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Generation and characterization of fruitless P1 promoter mutant in Drosophila melanogaster. 黑腹果蝇P1无果启动子突变体的产生及特性研究。
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2021-09-01 DOI: 10.1080/01677063.2021.1931179
Megan C Neville, Alexander Eastwood, Aaron M Allen, Ammerins de Haan, Tetsuya Nojima, Stephen F Goodwin

The identification of mutations in the gene fruitless (fru) paved the way for understanding the genetic basis of male sexual behavior in the vinegar fly Drosophila melanogaster. D. melanogaster males perform an elaborate courtship display to the female, ultimately leading to copulation. Mutations in fru have been shown to disrupt most aspects of the male's behavioral display, rendering males behaviorally sterile. The fru 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 fru 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 fru 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 fru P1-derived function in D. melanogaster. Our fruΔP1 mutant will be useful for future studies of fru P1-derived function, as it can be homozygosed without disrupting additional downstream promoter function and can be utilized in heterozygous combinations with other extant fru alleles.

无果基因(fru)突变的鉴定为理解黑腹果蝇雄性性行为的遗传基础铺平了道路。雄性黑腹龙会向雌性进行精心的求爱表演,最终导致交配。fru的突变已被证明会破坏雄性行为表现的大多数方面,使雄性行为不育。fru基因组位点编码来自多个启动子的多个转录因子亚型;只有那些受最末端P1启动子调控的基因才受性别决定等级的控制,并在男性特异性行为中发挥作用。在本研究中,我们使用基于CRISPR/ cas9的fru基因靶向基因组编辑,去除P1启动子区域。我们已经证明,P1启动子的移除会导致雄性对雌性的求爱表现和雄性特异性不育的急剧减少。我们扩大了对fru p1依赖行为的分析,研究了雄性在12小时的明暗周期中对求爱歌曲的反应和一般活动水平。我们的新等位基因扩展了突变库,可用于未来研究黑腹龙fru p1衍生功能。我们的fruΔP1突变体将对未来fru p1衍生功能的研究有用,因为它可以纯合而不破坏额外的下游启动子功能,并且可以与其他现存的fru等位基因进行杂合组合。
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引用次数: 1
Loss of mGluR1-LTD following cocaine exposure accumulates Ca2+-permeable AMPA receptors and facilitates synaptic potentiation in the prefrontal cortex. 可卡因暴露后mGluR1-LTD的丧失会积累Ca2+渗透性AMPA受体,并促进前额叶皮层的突触增强。
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2021-09-01 DOI: 10.1080/01677063.2021.1931180
Hongyu Ruan, Wei-Dong Yao

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 in vivo 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.

成瘾是由药物引起的多巴胺能奖赏回路突触可塑性机制的改变引起的。药物暴露后代谢性谷氨酸受体(mGluR)依赖的长期抑郁(LTD)受损和突触Ca2+渗透性AMPA受体(CP-AMPARs)的积累已成为药物渴求和复发的重要机制。本研究表明,体内重复的可卡因暴露会导致小鼠前额皮质(PFC)第5层锥体神经元中mGluR1-和mTOR(哺乳动物雷帕霉素靶)依赖性LTD的短暂但完全丧失,mTOR是奖励回路中主要的多巴胺能靶点。这种mGluR1-LTD损伤可以通过体内给药mGluR1阳性变构调节剂(PAM)来预防,并通过抑制多巴胺D1受体来恢复,这表明mGluR1音调受损和过度的D1信号传导是这种LTD缺陷的基础。同时,CP-AMPAR产生,表明对CP-AMPAR抑制剂Naspm的敏感性增加,突触AMPAR电流纠正,可卡因暴露小鼠的突触AMPAR电流被PAM逆转。最后,这些CP-AMPARs介导了可卡因暴露导致的异常尖峰时间依赖的长期增强。我们的发现揭示了一种机制,通过这种机制,可卡因损害LTD并重塑突触ampar,从而影响pfc的Hebbian可塑性。不经历LTD可能会阻止药物增强的脑回路逆转到基线状态,从而使成瘾行为永续。mGluR1-和mtor依赖性LTD存在于小鼠内侧前额皮质。体内多次可卡因暴露暂时但完全消除前额叶mGluR1-LTD。mGluR1功能受损和过量的D1 DA信号可能是可卡因损伤mGluR1- ltd的基础。Ca2+渗透性AMPA受体是由可卡因暴露产生的,可能是由mGluR1-LTD损伤引起的,并有助于可卡因诱导的延长尖峰时间LTP。
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引用次数: 5
Spontaneous motor-behavior abnormalities in two Drosophila models of neurodevelopmental disorders. 两种果蝇神经发育障碍模型的自发运动行为异常。
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2021-03-01 Epub Date: 2020-11-09 DOI: 10.1080/01677063.2020.1833005
David R Andrew, Mariah E Moe, Dailu Chen, Judith A Tello, Rachel L Doser, William E Conner, Jaswinder K Ghuman, Linda L Restifo

