mutations in HSAN reinforces the crucial role of heme in sensory neuron maintenance and pain perception. Moreover, our in vitro findings demonstrate that heme export is not completely lost in HSAN patients, thus suggesting the possibility to improve FLVCR1 expression/activity for therapeutic purposes.
Mutations in the translational initiator codon of the heme exporter FLVCR1 cause hereditary sensory and autonomic neuropathy.
aDepartment of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy
bCollege of Arts and Sciences, Indiana State University, IN, United States
cGenetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
dWeisskopf Child Evaluation Center, University of Louisville, Kentucky, United States
eDepartment of Biology, College of Arts and Sciences, Indiana State University, IN, United States
fThe Center for Genomic Advocacy, Indiana State University, IN, United States
*Corresponding Author. Address: Dept of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Via Nizza 52, 10126, Torino, Italy. E-mail address: firstname.lastname@example.org (D. Chiabrando).
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F. Bertino and K. Firestone contributed equally to this work.