Journal of neurogenetics最新文献

{"title":"Reduction of the α-synuclein expression promotes slowing down early neuropathology development in the Drosophila model of Parkinson’s disease","authors":"Ilia M Golomidov, Evgenia M. Latypova, E. Ryabova, O. Bolshakova, A. Komissarov, S. Sarantseva","doi":"10.1080/01677063.2022.2064462","DOIUrl":"https://doi.org/10.1080/01677063.2022.2064462","url":null,"abstract":"Abstract Parkinson’s disease (PD) is a neurodegenerative disease characterised by the formation of Lewy bodies and progressive loss of dopaminergic (DA) neurons in the substantia nigra. Lewy bodies mainly consist of α-synuclein, which plays a critical role in the pathophysiology of PD. The α-synuclein is encoded by the SNCA gene and is the first identified gene associated with hereditary PD. Currently, there are at least six disease-associated mutations in α-synuclein that cause dominantly inherited familial forms of PD. Targeted expression of human SNCA.WT/SNCA.A30P/SNCA.A53T gene in Drosophila melanogaster over specific times employing a temperature-dependent UAS/GAL4 – GAL80 system allows for the evaluation of neurodegenerative processes. In this study, SNCA was expressed only in the adult stage of Drosophila development for 1 or 2 weeks, followed by repression of gene expression for the rest of the fly’s life. It was demonstrated that the level of pathology significantly depends on the duration of α-synuclein expression. SNCA gene expression over a longer period of time caused the death of DA neurons, decreased levels of dopamine and locomotor ability. In this case, the observed neurodegenerative processes correlated with the accumulation of α-synuclein in the Drosophila brain. Importantly, repression of α-synuclein expression led to elimination of the soluble protein fraction, in contrast to the insoluble fraction. No further significant development of characteristic signs of pathology was observed after the α-synuclein expression was blocked. Thus, we suggest that reduction of α-synuclein expression alone contributes to slowing down the development of PD-like symptoms.","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":"36 1","pages":"1 - 10"},"PeriodicalIF":1.9,"publicationDate":"2022-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42383867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LncRNA GAS5 promotes epilepsy progression through the epigenetic repression of miR-219, in turn affecting CaMKIIγ/NMDAR pathway","authors":"Chen-sheng Zhao, Dong-xing Liu, Yanping Fan, Jian-kun Wu","doi":"10.1080/01677063.2022.2067536","DOIUrl":"https://doi.org/10.1080/01677063.2022.2067536","url":null,"abstract":"Abstract It has been widely reported that dysregulated long-chain noncoding RNAs (lncRNAs) are closely associated with epilepsy. This study aimed to probe the function of lncRNA growth arrest-specific 5 (GAS5), microRNA (miR)-219 and Calmodulin-dependent protein kinase II (CaMKII)γ/N-methyl-D-aspartate receptor (NMDAR) pathway in epilepsy. Epileptic cell and animal models were constructed using magnesium deficiency treatment and diazepam injection, respectively. GAS5 and miR-219 expressions in epileptic cell and animal models were determined using qRT-PCR assay. The protein levels of CaMKIIγ, NMDAR and apoptosis-related proteins levels were assessed by western blot. Cell counting kit-8 (CCK-8) assay was employed to determine cell proliferation. Besides, TNFα, IL-1β, IL-6 and IL-8 levels were analyzed using enzyme-linked immunosorbent assay (ELISA). Furthermore, cell apoptosis was evaluated using TUNEL staining and flow cytometric analysis. Finally, the binding relationship between GAS5 and EZH2 was verified using RIP and ChIP assay. Our results revealed that GAS5 was markedly upregulated in epileptic cell and animal models, while miR-219 was down-regulated. GAS5 knockdown dramatically increased cell proliferation of epileptic cells, whereas suppressed inflammation and the apoptosis. Furthermore, our results showed that GAS5 epigenetically suppressed transcriptional miR-219 expression via binding to EZH2. miR-219 mimics significantly enhanced cell proliferation of epileptic cells, while inhibited inflammation and the apoptosis, which was neutralized by CaMKIIγ overexpression. Finally, miR-219 inhibition reversed the effects of GAS5 silence on epileptic cells, which was eliminated by CaMKIIγ inhibition. In conclusion, GAS5 affected inflammatory response and cell apoptosis of epilepsy via inhibiting miR-219 and further regulating CaMKIIγ/NMDAR pathway (See graphic summary in Supplementary Material).","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":"36 1","pages":"32 - 42"},"PeriodicalIF":1.9,"publicationDate":"2022-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45916724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel