title: Loss-of-function mutations in the SIGMAR1 gene cause distal hereditary motor neuropathy by impairing ER-mitochondria tethering and Ca2+ signalling.
abstract: Distal hereditary motor neuropathies (dHMNs) are clinically and genetically heterogeneous neurological conditions characterized by degeneration of the lower motor neurons. So far, 18 dHMN genes have been identified, however, about 80% of dHMN cases remain without a molecular diagnosis. By a combination of autozygosity mapping, identity-by-descent segment detection and whole-exome sequencing approaches, we identified two novel homozygous mutations in the SIGMAR1 gene (p.E138Q and p.E150K) in two distinct Italian families affected by an autosomal recessive form of HMN. Functional analyses in several neuronal cell lines strongly support the pathogenicity of the mutations and provide insights into the underlying pathomechanisms involving the regulation of ER-mitochondria tethering, Ca2+homeostasis and autophagy. Indeed, in vitro, both mutations reduce cell viability, the formation of abnormal protein aggregates preventing the correct targeting of sigma-1R protein to the mitochondria-associated ER membrane (MAM) and thus impinging on the global Ca2+signalling. Our data definitively demonstrate the involvement of SIGMAR1 in motor neuron maintenance and survival by correlating, for the first time in the Caucasian population, mutations in this gene to distal motor dysfunction and highlight the chaperone activity of sigma-1R at the MAM as a critical aspect in dHMN pathology.
authors.affiliation: Department of Biology, University of Padova.
authors.forename: Elisa
authors.initials: E
authors.lastname: Gregianin
authors.affiliation: Department of Biomedical Sciences, University of Padova and CNR Neuroscience Institute, Padova, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Pallafacchina
authors.affiliation: Department of Biomedical Sciences, University of Padova and CNR Neuroscience Institute, Padova, Italy.
authors.forename: Sofia
authors.initials: S
authors.lastname: Zanin
authors.affiliation: Experimental Neurobiology Lab, IRCCS "C. Mondino" National Neurological Institute, Pavia, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Crippa
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rusmini
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Poletti
authors.affiliation: Department of Science & Technology, BGI-Shenzhen, Shenzhen, China.
authors.forename: Mingyan
authors.initials: M
authors.lastname: Fang
authors.affiliation: Department of Science & Technology, BGI-Shenzhen, Shenzhen, China.
authors.forename: Zhouxuan
authors.initials: Z
authors.lastname: Li
authors.affiliation: Medical Genetics, University Hospital "Tor Vergata", Roma, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Diano
authors.affiliation: Neuromuscular and Rare Neurological Diseases Centre Neurology & Neurophysiopathology Unit, ASO San Camillo-Forlanini Hospital of Rome, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Petrucci
authors.affiliation: Neuromuscular and Rare Neurological Diseases Centre Neurology & Neurophysiopathology Unit, ASO San Camillo-Forlanini Hospital of Rome, Rome, Italy.
authors.forename: Ludovico
authors.initials: L
authors.lastname: Lispi
authors.affiliation: Section of Neuropathology, Neurological and Movement Sciences, University of Verona, Verona, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Cavallaro
authors.affiliation: Section of Neuropathology, Neurological and Movement Sciences, University of Verona, Verona, Italy.
authors.forename: Gian M
authors.initials: GM
authors.lastname: Fabrizi
authors.affiliation: CNR Institute of Neurological Sciences, Mangone, Cosenza, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Muglia
authors.affiliation: Department of Biology, University of Padova.
authors.forename: Francesca
authors.initials: F
authors.lastname: Boaretto
authors.affiliation: Department of Biology, University of Padova.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vettori
authors.affiliation: Department of Biomedical Sciences, University of Padova and CNR Neuroscience Institute, Padova, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Rizzuto
authors.affiliation: Department of Biology, University of Padova.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Mostacciuolo
authors.affiliation: Department of Biology, University of Padova giovanni.vazza@unipd.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vazza
mesh_terms: D000328:Adult; D020013:Calcium Signaling; D002460:Cell Line; D002470:Cell Survival; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics*; D006801:Humans; D007558:Italy; D008297:Male; D051336:Mitochondrial Membranes / Q000378:metabolism*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017480:Receptors, sigma / Q000235:genetics*; D017422:Sequence Analysis, DNA; D000097605:Sigma-1 Receptor
chemical_list: D017480:Receptors, sigma; D000097605:Sigma-1 Receptor