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 Drosophila dfmr1 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 dfmr1 mutants spent excessive time grooming, with increased bout number and duration; both were rescued by transgenic wild-type dfmr1+. By two grooming-pattern measures, dfmr1-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 dfmr1 mutants, are complicated by excessive grooming. We also observed significantly increased grooming in CASK mutants, despite their dramatically decreased walking phenotype. The mutant flies, a model for human CASK-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.

数百个基因的突变导致神经发育障碍,伴有异常的运动行为和认知缺陷。患有脆性X染色体综合征(FXS)的男孩是导致智力残疾的主要单基因原因,他们经常表现出重复行为,这是自闭症的一个核心特征。通过直接观察和人工分析,我们对果蝇dfmr1突变体(FXS的建立模型)的自发运动行为表型进行了表征。我们在小范围内记录了个体1天大的成年果蝇,它们具有成熟的神经系统,在衰老开始之前。我们使用开源视频注释软件对行为进行评分,以生成连续的活动时间线,并以图形和定量的方式表示。年轻的dfmr1突变体花过多的时间梳理毛发,毛发数量和持续时间增加;均被转基因野生型dfmr1+拯救。通过两种梳理模式测量,dfmr1突变果蝇表现出与持久性一致的重复增加,这在FXS中很常见。此外,突变果蝇表现出对梳理身体后部结构的偏好,并且从一个部位到另一个部位的梳理速度增加。我们提出了一种可能性,即求爱和昼夜节律缺陷,之前报道的dfmr1突变体,由于过度梳理而变得复杂。我们还观察到CASK突变体显着增加了修饰,尽管他们的行走表型显着降低。突变果蝇是人类cask相关神经发育障碍的模型,在整个实验过程中表现出持续升高的梳理指数,但在放置在舞台后立即出现短暂的运动激活。基于已发表的fmrp靶转录物鉴定数据和导致人类遗传神经发育障碍的突变的功能分析,我们提出以下蛋白作为FXS过度重复行为的候选介质:CaMKIIα、NMDA受体亚基2A和2B、NLGN3和SHANK3。总之,这些果蝇突变表型和机制的见解为药物发现提供了起点,以确定减少功能失调的重复行为的化合物。
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引用次数: 3
De novo mutation in SLC25A22 gene: expansion of the clinical and electroencephalographic phenotype. SLC25A22基因的新生突变:临床和脑电图表型的扩展。
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2021-03-01 Epub Date: 2021-04-06 DOI: 10.1080/01677063.2021.1892094
Antonio Gennaro Nicotera, Daniela Dicanio, Erica Pironti, Maria Bonsignore, Anna Cafeo, Stephanie Efthymiou, Patrizia Mondello, Vincenzo Salpietro, Henry Houlden, Gabriella Di Rosa

The SLC25A22 (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 SLC25A22 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 SLC25A22 variants, characterized by dyskinetic movements and oculogyric crisis.