insights into the genetic profile of hereditary spastic paraplegia in India","authors":"Sundarapandian Narendiran, M. Debnath, S. Shivaram, Ramakrishnan Kannan, Shivani Sharma, R. Christopher, D. Seshagiri, S. Jain, M. Purushottam, Sandhya Mangalore, R. Bharath, P. Bindu, S. Sinha, A. Taly, M. Nagappa","doi":"10.1080/01677063.2022.2064463","DOIUrl":"https://doi.org/10.1080/01677063.2022.2064463","url":null,"abstract":"Abstract The Hereditary Spastic Paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders characterized by length dependent degeneration of the corticospinal tracts. Genetic data related to HSPs are limited from India. We aimed to comprehensively analyse the phenotypic characteristics and genetic basis of a large cohort of HSP from India. Patients with HSP phenotype were evaluated for their clinical features, electrophysiological and radiological abnormalities. Genetic analyses were carried out by clinical exome sequencing (n = 52) and targeted sequencing (n = 5). The cohort comprised of 57 probands (M:F 40:17, age: 3.5–49 years). Based on the phenotype, the cohort could be categorized as ‘pure’ (n = 15, 26.3%) and ‘complicated’ (n = 42, 73.7%) HSP. Brain MRI showed thin corpus callosum (n = 10), periventricular hyperintensities (n = 20), cerebral atrophy (n = 3), cerebellar atrophy (n = 3) and diffuse atrophy (n = 4). Sixty-seven variants representing 40 genes were identified including 47 novel variants. Forty-eight patients (84.2%) had variants in genes previously implicated in HSP and other spastic paraplegia syndromes (SPG genes = 24, non-SPG genes = 24); among these 13 had variations in more than one gene and 12 patients (21.0%) had variations in genes implicated in potentially treatable/modifiable metabolic disorders (MTHFR = 8, MTRR = 1, ARG1 = 2 and ABCD1 = 1). In nine patients, no genetic variants implicated in spastic paraplegia phenotype were identified. Thus, the present study from India highlights the phenotypic complexities and spectrum of genetic variations in patients with HSP including those implicated in metabolically modifiable disorders. It sets a platform for carrying out functional studies to validate the causal role of the novel variants and variants of uncertain significance.","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":"36 1","pages":"21 - 31"},"PeriodicalIF":1.9,"publicationDate":"2022-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43417024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fly seizure EEG: field potential activity in the <i>Drosophila</i> brain.","authors":"Atulya Iyengar,&nbsp;Chun-Fang Wu","doi":"10.1080/01677063.2021.1950714","DOIUrl":"https://doi.org/10.1080/01677063.2021.1950714","url":null,"abstract":"<p><p>Hypersynchronous neural activity is a characteristic feature of seizures. Although many <i>Drosophila</i> mutants of epilepsy-related genes display clear behavioral spasms and motor unit hyperexcitability, field potential measurements of aberrant hypersynchronous activity across brain regions during seizures have yet to be described. Here, we report a straightforward method to observe local field potentials (LFPs) from the <i>Drosophila</i> brain to monitor ensemble neural activity during seizures in behaving tethered flies. High frequency stimulation across the brain reliably triggers a stereotypic sequence of electroconvulsive seizure (ECS) spike discharges readily detectable in the dorsal longitudinal muscle (DLM) and coupled with behavioral spasms. During seizure episodes, the LFP signal displayed characteristic large-amplitude oscillations with a stereotypic temporal correlation to DLM flight muscle spiking. ECS-related LFP events were clearly distinct from rest- and flight-associated LFP patterns. We further characterized the LFP activity during different types of seizures originating from genetic and pharmacological manipulations. In the 'bang-sensitive' sodium channel mutant <i>bangsenseless</i> (<i>bss</i>), the LFP pattern was prolonged, and the temporal correlation between LFP oscillations and DLM discharges was altered. Following administration of the pro-convulsant GABA_A blocker picrotoxin, we uncovered a qualitatively different LFP activity pattern, which consisted of a slow (1-Hz), repetitive, waveform, closely coupled with DLM bursting and behavioral spasms. Our approach to record brain LFPs presents an initial framework for electrophysiological analysis of the complex brain-wide activity patterns in the large collection of <i>Drosophila</i> excitability mutants.