Rare diseases (Austin, Tex.)最新文献_第9页

GSK3β is a new therapeutic target for myotonic dystrophy type 1. GSK3β是治疗1型强直性肌营养不良的新靶点。

Rare diseases (Austin, Tex.) Pub Date : 2013-09-26 eCollection Date: 2013-01-01 DOI: 10.4161/rdis.26555

Christina Wei, Karlie Jones, Nikolai A Timchenko, Lubov Timchenko

{"title":"GSK3β is a new therapeutic target for myotonic dystrophy type 1.","authors":"Christina Wei, Karlie Jones, Nikolai A Timchenko, Lubov Timchenko","doi":"10.4161/rdis.26555","DOIUrl":"https://doi.org/10.4161/rdis.26555","url":null,"abstract":"Myotonic dystrophy type 1 (DM1), an incurable, neuromuscular disease, is caused by the expansion of CTG repeats within the 3' UTR of DMPK on chromosome 19q. In DM1 patients, mutant DMPK transcripts deregulate RNA metabolism by altering CUG RNA-binding proteins. Several approaches have been proposed for DM1 therapy focused on specific degradation of the mutant CUG repeats or on correction of RNA-binding proteins, affected by CUG repeats. One such protein is CUG RNA-binding protein (CUGBP1). The ability of CUGBP1 to increase or inhibit translation depends on phosphorylation at Ser302, which is mediated by cyclin D3-CDK4. The mutant CUG repeats increase the levels of CUGBP1 protein and inhibit Ser302 phosphorylation, leading to the accumulation of CUGBP1 isoforms that repress translation (i.e., CUGBP1(REP)). Elevation of CUGBP1(REP) in DM1 is caused by increased GSK3β kinase, which reduces the cyclin D3-CDK4 pathway and subsequent phosphorylation of CUGBP1 at Ser302. In this review, we discuss our recent discovery showing that correction of GSK3β activity in the DM1 mouse model (i.e., HSA(LR) mice) reduces DM1 muscle pathology. These findings demonstrate that GSK3β is a novel therapeutic target for treating DM1. ","PeriodicalId":74639,"journal":{"name":"Rare diseases (Austin, Tex.)","volume":"1 ","pages":"e26555"},"PeriodicalIF":0.0,"publicationDate":"2013-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4161/rdis.26555","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32486646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 16

WNK1/HSN2 isoform and the regulation of KCC2 activity. WNK1/HSN2亚型与KCC2活性调控。

Rare diseases (Austin, Tex.) Pub Date : 2013-09-19 eCollection Date: 2013-01-01 DOI: 10.4161/rdis.26537

Valérie Bercier

引用次数: 3

Mutation in SNAP25 as a novel genetic cause of epilepsy and intellectual disability. SNAP25突变作为癫痫和智力残疾的新遗传原因。

Rare diseases (Austin, Tex.) Pub Date : 2013-09-05 eCollection Date: 2013-01-01 DOI: 10.4161/rdis.26314

Luis Rohena, Julie Neidich, Megan Truitt Cho, Kelly Df Gonzalez, Sha Tang, Orrin Devinsky, Wendy K Chung

{"title":"Mutation in SNAP25 as a novel genetic cause of epilepsy and intellectual disability.","authors":"Luis Rohena, Julie Neidich, Megan Truitt Cho, Kelly Df Gonzalez, Sha Tang, Orrin Devinsky, Wendy K Chung","doi":"10.4161/rdis.26314","DOIUrl":"https://doi.org/10.4161/rdis.26314","url":null,"abstract":"Whole exome sequencing using a parent-child trio design to identify de novo mutations provides an efficient method to identify novel genes for rare diseases with low reproductive fitness that are difficult to study by more classical genetic methods of linkage analysis. We describe a 15 y old female with severe static encephalopathy, intellectual disability, and generalized epilepsy. After extensive metabolic and genetic testing, whole exome sequencing identified a novel de novo variant in Synaptosomal-associated protein-25 (SNAP25), c.142G > T p.Phe48Val alteration. This variant is predicted to be damaging by all prediction algorithms. SNAP25 is part of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein complex which is involved in exocytotic release of neurotransmitters. Genetic alterations in Snap25 in animal models can cause anxiety-related behavior, ataxia and seizures. We suggest that SNAP25 mutations in humans are a novel genetic cause of intellectual disability and epilepsy. ","PeriodicalId":74639,"journal":{"name":"Rare diseases (Austin, Tex.)","volume":"1 ","pages":"e26314"},"PeriodicalIF":0.0,"publicationDate":"2013-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4161/rdis.26314","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32487213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 60

Facioscapulohumeral muscular dystrophy: Are telomeres the end of the story? 面肩肱肌营养不良症:端粒是故事的终点吗?

