Pubblicazioni

Autori:

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 Maria; Muglia, Maria; Boaretto, Francesca; Vettori, Andrea; Rizzuto, Rosario; Mostacciuolo, Maria L; Vazza, Giovanni

Titolo:

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

Anno:

2016

Tipologia prodotto:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Lingua:

Inglese

Formato:

A Stampa

Referee:

Sì

Nome rivista:

Human Molecular Genetics

ISSN Rivista:

0964-6906

N° Volume:

25

Numero o Fascicolo:

17

Intervallo pagine:

3741-3753

Parole chiave:

distal hereditary motor neuropathy; Ca2+ signalling; SIGMAR1 gene; p.E138Q; p.E150K; mitochondria-associated ER membrane

Breve descrizione dei contenuti:

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, Ca(2+ )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 Ca(2+ )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.

Pagina Web:

https://dx.doi.org/ 10.1093/hmg/ddw220

Id prodotto:

95556

Handle IRIS:

11562/957304

ultima modifica:

26 novembre 2022

Citazione bibliografica:

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 Maria; Muglia, Maria; Boaretto, Francesca; Vettori, Andrea; Rizzuto, Rosario; Mostacciuolo, Maria L; Vazza, Giovanni, Loss-of-function mutations in the SIGMAR1 gene cause distal hereditary motor neuropathy by impairing ER-mitochondria tethering and Ca2+ signalling «Human Molecular Genetics» , vol. 25 , n. 17 , 2016 , pp. 3741-3753

Consulta la scheda completa presente nel repository istituzionale della Ricerca di Ateneo