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":"35 3","pages":"295-305"},"PeriodicalIF":1.9,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/01677063.2021.1950714","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9113709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generation and characterization of <i>fruitless</i> P1 promoter mutant in <i>Drosophila melanogaster</i>.","authors":"Megan C Neville,&nbsp;Alexander Eastwood,&nbsp;Aaron M Allen,&nbsp;Ammerins de Haan,&nbsp;Tetsuya Nojima,&nbsp;Stephen F Goodwin","doi":"10.1080/01677063.2021.1931179","DOIUrl":"https://doi.org/10.1080/01677063.2021.1931179","url":null,"abstract":"<p><p>The identification of mutations in the gene <i>fruitless</i> (<i>fru</i>) paved the way for understanding the genetic basis of male sexual behavior in the vinegar fly <i>Drosophila melanogaster</i>. <i>D. melanogaster</i> males perform an elaborate courtship display to the female, ultimately leading to copulation. Mutations in <i>fru</i> have been shown to disrupt most aspects of the male's behavioral display, rendering males behaviorally sterile. The <i>fru</i> genomic locus encodes for multiple transcription factor isoforms from several promoters; only those under the regulation of the most distal P1 promoter are under the control of the sex determination hierarchy and play a role in male-specific behaviors. In this study, we used CRISPR/Cas9-based targeted genome editing of the <i>fru</i> gene, to remove the P1 promoter region. We have shown that removal of the P1 promoter leads to a dramatic decrease in male courtship displays towards females and male-specific sterility. We have expanded the analysis of <i>fru</i> P1-dependent behaviors, examining male's response to courtship song and general activity levels during12-hour light: dark cycles. Our novel allele expands the mutant repertoire available for future studies of <i>fru</i> P1-derived function in <i>D. melanogaster</i>. Our <i>fru^ΔP1</i> mutant will be useful for future studies of <i>fru</i> P1-derived function, as it can be homozygosed without disrupting additional downstream promoter function and can be utilized in heterozygous combinations with other extant <i>fru</i> alleles.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":"35 3","pages":"285-294"},"PeriodicalIF":1.9,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/01677063.2021.1931179","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9311488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of mGluR1-LTD following cocaine exposure accumulates Ca²⁺-permeable AMPA receptors and facilitates synaptic potentiation in the prefrontal cortex.","authors":"Hongyu Ruan,&nbsp;Wei-Dong Yao","doi":"10.1080/01677063.2021.1931180","DOIUrl":"https://doi.org/10.1080/01677063.2021.1931180","url":null,"abstract":"<p><p>Addiction results from drug-elicited alterations of synaptic plasticity mechanisms in dopaminergic reward circuits. Impaired metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) and accumulation of synaptic Ca²⁺-permeable AMPA receptors (CP-AMPARs) following drug exposure have emerged as important mechanisms underlying drug craving and relapse. Here we show that repeated cocaine exposure in vivo causes transient but complete loss of mGluR1- and mTOR (mammalian target of rapamycin)-dependent LTD in layer 5 pyramidal neurons of mouse prefrontal cortex (PFC), a major dopaminergic target in the reward circuitry. This mGluR1-LTD impairment was prevented by in vivo administration of an mGluR1 positive allosteric modulator (PAM) and rescued by inhibition of dopamine D1 receptors, suggesting that impaired mGluR1 tone and excessive D1 signaling underlie this LTD deficit. Concurrently, CP-AMPARs were generated, indicated by increased sensitivity to the CP-AMPAR inhibitor Naspm and rectification of synaptic AMPAR currents, which were reversed by PAM in cocaine-exposed mice. Finally, these CP-AMPARs mediate an abnormal spike-timing-dependent long-term potentiation enabled by cocaine exposure. Our findings reveal a mechanism by which cocaine impairs LTD and remodels synaptic AMPARs to influence Hebbian plasticity in the PFC. Failure to undergo LTD may prevent the reversal of drug-potentiated brain circuits to their baseline states, perpetuating addictive behaviors.HIGHLIGHTSA mGluR1- and mTOR-dependent LTD is present in the mouse medial prefrontal cortex.Repeated cocaine exposure <i>in vivo</i> temporally but completely abolishes prefrontal mGluR1-LTD.Impaired mGluR1 function and excessive D1 DA signaling likely underlie cocaine impairment of mGluR1-LTD.Ca²⁺-permeable AMPA receptors are generated by cocaine exposure, likely resulting from mGluR1-LTD impairment, and contribute to a cocaine-induced extended spike timing LTP.