Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12857/116009
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 
Pallafacchina, Giorgia 
Zanin, Sofia 
Crippa, Valeria
Rusmini, Paola
Poletti, Angelo
Fang, Mingyan
Li, Zhouxuan
Diano, Laura
Petrucci, Antonio
Lispi, Ludovico
Cavallaro, Tiziana
Fabrizi, Gian M
Muglia, Maria
Boaretto, Francesca 
Vettori, Andrea 
Rizzuto, Rosario 
Mostacciuolo, Maria L
Vazza, Giovanni 
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.
URI: http://hdl.handle.net/20.500.12857/116009
ISSN: 09646906
DOI: 10.1093/hmg/ddw220
Appears in Collections:Articles

Show full item record

PubMed Central
Citations 50

32
Last Week
0
Last month
checked on Jul 21, 2021

SCOPUSTM   
Citations 20

30
checked on Aug 31, 2020

WEB OF SCIENCETM
Citations

56
checked on Nov 24, 2021

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.