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Zanin 2016 Abstract Mito Xmas Meeting Innsbruck

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

Link:

Zanin S, Gregianin E, Petrucci A, Fabrizi GM, Rizzuto R, Vazza G, Pallafacchina G (2016)

Event: Mito Xmas Meeting 2016 Innsbruck AT

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 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.

Sigma receptor 1 (ฯƒ-1R), a 28 kDa chaperone of the endoplasmic reticulum (ER), localizes at the mitochondria-associated ER membrane (MAM) and is implicated in many aspects of cellular homeostasis in the nervous system, including regulation of ion channels and Ca2+ signaling. Functional analyses in several neuronal cell lines strongly support the pathogenicity of the ฯƒ-1R mutations and provide insights into the underlying pathomechanisms involving the regulation of ER-mitochondria tethering, Ca2+ homeostasis and autophagy. We demonstrated that ฯƒ-1R substitutions behave as โ€œloss-of-functionโ€ mutations affecting cell viability and altering Ca2+ homeostasis due to a derangement of ER-mitochondrial tethers. Moreover, primary skin fibroblasts from patients homozygous for the E150K mutation showed MAM disorganization and a higher level of autophagy compared to controls.

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 ฯƒ-1R at the MAM as a critical aspect in motor neuron survival and dHMN pathology.


Labels: Pathology: Inherited, Neurodegenerative 

Organism: Human  Tissue;cell: Endothelial;epithelial;mesothelial cell, Neuroblastoma, Fibroblast  Preparation: Intact cells 

Regulation: Calcium 


Event: Poster  Labelled by author 

Affiliations

Zanin S(1), Gregianin E(2), Petrucci A(3), Fabrizi GM(4), Rizzuto R(1), Vazza G(2), Pallafacchina G(1)
  1. Dept Biomedical Sc, Univ Padova CNR Neuroscience Inst, Italy
  2. Dept Biology, Univ Padova, Italy
  3. Neuromuscular Rare Neurological Diseases Centre Neurology & Neurophysiopathology Unit, ASO San Camillo-Forlanini Hospital Rome, Italy
  4. Section Neuropathology, Neurological Movement Sc, Univ Verona, Italy