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":"35 4","pages":"358-369"},"PeriodicalIF":1.9,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/01677063.2021.1931180","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10441038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spontaneous motor-behavior abnormalities in two <i>Drosophila</i> models of neurodevelopmental disorders.","authors":"David R Andrew,&nbsp;Mariah E Moe,&nbsp;Dailu Chen,&nbsp;Judith A Tello,&nbsp;Rachel L Doser,&nbsp;William E Conner,&nbsp;Jaswinder K Ghuman,&nbsp;Linda L Restifo","doi":"10.1080/01677063.2020.1833005","DOIUrl":"https://doi.org/10.1080/01677063.2020.1833005","url":null,"abstract":"<p><p>Mutations in hundreds of genes cause neurodevelopmental disorders with abnormal motor behavior alongside cognitive deficits. Boys with fragile X syndrome (FXS), a leading monogenic cause of intellectual disability, often display repetitive behaviors, a core feature of autism. By direct observation and manual analysis, we characterized spontaneous-motor-behavior phenotypes of <i>Drosophila dfmr1</i> mutants, an established model for FXS. We recorded individual 1-day-old adult flies, with mature nervous systems and prior to the onset of aging, in small arenas. We scored behavior using open-source video-annotation software to generate continuous activity timelines, which were represented graphically and quantitatively. Young <i>dfmr1</i> mutants spent excessive time grooming, with increased bout number and duration; both were rescued by transgenic wild-type <i>dfmr1⁺</i>. By two grooming-pattern measures, <i>dfmr1</i>-mutant flies showed elevated repetitions consistent with perseveration, which is common in FXS. In addition, the mutant flies display a preference for grooming posterior body structures, and an increased rate of grooming transitions from one site to another. We raise the possibility that courtship and circadian rhythm defects, previously reported for <i>dfmr1</i> mutants, are complicated by excessive grooming. We also observed significantly increased grooming in <i>CASK</i> mutants, despite their dramatically decreased walking phenotype. The mutant flies, a model for human <i>CASK</i>-related neurodevelopmental disorders, displayed consistently elevated grooming indices throughout the assay, but transient locomotory activation immediately after placement in the arena. Based on published data identifying FMRP-target transcripts and functional analyses of mutations causing human genetic neurodevelopmental disorders, we propose the following proteins as candidate mediators of excessive repetitive behaviors in FXS: CaMKIIα, NMDA receptor subunits 2A and 2B, NLGN3, and SHANK3. Together, these fly-mutant phenotypes and mechanistic insights provide starting points for drug discovery to identify compounds that reduce dysfunctional repetitive behaviors.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":"35 1","pages":"1-22"},"PeriodicalIF":1.9,"publicationDate":"2021-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/01677063.2020.1833005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38583553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"De novo mutation in <i>SLC25A22</i> gene: expansion of the clinical and electroencephalographic phenotype.","authors":"Antonio Gennaro Nicotera,&nbsp;Daniela Dicanio,&nbsp;Erica Pironti,&nbsp;Maria Bonsignore,&nbsp;Anna Cafeo,&nbsp;Stephanie Efthymiou,&nbsp;Patrizia Mondello,&nbsp;Vincenzo Salpietro,&nbsp;Henry Houlden,&nbsp;Gabriella Di Rosa","doi":"10.1080/01677063.2021.1892094","DOIUrl":"https://doi.org/10.1080/01677063.2021.1892094","url":null,"abstract":"<p><p>The <i>SLC25A22</i> (Solute Carrier Family 25, Member 22) gene encodes for a mitochondrial glutamate/H⁺ symporter and is involved in the mitochondrial transport of metabolites across the mitochondrial membrane. We hereby report a 12-year-old girl presenting with early-onset epileptic encephalopathy, hypotonia, and global developmental delay. Whole exome sequencing identified a novel homozygous missense mutation in <i>SLC25A22</i> gene (c.97A>G; p.Lys33Glu), as the likely cause of the disease. The phenotype of our patient and EEG recordings do not completely overlap with the phenotypes previously described, leading to a new and more complex form of disease associated with <i>SLC25A22</i> variants, characterized by dyskinetic movements and oculogyric crisis.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":"35 2","pages":"67-73"},"PeriodicalIF":1.9,"publicationDate":"2021-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/01677063.2021.1892094","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25563588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Change in gene expression levels of GABA, glutamate and neurosteroid pathways due to acoustic trauma in the cochlea.","authors":"Meltem Cerrah Gunes,&nbsp;Murat Salih Gunes,&nbsp;Alperen Vural,&nbsp;Fatma Aybuga,&nbsp;Arslan Bayram,&nbsp;Keziban Korkmaz Bayram,&nbsp;Mehmet Ilhan Sahin,&nbsp;Muhammet Ensar Dogan,&nbsp;Sevda Yesim Ozdemir,&nbsp;Yusuf Ozkul","doi":"10.1080/01677063.2021.1904922","DOIUrl":"https://doi.org/10.1080/01677063.2021.1904922","url":null,"abstract":"<p><p>The characteristic feature of noise-induced hearing loss (NIHL) is the loss or malfunction of the outer hair cells (OHC) and the inner hair cells (IHC) of the cochlea. 