Genetic analysis of SIGMAR1 as a cause of familial ALS with dementia

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron diseases (MND), while frontotemporal lobar degeneration (FTLD) is the second most common cause of early-onset dementia. Many ALS families segregating FTLD have been reported, particularly over the last decade. Recently, mutations in TARDBP, FUS/TLS, and C9ORF72 have been identified in both ALS and FTLD patients, while mutations in VCP, a FTLD associated gene, have been found in ALS families. Distinct variants located in the 3 0 -untranslated region (UTR) of the SIGMAR1 gene were previously reported in three unrelated FTLD or FTLD-MND families. We directly sequenced the coding and UTR regions of the SIGMAR1 gene in a targeted cohort of 25 individual familial ALS cases of Caucasian origin with a history of cognitive impairments. This screening identified one variant in the 3 0 -UTR of the SIGMAR1 gene in one ALS patient, but the same variant was also observed in 1 out of 380 control chromosomes. Subsequently, we screened the same samples for a C9ORF72 repeat expansion: 52% of this cohort was found expanded, including the sample with the SIGMAR1 3 0 -UTR variant. Consequently, coding and noncoding variants located in the 3 0 -UTR region of the SIGMAR1 gene are not the cause of FTLD-MND in our cohort, and more than half of this targeted cohort is genetically explained by C9ORF72 repeat expansions. European Journal of Human Genetics (2013) 21, 237-239; doi:10.1038/ejhg.2012.135; published online 27 June 2012Keywords: amyotrophic lateral sclerosis; frontotemporal lobar degeneration; motor neuron disease; dementia INTRODUCTION Amyotrophic lateral sclerosis (ALS) is the most common motor neuron diseases (MND), with an incidence of 1-2/100 000 personyears, 1 while frontotemporal lobar degeneration (FTLD) is the second most common cause of early-onset dementia with an incidence of 3-5/100 000 person-years. 2 Interestingly, up to 50% of ALS patients are deemed likely to develop some cognitive impairments. 3 In 2006, the TDP-43 protein was found to be an important constituent of aggregates in neurons of MND-FTLD patients, 4 which suggested a common pathological pathway for the two conditions. Mutations in the TARDBP gene encoding the TDP-43 protein, 5,6 and the FUS/TLS gene encoding the FUS protein 7,8 been identified in both ALS and FTLD patients, while mutations in ALS cases recently reported in VCP, 9 a gene in which mutations were previously associated with FTLD. 10 Furthermore, neurons of ALS and FTLD patients both display a nuclear clearing and cytoplasmic sequestration of normal cellular TDP-43 or FUS proteins, 11 which are encoded by genes that, when mutated, are estimated to account for up to 5-10% of all ALS cases. 6,7 Twelve families linked to a locus on chromosome 9p have been reported to have members with either MND or FTLD, while a few members displayed both phenotypes. [12][13][14][15][16][17] The causative pathogenic hexanucleotide repeat in the gene C9ORF72 was recently identified by two different groups. 18,19 One of these reports found t...

Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

“…Those results support the notion that Sig-1Rs, by interacting with endogenous myristic acid, play a pivotal role in the p35 myristoylation and degradation. Discussion Sig-1Rs have been reported to play a role in the pathogenesis of neurodegenerative disorders including AD (30,45,46), Parkinson's disease (47,48), and motor neuron disorders (49)(50)(51). The underlying molecular mechanisms of Sig-1R action remain to be totally clarified.…”

Methyl pyruvate rescues mitochondrial damage caused by SIGMAR1 mutation related to amyotrophic lateral sclerosis

“…Finally, several 3′ UTR variants and a missense mutation in SIGMAR1 gene are reported in ALS and FTLD patients [11][12][13]. Interestingly, some 3′ UTR variants (c.672*51GNT and c.672*43GNT) but not the c.672*26CNT substitution co-segregate with hexanucleotide repeat expansions in C9ORF72, and those two variants are likely not responsible for the onset of ALS or FTLD [12,63].…”

“…These variants (c.672*51GNT, c.672*26CNT and c.672*47GNA) were associated with dysregulated SIGMAR1 transcription. Meanwhile, Belzil et al reported a different SIGMAR1 variant (c.672*43GNT) in Caucasian ALS patients who showed cognitive deficits [12]. In addition, a missense SIGMAR1 mutation (c.304GNC), which results in substitution of glutamine for glutamic acid at amino acid residue 102 (p.E102Q), was reported in familial ALS patients [13].…”

In silico analysis of SIGMAR1 variant (rs4879809) segregating in a consanguineous Pakistani family showing amyotrophic lateral sclerosis without frontotemporal lobar dementia

“…Expression profiles of these variants showed that there was an alteration in SIGMAR1 transcription. Another variant of SIGMAR1 gene (c.672*43G>T) was found in Caucasian ALS patients with cognitive deficits but was also found in one control after screening in a healthy population [16]. In addition, a missense SIGMAR1 mutation (c.304G>C), which results in the substitution of glutamine for glutamic acid (p.E102Q) in the highly conserved transmembrane domain of SIGMAR1, was identified in three families of fALS-FTLD showing autosomal dominant pattern.…”

“…3′-UTR variants of SIGMAR1 have been found associated with ALS-FLTD in both autosomal dominant form and sporadic cases [4]. In another study, the SIGMAR1 3′-UTR region in Caucasian ALS patients was investigated along with a repeat expansion in C9ORF72 [16]. Previously, C9ORF72 repeat expansions were reported in FTLD and fALS [17,18].…”