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Hum Mol Genet. 2016 Sep 1;25(17):3741-3753. doi: 10.1093/hmg/ddw220. Epub 2016 Jul 8.

Loss-of-function mutations in the SIGMAR1 gene cause distal hereditary motor neuropathy by impairing ER-mitochondria tethering and Ca2+ signalling.

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Department of Biology, University of Padova.
Department of Biomedical Sciences, University of Padova and CNR Neuroscience Institute, Padova, Italy.
Experimental Neurobiology Lab, IRCCS "C. Mondino" National Neurological Institute, Pavia, Italy.
Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
Department of Science & Technology, BGI-Shenzhen, Shenzhen, China.
Medical Genetics, University Hospital "Tor Vergata", Roma, Italy.
Neuromuscular and Rare Neurological Diseases Centre Neurology & Neurophysiopathology Unit, ASO San Camillo-Forlanini Hospital of Rome, Rome, Italy.
Section of Neuropathology, Neurological and Movement Sciences, University of Verona, Verona, Italy.
CNR Institute of Neurological Sciences, Mangone, Cosenza, Italy.
Department of Biology, University of Padova


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.

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