SLC25A22(溶质载体家族25,成员22)基因编码线粒体谷氨酸/H+同调体,并参与代谢物在线粒体膜上的线粒体运输。我们在此报告一位12岁的女孩,表现为早发性癫痫性脑病、张力低下和整体发育迟缓。全外显子组测序发现SLC25A22基因纯合错义突变(c.97A>G;p.Lys33Glu),作为该疾病的可能原因。我们患者的表型和脑电图记录与先前描述的表型不完全重叠,导致与SLC25A22变异相关的一种新的更复杂的疾病形式,其特征是运动障碍和眼神经危象。
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引用次数: 2
Change in gene expression levels of GABA, glutamate and neurosteroid pathways due to acoustic trauma in the cochlea. 耳蜗声损伤后GABA、谷氨酸和神经类固醇通路基因表达水平的变化。
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2021-03-01 Epub Date: 2021-04-07 DOI: 10.1080/01677063.2021.1904922
Meltem Cerrah Gunes, Murat Salih Gunes, Alperen Vural, Fatma Aybuga, Arslan Bayram, Keziban Korkmaz Bayram, Mehmet Ilhan Sahin, Muhammet Ensar Dogan, Sevda Yesim Ozdemir, Yusuf Ozkul

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 Cyp11a1, Gls, Gabra1, Grin2b, Sult1a1, Gad1, and Slc1a2 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 Slc6a1 and Slc17a8 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.

噪声性听力损失(NIHL)的特征是耳蜗外毛细胞(OHC)和内毛细胞(IHC)的损失或功能障碍。形成耳蜗神经细胞体的螺旋神经节神经元中有90-95%与间充质干细胞发生突触。谷氨酸是ihc -听觉神经突触中最有效的兴奋性神经递质。在声损伤(AT)的反应中,谷氨酸的过度释放可能引起兴奋性毒性,引起螺旋神经节神经元(SGN)的损伤或螺旋神经节树突的损失,突触后到ihc。另一种神经递质GABA在外周损伤后的声刺激加工和中枢调节中发挥重要作用,因此它可能与噪声后的听觉功能和灵敏度调节有关。本研究旨在探讨AT对谷氨酸兴奋毒性、GABA抑制和神经类固醇合成基因表达的影响。我们将24只BALB/c小鼠暴露于AT。对照组在无噪声暴露的情况下处死,在噪声暴露后第1天和第15天分别处死at后(1)和at后(15)。采用实时荧光定量PCR法比较各组间谷氨酸、GABA和神经类固醇通路相关基因的表达情况。Cyp11a1、Gls、Gabra1、Grin2b、Sult1a1、Gad1和Slc1a2基因在at后(15)小鼠中的表达与对照组和at后(1)小鼠相比显著降低。Slc6a1和Slc17a8基因的表达差异无统计学意义。这些发现支持谷氨酸兴奋毒性和GABA抑制之间的平衡可能在AT后的几天内被破坏,并且一些神经类固醇如孕烯醇酮硫酸盐的合成可能在这种平衡中起重要作用。
{"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}
引用次数: 3
Description of clinical features and genetic analysis of one ultra-rare (SPG64) and two common forms (SPG5A and SPG15) of hereditary spastic paraplegia families. 遗传性痉挛性截瘫家族1个超罕见型(SPG64)和2个常见型(SPG5A和SPG15)的临床特征描述及遗传分析。
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2021-03-01 Epub Date: 2021-03-26 DOI: 10.1080/01677063.2021.1895146
Mahdieh Pashaei, Atefeh Davarzani, Reza Hajati, Babak Zamani, Shahriar Nafissi, Farzaneh Larti, Yalda Nilipour, Mohammad Rohani, Afagh Alavi

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 ENTPD1, CYP7B1, and ZFYVE26 were identified, respectively. Intra and interfamilial clinical variability were observed among affected individuals. Mutations in CYP7B1 and ZFYVE26 are relatively common causes of HSP and associated with SPG5A and SPG15, respectively. However, mutations in ENTPD1 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.

