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, bothmutations reduce cell viability, the formation of abnormal protein aggregates preventing the correct targeting of sigma-1R protein to themitochondria-associated ER membrane (MAM) and thus impinging on the global Ca2+signalling. Our data definitively demonstrate the involvement of SIGMAR1 in motor neuronmaintenance 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 theMAM as a critical aspect in dHMN pathology.
ASJC Scopus subject areas
- Molecular Biology