90-95% of the spiral ganglion neurons, forming the cell bodies of cochlear nerve, synapse with the IHCs. Glutamate is the most potent excitatory neurotransmitter for IHC-auditory nerve synapses. Excessive release of glutamate in response to acoustic trauma (AT), may cause excitotoxicity by causing damage to the spiral ganglion neurons (SGN) or loss of the spiral ganglion dendrites, post-synaptic to the IHCs. Another neurotransmitter, GABA, plays an important role in the processing of acoustic stimuli and central regulation after peripheral injury, so it is potentially related to the regulation of hearing function and sensitivity after noise. The aim of this study is to evaluate the effect of AT on the expressions of glutamate excitotoxicity, GABA inhibition and neurosteroid synthesis genes.We exposed 24 BALB/c mice to AT. Controls were sacrificed without exposure to noise, Post-AT(1) and Post-AT(15) were sacrificed on the 1st and 15th day, respectively, after noise exposure. The expressions of various genes playing roles in glutamate, GABA and neurosteroid pathways were compared between groups by real-time PCR.Expressions of <i>Cyp11a1</i>, <i>Gls</i>, <i>Gabra1</i>, <i>Grin2b</i>, <i>Sult1a1</i>, <i>Gad1,</i> and <i>Slc1a2</i> genes in Post-AT(15) mice were significantly decreased in comparison to control and Post-AT(1) mice. No significant differences in the expression of <i>Slc6a1</i> and <i>Slc17a8</i> genes was detected.These findings support the possible role of balance between glutamate excitotoxicity and GABA inhibition is disturbed during the post AT days and also the synthesis of some neurosteroids such as pregnenolone sulfate may be important in this balance.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":"35 1","pages":"45-57"},"PeriodicalIF":1.9,"publicationDate":"2021-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/01677063.2021.1904922","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25568122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Description of clinical features and genetic analysis of one ultra-rare (SPG64) and two common forms (SPG5A and SPG15) of hereditary spastic paraplegia families.","authors":"Mahdieh Pashaei,&nbsp;Atefeh Davarzani,&nbsp;Reza Hajati,&nbsp;Babak Zamani,&nbsp;Shahriar Nafissi,&nbsp;Farzaneh Larti,&nbsp;Yalda Nilipour,&nbsp;Mohammad Rohani,&nbsp;Afagh Alavi","doi":"10.1080/01677063.2021.1895146","DOIUrl":"https://doi.org/10.1080/01677063.2021.1895146","url":null,"abstract":"<p><p>Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous neurodegenerative disorder, characterized by lower-limb spasticity and weakness. To date, more than 82 loci/genes (SPG1-SPG82) have been identified that contribute to the cause of HSP. Despite the use of next-generation sequencing-based methods, genetic-analysis has failed in the finding of causative genes in more than 50% of HSP patients, indicating a more significant heterogeneity and absence of a given phenotype-genotype correlation. Here, we performed whole-exome sequencing (WES) to identify HSP-causing genes in three unrelated-Iranian probands. Candidate variants were detected and confirmed in the probands and co-segregated in the family members. The phenotypic data gathered and compared with earlier cases with the same sub-types of disease. Three novel homozygous variants, c.978delT; p.Q327Kfs*39, c.A1208G; p.D403G and c.3811delT; p.S1271Lfs*44, in known HSP-causing genes including <i>ENTPD1</i>, <i>CYP7B1</i>, and <i>ZFYVE26</i> were identified, respectively. Intra and interfamilial clinical variability were observed among affected individuals. Mutations in <i>CYP7B1</i> and <i>ZFYVE26</i> are relatively common causes of HSP and associated with SPG5A and SPG15, respectively. However, mutations in <i>ENTPD1</i> are related to SPG64 which is an ultra-rare form of HSP. The research affirmed more complexities of phenotypic manifestations and allelic heterogeneity in HSP. Due to these complexities, it is not feasible to show a clear phenotype-genotype correlation in HSP cases. Identification of more families with mutations in HSP-causing genes may help the establishment of this correlation, further understanding of the molecular basis of the disease, and would provide an opportunity for genetic-counseling in these families.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":"35 2","pages":"84-94"},"PeriodicalIF":1.9,"publicationDate":"2021-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/01677063.2021.1895146","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25520610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}