遗传性痉挛性截瘫(HSP)是一种临床和遗传异质性的神经退行性疾病,以下肢痉挛和虚弱为特征。迄今为止,已经确定了超过82个位点/基因(SPG1-SPG82)与HSP有关。尽管使用了基于新一代测序的方法,遗传分析仍未能在50%以上的HSP患者中发现致病基因,这表明存在更显著的异质性,并且缺乏给定的表型-基因型相关性。在这里,我们进行了全外显子组测序(WES)来鉴定三个不相关的伊朗先证者的热敏感蛋白引起基因。候选变异在先证者中检测和确认,并在家庭成员中共同分离。收集表型数据并与具有相同亚型疾病的早期病例进行比较。三个新的纯合变异体,c.978delT;c.A1208G p.Q327Kfs * 39;p.D403G和c.3811delT;p.S1271Lfs*44,分别在已知的引起热休克的基因包括ENTPD1、CYP7B1和ZFYVE26中被鉴定出来。在受影响的个体中观察到家族内和家族间的临床变异性。CYP7B1和ZFYVE26突变是相对常见的HSP病因,分别与SPG5A和SPG15相关。然而,ENTPD1的突变与SPG64有关,SPG64是一种超罕见的HSP。本研究证实了HSP的表型表现和等位基因异质性的复杂性。由于这些复杂性,在HSP病例中显示明确的表型-基因型相关性是不可行的。鉴定更多具有热休克蛋白致病基因突变的家庭可能有助于建立这种相关性,进一步了解疾病的分子基础,并将为这些家庭的遗传咨询提供机会。
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引用次数: 7
Compound heterozygous KCTD7 variants in progressive myoclonus epilepsy. 进行性肌阵挛性癫痫的复合杂合KCTD7变异。
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2021-03-01 Epub Date: 2021-05-10 DOI: 10.1080/01677063.2021.1892095
Elizabeth A Burke, Morgan Sturgeon, Diane B Zastrow, Liliana Fernandez, Cameron Prybol, Shruti Marwaha, Edward P Frothingham, Patricia A Ward, Christine M Eng, Laure Fresard, Stephen B Montgomery, Gregory M Enns, Paul G Fisher, Lynne A Wolfe, Brian Harding, Blake Carrington, Kevin Bishop, Raman Sood, Yan Huang, Abdel Elkahloun, Camilo Toro, Alexander G Bassuk, Matthew T Wheeler, Thomas C Markello, William A Gahl, May Christine V Malicdan

KCTD7 is a member of the potassium channel tetramerization domain-containing protein family and has been associated with progressive myoclonic epilepsy (PME), characterized by myoclonus, epilepsy, and neurological deterioration. Here we report four affected individuals from two unrelated families in which we identified KCTD7 compound heterozygous single nucleotide variants through exome sequencing. RNAseq was used to detect a non-annotated splicing junction created by a synonymous variant in the second family. Whole-cell patch-clamp analysis of neuroblastoma cells overexpressing the patients' variant alleles demonstrated aberrant potassium regulation. While all four patients experienced many of the common clinical features of PME, they also showed variable phenotypes not previously reported, including dysautonomia, brain pathology findings including a significantly reduced thalamus, and the lack of myoclonic seizures. To gain further insight into the pathogenesis of the disorder, zinc finger nucleases were used to generate kctd7 knockout zebrafish. Kctd7 homozygous mutants showed global dysregulation of gene expression and increased transcription of c-fos, which has previously been correlated with seizure activity in animal models. Together these findings expand the known phenotypic spectrum of KCTD7-associated PME, report a new animal model for future studies, and contribute valuable insights into the disease.