Rare diseases (Austin, Tex.) Pub Date : 2013-08-14 eCollection Date: 2013-01-01 DOI: 10.4161/rdis.26142

Guido Stadler, Oliver D King, Jerome D Robin, Jerry W Shay, Woodring E Wright

{"title":"Facioscapulohumeral muscular dystrophy: Are telomeres the end of the story?","authors":"Guido Stadler, Oliver D King, Jerome D Robin, Jerry W Shay, Woodring E Wright","doi":"10.4161/rdis.26142","DOIUrl":"https://doi.org/10.4161/rdis.26142","url":null,"abstract":"Facioscapulohumeral muscular dystrophy (FSHD) is a progressive myopathy with a relatively late age of onset (usually in the late teens) compared with Duchenne and many other muscular dystrophies. The current FSHD disease model postulates that contraction of the D4Z4 array at chromosome 4q35 leads to a more open chromatin conformation in that region and allows transcription of the DUX4 gene. DUX4 mRNA is stable only when transcribed from certain haplotypes that contain a polyadenylation signal. DUX4 protein is hypothesized to cause FSHD by mediating cytotoxicity and impairing skeletal muscle differentiation. We recently showed in a cell culture model that DUX4 expression is regulated by telomere length, suggesting that telomere shortening during aging may be partially responsible for the delayed onset and progressive nature of FSHD. We here put our data in the context of other recent findings arguing that progressive telomere shortening may play a critical role in FSHD but is not the whole story and that the current disease model needs additional refinement. ","PeriodicalId":74639,"journal":{"name":"Rare diseases (Austin, Tex.)","volume":"1 ","pages":"e26142"},"PeriodicalIF":0.0,"publicationDate":"2013-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4161/rdis.26142","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32487211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

A human de novo mutation in MYH10 phenocopies the loss of function mutation in mice. 人类MYH10的新生突变在小鼠中表现出功能突变的丧失。

Rare diseases (Austin, Tex.) Pub Date : 2013-08-14 eCollection Date: 2013-01-01 DOI: 10.4161/rdis.26144

Lea Tuzovic, Lan Yu, Wenqi Zeng, Xiang Li, Hong Lu, Hsiao-Mei Lu, Kelly Df Gonzalez, Wendy K Chung

{"title":"A human de novo mutation in MYH10 phenocopies the loss of function mutation in mice.","authors":"Lea Tuzovic, Lan Yu, Wenqi Zeng, Xiang Li, Hong Lu, Hsiao-Mei Lu, Kelly Df Gonzalez, Wendy K Chung","doi":"10.4161/rdis.26144","DOIUrl":"https://doi.org/10.4161/rdis.26144","url":null,"abstract":"We used whole exome sequence analysis to investigate a possible genetic etiology for a patient with the phenotype of intrauterine growth restriction, microcephaly, developmental delay, failure to thrive, congenital bilateral hip dysplasia, cerebral and cerebellar atrophy, hydrocephalus, and congenital diaphragmatic hernia (CDH). Whole exome sequencing identified a novel de novo c.2722G > T (p.E908X) mutation in the Myosin Heavy Chain 10 gene (MYH10) which encodes for non-muscle heavy chain II B (NMHC IIB). Mutations in MYH10 have not been previously described in association with human disease. The E908X mutation is located in the coiled-coil region of the protein and is expected to delete the tail domain and disrupt filament assembly. Nonmuscle myosin IIs (NM IIs) are a group of ubiquitously expressed proteins, and NM II B is specifically enriched in neuronal tissue and is thought to be important in neuronal migration. It is also expressed in cardiac myocytes along with NM IIC. Homozygous NMHC II B-/B- mouse knockouts die by embryonic day (E)14.5 with severe cardiac defects (membranous ventricular septal defect and cardiac outflow tract abnormalities) and neurodevelopmental disorders (progressive hydrocephalus and neuronal migrational abnormalities). A heterozygous MYH10 loss of function mutation produces a severe neurologic phenotype and CDH but no apparent cardiac phenotype and suggests that MYH10 may represent a novel gene for brain malformations and/or CDH. ","PeriodicalId":74639,"journal":{"name":"Rare diseases (Austin, Tex.)","volume":"1 ","pages":"e26144"},"PeriodicalIF":0.0,"publicationDate":"2013-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4161/rdis.26144","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32487212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 40

