Distal hereditary motor neuronopathy of the Jerash type is caused by a novel SIGMAR1 c.500A>T missense mutation

Abstract

BackgroundDistal hereditary motor neuronopathies (dHMN) are a group of genetic disorders characterised by motor neuron degeneration leading to muscle weakness that are caused by mutations in various genes. HMNJ is a distinct form of the disease that has been identified in patients from the Jerash region of Jordan. Our aim was to identify and characterise the genetic cause of HMNJ.MethodsWe used whole exome and Sanger sequencing to identify a novel genetic variant associated with the disease and then carried out immunoblot, immunofluorescence and apoptosis assays to extract functional data and clarify the effect of this novel SIGMAR1 mutation. Physical and neurological examinations were performed on selected patients and unaffected individuals in order to re-evaluate clinical status of patients 20 years after the initial description of HMNJ as well as to evaluate new and previously undescribed patients with HMNJ.ResultsA homozygous missense mutation (c.500A>T, N167I) in exon 4 of the SIGMAR1 gene was identified, cosegregating with HMNJ in the 27 patients from 7 previously described consanguineous families and 3 newly ascertained patients. The mutant SIGMAR1 exhibits reduced expression, altered subcellular distribution and elevates cell death when expressed.ConclusionIn conclusion, the homozygous SIGMAR1 c.500A>T mutation causes dHMN of the Jerash type, possibly due to a significant drop of protein levels. This finding is in agreement with other SIGMAR1 mutations that have been associated with autosomal recessive dHMN with pyramidal signs; thus, our findings further support that SIGMAR1 be added to the dHMN genes diagnostic panel.

The role of sigma 1 receptor in organization of endoplasmic reticulum signaling microdomains

“…Analysis of S1R knockout (KO) mice revealed a number of nervous system abnormalities ( Couly et al, 2020 ), suggesting that S1R plays an important role in neurons. In humans, mutations in S1R lead to a juvenile form of amyotrophic lateral sclerosis (ALS) ( Al-Saif et al, 2011 ) and distal hereditary motor neuropathies (dHMNs) ( Almendra et al, 2018 ; Gregianin et al, 2016 ; Horga et al, 2016 ; Li et al, 2015 ; Ververis et al, 2020 ). In animal models, genetic ablation of S1R exacerbates pathology of several neurological disorders ( Hong et al, 2017a ; Mavlyutov et al, 2013 ; Wang et al, 2017 ).…”

Sigma 1 receptor as a therapeutic target for amyotrophic lateral sclerosis

“…In FTD-ALS, patient's other mutations in the 3 0 -untranslated region of the SIGMA1R gene have been described (Luty et al, 2010). A neuropathological feature in these patients was the (Gregianin et al, 2016;Lee et al, 2016;Li et al, 2015;Ververis et al, 2020). In vitro evidence suggests that cells expressing sigma 1 receptor E138Q and E150K mutations are more susceptible to die in basal conditions, under oxidative stress and following autophagy induction (Gregianin et al, 2016).…”

“…Distal hereditary motor neuropathies (also called distal spinal muscular atrophy) are a group of rare genetic disorders characterized by degeneration of the lower motoneurons, with progressive distal motor weakness without sensory symptoms. Several missense mutations in the SIGMA1R gene have been found by diagnostic whole exome sequencing in some familial cases of different ethnic origin affected by such motor neuropathy (Gregianin et al, 2016; Lee et al, 2016; Li et al, 2015; Ververis et al, 2020). In vitro evidence suggests that cells expressing sigma 1 receptor E138Q and E150K mutations are more susceptible to die in basal conditions, under oxidative stress and following autophagy induction (Gregianin et al, 2016).…”

Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases

“…Thus, there is a gene dosage relationship between S1R activity and the age of onset of ALS with the complete loss of S1R associated with the earliest age of onset. Additional LOF mutations in the S1R cause distal hereditary motor neuropathies (dHMN) [ 15 , 16 , 17 , 18 , 19 ]. Furthermore, S1R expression levels are reduced in sporadic ALS [ 20 ], Parkinson’s disease (PD), and Alzheimer’s disease (AD) patients [ 21 , 22 ].…”