A novel peripherin gene (PRPH) mutation identified in one sporadic amyotrophic lateral sclerosis patient

Department Medical Sciences, Interdisciplinary Research Center of Autoimmune Diseases, University of Eastern Piedmont, Novara, Italy.
Neurobiology of aging (Impact Factor: 5.01). 04/2010; 32(3):552.e1-6. DOI: 10.1016/j.neurobiolaging.2010.02.011
Source: PubMed


Motor neurons in amyotrophic lateral sclerosis (ALS) are characterized by the presence of inclusion bodies composed of intermediate filament (IF) proteins. Peripherin protein is as components of these inclusions and rare mutations in peripherin gene (PRPH) were identified in sporadic ALS cases. The aim of this study was to further define the spectrum of PRPH mutations in a cohort of 122 Italian ALS patients. We screened the coding sequence, the exon/intron boundaries, and the 5'-3' un-translated regions (UTRs) in 122 ALS patients. Eighteen sequence variations were detected. Seven variants were not identified in a panel of at least 245 matched controls, including 2 missense variations, namely p.R133P and p.D141Y, each identified in one heterozygous patient. p.R133P was newly identified whereas p.D141Y was previously described in one homozygous sporadic ALS patient. These 2 variants were predicted to have a deleterious effect on protein structure or function. This work contributes to determine the role of PRPH gene variants in ALS. Further studies are necessary to define the mechanisms through which the mutant peripherin could cause ALS phenotype.

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Available from: Cristina Cereda, Dec 30, 2015
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    • "Peripherin inclusions are associated with cytoprotection during oxidative stress Peripherin mutations have been described in sporadic ALS cases (Corrado et al., 2010; Gros-Louis et al., 2004; Leung et al., 2004) and transgenic mice overexpressing wild-type peripherin demonstrate select motor neuron degeneration (Beaulieu et al., 1999). Recently, peripherin was identified as a strong interacting partner of mutant RAB7A proteins, which are causative of the peripheral ulceromutilating neuropathy Charcot–Marie–Tooth type 2B (Cogli et al., 2013). "
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    ABSTRACT: Intracellular proteinaceous inclusions are well-documented hallmarks of the fatal motor neuron disorder amyotrophic lateral sclerosis (ALS). The pathological significance of these inclusions remains unknown. Peripherin, a type III intermediate filament protein, is upregulated in ALS and identified as a component within different types of ALS inclusions. The formation of these inclusions may be associated with abnormal peripherin splicing, whereby an increase in mRNA retaining introns 3 and 4 (Per-3,4) leads to the generation of an aggregation-prone isoform, Per-28. During the course of evaluating peripherin filament assembly in SW-13 cells, we identified that expression of both Per-3,4 and Per-28 transcripts formed inclusions with categorically distinct morphology: Per-3,4 was associated with cytoplasmic condensed/bundled filaments, small inclusions (<10μM), or large inclusions (≥10μM); while Per-28 was associated with punctate inclusions in the nucleus and/or cytoplasm. We found temporal and spatial changes in inclusion morphology between 12-48hr post-transfected cells, which were accompanied by unique immunofluorescent and biochemical changes of other ALS-relevant proteins, including TDP-43 and ubiquitin. Despite mild cytotoxicity associated with peripherin transfection, Per-3,4 and Per-28 expression increased cell viability during H2O2-mediated oxidative stress in BE(2)-M17 neuroblastoma cells. Taken together, this study shows that ALS-associated peripherin isoforms form dynamic cytoplasmic and intranuclear inclusions, effect changes in local endogenous protein expression, and afford cytoprotection against oxidative stress. These findings may have important relevance to understanding the pathophysiological role of inclusions in ALS.
    Full-text · Article · Jun 2014 · Experimental Neurology
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    • "Overexpression of wild-type PRPH in transgenic mice develops a selective, large scale late-onset motor neuron degeneration characterized by intermediate filament inclusions [102]. Later on 2 homozygous missense mutations have been identified in PRPH gene [103]. A study on 122 Italian ALS patients has identified eighteen sequence variations on PRPH including 2 missense variations, namely p.R133P and p.D141Y [103]. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving both upper motor neurons (UMN) and lower motor neurons (LMN). Enormous research has been done in the past few decades in unveiling the genetics of ALS, successfully identifying at least fifteen candidate genes associated with familial and sporadic ALS. Numerous studies attempting to define the pathogenesis of ALS have identified several plausible determinants and molecular pathways leading to motor neuron degeneration, which include oxidative stress, glutamate excitotoxicity, apoptosis, abnormal neurofilament function, protein misfolding and subsequent aggregation, impairment of RNA processing, defects in axonal transport, changes in endosomal trafficking, increased inflammation, and mitochondrial dysfunction. This review is to update the recent discoveries in genetics of ALS, which may provide insight information to help us better understanding of the devastating disease.
    Full-text · Article · Aug 2013 · Molecular Neurodegeneration
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    • "Increasing evidence has shown that among these pathogeneses, cytoskeletal and axonal growth defects contribute to ALS development (Lariviere and Julien, 2004). Mutations in the encoding subunits of neurofilament genes composed of light (NEFL), medium (NEFM), and heavy polypeptides (NEFH) (Figlewicz, et al., 1994), as well as peripherin (PRPH) (Corrado, et al., 2011) and dynactin (DCTN1) genes, have been identified as responsible for ALS. Profilin 1 (PFN1), another gene that has an important function in the conversion of monomeric (G)eactin to filamentous (F) eactin, was recently identified as a causative gene that disrupts cytoskeletal pathways in ALS pathogenesis (Wu, et al., 2012). "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unknown pathophysiological mechanisms. Profilin 1 gene (PFN1) has been identified as a causative gene, which accounts for 1% to 2% of familial ALS. In this study, we investigated the mutation spectrum of PFN1 in Chinese patients with ALS. A total of 550 ALS patients (including 540 sporadic ALS [SALS] and 10 familial ALS) from the Department of Neurology, West China Hospital of Sichuan University, were recruited for the study. From the same region, 545 healthy control individuals (HC) were recruited as a control group. The encoding regions of the PFN1 gene were screened by direct sequencing. Novel candidate mutations or variations were confirmed by polymerase chain reaction-restriction fragment length polymorphism. A novel nonsynonymous p.R136W mutation was identified in an early-onset SALS female patient. A novel synonymous mutation p.L88L detected in a late-onset SALS female patient was considered nonpathogenic, as it was also detected in a control subject. No mutations were found in 10 familial ALS patients. Moreover, we found a significant difference in the genotype distribution of reported rs13204 (p.L112L) between SALS patients and HC (p = 0.0030). The frequency of minor allele 'T' of rs13204 in the SALS group was significantly lower than that in HC (p = 0.0040, OR = 0.7270, 95% CI = 0.5848-0.9039). Our results suggest that PFN1 mutation is an uncommon cause of ALS in the Han Chinese population. The SNP rs13204 of the PFN1 gene may have an important function in ALS development. The phenotype of ALS patients with mutantPFN1 gene varies among different genetic backgrounds.
    Full-text · Article · Feb 2013 · Neurobiology of aging
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