Synaptic protein dysregulation in myotonic dystrophy type 1: Disease neuropathogenesis beyond missplicing. 1型强直性肌营养不良的突触蛋白失调:错误剪接之外的疾病神经发病机制。

Rare diseases (Austin, Tex.) Pub Date : 2013-06-26 eCollection Date: 2013-01-01 DOI: 10.4161/rdis.25553

Oscar Hernández-Hernández, Géraldine Sicot, Diana M Dinca, Aline Huguet, Annie Nicole, Luc Buée, Arnold Munnich, Nicolas Sergeant, Geneviève Gourdon, Mário Gomes-Pereira

{"title":"Synaptic protein dysregulation in myotonic dystrophy type 1: Disease neuropathogenesis beyond missplicing.","authors":"Oscar Hernández-Hernández, Géraldine Sicot, Diana M Dinca, Aline Huguet, Annie Nicole, Luc Buée, Arnold Munnich, Nicolas Sergeant, Geneviève Gourdon, Mário Gomes-Pereira","doi":"10.4161/rdis.25553","DOIUrl":"https://doi.org/10.4161/rdis.25553","url":null,"abstract":"The toxicity of expanded transcripts in myotonic dystrophy type 1 (DM1) is mainly mediated by the disruption of alternative splicing. However, the detailed disease mechanisms in the central nervous system (CNS) have not been fully elucidated. In our recent study, we demonstrated that the accumulation of mutant transcripts in the CNS of a mouse model of DM1 disturbs splicing in a region-specific manner. We now discuss that the spatial- and temporal-regulated expression of splicing factors may contribute to the region-specific spliceopathy in DM1 brains. In the search for disease mechanisms operating in the CNS, we found that the expression of expanded CUG-containing RNA affects the expression and phosphorylation of synaptic vesicle proteins, possibly contributing to DM1 neurological phenotypes. Although mediated by splicing regulators with a described role in DM1, the misregulation of synaptic proteins was not associated with missplicing of their coding transcripts, supporting the view that DM1 mechanisms in the CNS have also far-reaching implications beyond the disruption of a splicing program. ","PeriodicalId":74639,"journal":{"name":"Rare diseases (Austin, Tex.)","volume":"1 ","pages":"e25553"},"PeriodicalIF":0.0,"publicationDate":"2013-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4161/rdis.25553","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32487210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 14

Explaining intermediate filament accumulation in giant axonal neuropathy. 巨轴索神经病中纤维积聚的解释。

Rare diseases (Austin, Tex.) Pub Date : 2013-06-17 eCollection Date: 2013-01-01 DOI: 10.4161/rdis.25378

Puneet Opal, Robert D Goldman

引用次数: 10

Senataxin protects the genome: Implications for neurodegeneration and other abnormalities. Senataxin保护基因组:对神经变性和其他异常的影响。

Rare diseases (Austin, Tex.) Pub Date : 2013-06-06 eCollection Date: 2013-01-01 DOI: 10.4161/rdis.25230

