A
            <i>SIGMAR1</i>
            splice-site mutation causes distal hereditary motor neuropathy

Li, Xiaobo; Hu, Zhengmao; Liu, Lei; Xie, Yuanyang; Zhan, Yajing; Zi, Xiaohong; Wang, Junling; Wu, Lixiang; Xia, Kun; Tang, Beisha; Zhang, Ruxu

doi:10.1212/wnl.0000000000001680

Cited by 68 publications

(80 citation statements)

References 26 publications

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“…In this study, we characterized the subcellular and functional dynamics of the s-1R mutations underlying ALS16 (AlSaif et al, 2011) and dHMN (Li et al, 2015). We show that fluorescently tagged s-1R-E102Q-YFP (yellow fluorescent protein) and s-1R-D31-50-YFP have significantly different subcellular distribution and mobility between themselves and when compared with the wild-type (WT) s-1R-YFP.…”

Section: Introductionmentioning

confidence: 84%

“…The s-1R is widely distributed throughout both the peripheral and central nervous system Largent et al, 1986;Zukin et al, 1986;Walker et al, 1992) and is enriched in lower motor neuron cell bodies of the spinal cord (Mavlyutov et al, 2010). As such, the s-1R has been implicated in diseases associated with motor neuron dysfunction, such as amyotrophic lateral sclerosis (ALS) (Rothstein, 2009;Nassif et al, 2010;Al-Saif et al, 2011;Matus et al, 2013) and a group of genetically and clinically heterogeneous diseases known as distal hereditary motor neuropathies (dHMN) (Rossor et al, 2012;Li et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…This mutation results in a substitution of glutamine for glutamic acid at position 102 (E102Q) located in the linker region between b2 and b3, which form the base of the ligandbinding b-barrel (Schmidt et al, 2016). Another SIGMAR1 gene mutation (c15111G.T) has been identified in a consanguineous Chinese family (Li et al, 2015). This mutation leads to an in-frame deletion of 60 base pairs in exon one, generating a s-1R that lacks the a2 helix encoded by amino acids 31-50 (Schmidt et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…This mutation leads to an in-frame deletion of 60 base pairs in exon one, generating a s-1R that lacks the a2 helix encoded by amino acids 31-50 (Schmidt et al, 2016). Expression of this shortened s-1R variant results in a dHMN phenotype characterized by significant muscle atrophy (Li et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases

et al. 2016

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The sigma-1 receptor (s-1R) is an endoplasmic reticulum resident chaperone protein involved in a plethora of cellular functions, and whose disruption has been implicated in a wide range of diseases. Genetic analysis has revealed two s-1R mutants involved in neuromuscular disorders. A point mutation (E102Q) in the ligand-binding domain results in the juvenile form of amyotrophic lateral sclerosis (ALS16), and a 20 amino-acid deletion (D31-50) in the putative cytosolic domain leads to a form of distal hereditary motor neuropathy. We investigated the localization and functional properties of these mutants in cell lines using confocal imaging and electrophysiology. The s-1R mutants exhibited a significant increase in mobility, aberrant localization, and enhanced block of the inwardly rectifying K 1 channel K ir 2.1, compared with the wild-type s-1R. Thus, these s-1R mutants have different functional properties that could contribute to their disease phenotypes.

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Section: Introductionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases

et al. 2016

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“…S1R-activating ligands have also been shown to modulate cholinergic neurotransmission (13) and to have antiamnesic properties in models of Alzheimer's disease (AD) and cognitive decline (13). Conversely, mutations in S1R have been causally linked with a number of neurodegenerative disorders, including juvenile amyotrophic lateral sclerosis (14), frontotemporal lobar degeneration-motor neuron disease (15), and hereditary motor neuropathy (16). Furthermore, genetic polymorphisms in S1R have been described as genetic risk factors for AD, influencing the severity of the disorder (17).…”

Section: Introductionmentioning

confidence: 99%

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice

et al. 2017

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Variants in MME are associated with autosomal‐recessive distal hereditary motor neuropathy

Hong

Yao

et al. 2019

Ann Clin Transl Neurol

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Objective To identify a new genetic cause in patients segregating distal hereditary motor neuropathy (dHMN) with an autosomal recessive pattern. Methods Whole‐exome sequencing was conducted in two siblings and was combined with segregation analysis. Additionally, 83 unrelated dHMN patients with unknown genetic cause were screened. RNA analysis was performed using blood lymphocytes and HEK293 cells transfected with mutant plasmids. Immunohistochemistry and Western blot analysis was applied to the nerve tissue. The enzymatic activities of mutant proteins were measured in the cultured cells to verify the pathogenicity of variants. Results The clinical features of the patients showed late‐onset phenotype of distal motor neuropathy without sensory involvement. We identified that compound heterozygous variants of c.1342C>T and c.2071_2072delGCinsTT in the membrane metalloendopeptidase (MME) gene co‐segregated with the phenotype in a dHMN family. In an additional group of 83 patients with dHMN, compound heterozygous variants of c.1416+2T>C and c.2027C>T in MME were identified in one patient. The splice site variant c.1416+2T>C results in skipping of exon 13. The stop variant c.1342C>T induces mRNA degradation via nonsense‐mediated mRNA decay. Transcript levels of MME in the lymphocytes showed no significant differences between the patients and controls. We also identified that MME variants were associated with mild decrease in protein expression in the sural nerve and significant impairments of enzymatic activity. Interpretation Variants in the MME gene were associated with not only a Charcot‐Marie‐Tooth neuropathy phenotype but also with an autosomal‐recessive dHMN phenotype. Loss of function may play a role in the pathogenesis of dHMN.

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A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathy

Abstract: The homozygous c.151+1G>T mutation in SIGMAR1 caused a novel form of autosomal recessive dHMN in a Chinese consanguineous family. Endoplasmic reticulum stress may have a role in the pathogenesis of dHMN.

Cited by 68 publications

References 26 publications

Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases

Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice

Variants in MME are associated with autosomal‐recessive distal hereditary motor neuropathy

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