Please use this identifier to cite or link to this item:
|Title:||Loss-of-function mutations in the SIGMAR1 gene cause distal hereditary motor neuropathy by impairing ER-mitochondria tethering and Ca2+ signalling||Authors:||Gregianin, Elisa
Fabrizi, Gian M
Mostacciuolo, Maria L
|Keywords Plus:||AMYOTROPHIC-LATERAL-SCLEROSIS;RECEPTOR;AUTOPHAGY;RESPONSES;FORM;RELEASE;PROTEIN;CELLS;TUMOR||Mesh headings:||Endoplasmic Reticulum;Hereditary Sensory and Motor Neuropathy;Mitochondrial Membranes;Polymorphism, Single Nucleotide;Receptors, sigma||Secondary Mesh headings:||Adult;Calcium Signaling;Cell Line;Cell Survival;Female;Genetic Predisposition to Disease;Genotyping Techniques;Humans;Italy;Male;Pedigree;Sequence Analysis, DNA||Issue Date:||2016||Publisher:||OXFORD UNIV PRESS||Journal:||Human molecular genetics||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.
|Appears in Collections:||Articles|
Show full item record
checked on Jul 21, 2021
checked on Aug 31, 2020
WEB OF SCIENCETM
checked on Nov 24, 2021
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.