Martin F Lavin, Abrey J Yeo, Olivier J Becherel

{"title":"Senataxin protects the genome: Implications for neurodegeneration and other abnormalities.","authors":"Martin F Lavin, Abrey J Yeo, Olivier J Becherel","doi":"10.4161/rdis.25230","DOIUrl":"https://doi.org/10.4161/rdis.25230","url":null,"abstract":"Ataxia oculomotor apraxia type 2 (AOA2) is a rare autosomal recessive disorder characterized by cerebellar atrophy, peripheral neuropathy, loss of Purkinje cells and elevated α-fetoprotein. AOA2 is caused by mutations in the SETX gene that codes for the high molecular weight protein senataxin. Mutations in this gene also cause dominant neurodegenerative disorders. Similar to that observed for other autosomal recessive ataxias, this protein protects the integrity of the genome against oxidative and other forms of DNA damage to reduce the risk of neurodegeneration. Senataxin functions in transcription termination and RNA splicing and it has been shown to resolve RNA/DNA hybrids (R-loops) that arise at transcription pause sites or when transcription is blocked. Recent data suggest that this protein functions at the interface between transcription and DNA replication to minimise the risk of collision and maintain genome stability. Our recent data using SETX gene-disrupted mice revealed that male mice were defective in spermatogenesis and were infertile. DNA double strand-breaks persisted throughout meiosis and crossing-over failed in SETX mutant mice. These changes can be explained by the accumulation of R-loops, which interfere with Holiday junctions and crossing-over. We also showed that senataxin was localized to the XY body in pachytene cells and was involved in transcriptional silencing of these chromosomes. While the defect in meiotic recombination was striking in these animals, there was no evidence of neurodegeneration as observed in AOA2 patients. We discuss here potentially different roles for senataxin in proliferating and post-mitotic cells. ","PeriodicalId":74639,"journal":{"name":"Rare diseases (Austin, Tex.)","volume":"1 ","pages":"e25230"},"PeriodicalIF":0.0,"publicationDate":"2013-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4161/rdis.25230","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32487208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 15

Lifetime risk estimators in epidemiological studies of Krabbe Disease: Review and Monte Carlo comparison. 克拉伯病流行病学研究中的终生风险估计:综述和蒙特卡洛比较。

Rare diseases (Austin, Tex.) Pub Date : 2013-05-30 eCollection Date: 2013-01-01 DOI: 10.4161/rdis.25212

Alexander H Foss, Patricia K Duffner, Randy L Carter

引用次数: 20

Disease mutations in the prion-like domains of hnRNPA1 and hnRNPA2/B1 introduce potent steric zippers that drive excess RNP granule assembly. hnRNPA1和hnRNPA2/B1的朊病毒样结构域的疾病突变引入了有效的立体拉链，驱动过量的RNP颗粒组装。

Rare diseases (Austin, Tex.) Pub Date : 2013-05-29 eCollection Date: 2013-01-01 DOI: 10.4161/rdis.25200

James Shorter, J Paul Taylor

{"title":"Disease mutations in the prion-like domains of hnRNPA1 and hnRNPA2/B1 introduce potent steric zippers that drive excess RNP granule assembly.","authors":"James Shorter, J Paul Taylor","doi":"10.4161/rdis.25200","DOIUrl":"https://doi.org/10.4161/rdis.25200","url":null,"abstract":"Approximately 1% of human proteins harbor a prion-like domain (PrLD) of similar low complexity sequence and amino acid composition to domains that drive prionogenesis of yeast proteins like Sup35. PrLDs are over-represented in human RNA-binding proteins and mediate phase transitions underpinning RNP granule assembly. This modality renders PrLDs prone to misfold into conformers that accrue in pathological inclusions that characterize various fatal neurodegenerative diseases. For example, TDP-43 and FUS form cytoplasmic inclusions in amyotrophic lateral sclerosis (ALS) and mutations in TDP-43 and FUS can cause ALS. Here, we review our recent discovery of discrete missense mutations that alter a conserved gatekeeper aspartate residue in the PrLDs of hnRNPA2/B1 and hnRNPA1 and cause multisystem proteinopathy and ALS. The missense mutations generate potent steric zippers in the PrLDs, which enhance a natural propensity to form self-templating fibrils, promote recruitment to stress granules and drive cytoplasmic inclusion formation. PrLDs occur in ~250 human proteins and could contribute directly to the etiology of various degenerative disorders. ","PeriodicalId":74639,"journal":{"name":"Rare diseases (Austin, Tex.)","volume":"1 ","pages":"e25200"},"PeriodicalIF":0.0,"publicationDate":"2013-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4161/rdis.25200","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32485729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 40