KCTD7是含钾通道四聚结构域蛋白家族的成员,与进行性肌阵挛性癫痫(PME)有关,其特征是肌阵挛、癫痫和神经功能恶化。在这里,我们报告了来自两个不相关家族的四个受影响个体,我们通过外显子组测序鉴定了KCTD7复合杂合单核苷酸变异。RNAseq用于检测由第二家族的同义变体产生的无注释剪接连接。过表达患者变异等位基因的神经母细胞瘤细胞的全细胞膜片钳分析显示钾调控异常。虽然所有4名患者都经历了PME的许多常见临床特征,但他们也表现出以前未报道的可变表型,包括自主神经异常,脑部病理发现包括丘脑显着减少,以及肌阵挛性癫痫的缺乏。为了进一步了解这种疾病的发病机制,我们使用锌指核酸酶来产生kctd7基因敲除的斑马鱼。Kctd7纯合突变体表现出基因表达的全局失调和c-fos转录的增加,这在之前的动物模型中与癫痫活动相关。总之,这些发现扩大了已知的kctd7相关PME的表型谱,为未来的研究报告了一个新的动物模型,并为该疾病提供了有价值的见解。
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引用次数: 1
A rapid molecular diagnostic method for spinal muscular atrophy. 脊髓性肌萎缩症的快速分子诊断方法。
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2021-03-01 Epub Date: 2020-12-17 DOI: 10.1080/01677063.2020.1853721
Kai-Chen Wang, Chiao-Yuan Fang, Chi-Chang Chang, Chien-Kuan Chiang, Yi-Wen Chen

Spinal muscular atrophy (SMA) is a common autosomal recessive disorder which has been considered as the second common cause of infant death, with an estimated prevalence of 1 in 10,000 live births. The disorder is caused by survival motor neuron 1 gene (SMN1) deficiency leading to limb weakness, difficult swallowing and abnormal breathing. Here, a fast and accurate method for SMA detection has been developed. Genomic DNA sample collected from whole blood, amniotic fluid, or dried blood spots can be analysed by using the Clarity™ Digital PCR (dPCR) System for determining the copy numbers of SMN1 and SMN2 genes. Two hundred and fourteen clinical samples determined by qPCR-based method were enrolled and used to establish the cut-off ranges for unaffected individual, SMA carrier and SMA patient categories. After setting the cut-off range for each group, 12 samples were analyzed by both dPCR-based method and MLPA (multiplex ligation-dependent probe amplification), the current testing golden standard for SMA, and 100% concordant results between the two testing methods were performed. CSB SMA Detection Kit combined with dPCR platform provides a robust and precise approach to distinguish unaffected individuals, SMA carrier and SMA patients. This rapid molecular diagnostic method can be adapted to pre-pregnancy eugenics inspection, prenatal testing as well as newborns screening and help physicians or genetic counselors to improve population SMA incidence.

脊髓性肌萎缩症(SMA)是一种常见的常染色体隐性遗传病,被认为是婴儿死亡的第二大常见原因,估计患病率为1 / 10,000活产。这种疾病是由生存运动神经元1基因(SMN1)缺乏引起的,导致肢体无力、吞咽困难和呼吸异常。本文提出了一种快速、准确的SMA检测方法。从全血、羊水或干血斑点收集的基因组DNA样本可以使用Clarity™数字PCR (dPCR)系统进行分析,以确定SMN1和SMN2基因的拷贝数。通过基于qpcr的方法确定214份临床样本,并用于建立未受影响个体、SMA携带者和SMA患者类别的截止范围。在设定每组的截止范围后,对12个样本进行基于dpcr的方法和当前SMA检测黄金标准MLPA (multiple - lig- dependent probe amplification,多路连接依赖探针扩增)的分析,两种检测方法的结果100%一致。CSB SMA检测试剂盒结合dPCR平台,提供了一种强大而精确的方法来区分未受影响的个体、SMA携带者和SMA患者。这种快速分子诊断方法可适用于孕前优生学检查、产前检测和新生儿筛查,帮助医生或遗传咨询师提高人群SMA发病率。
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引用次数: 5
Biallelic ZNF335 mutations cause basal ganglia abnormality with progressive cerebral/cerebellar atrophy. 双等位基因ZNF335突变导致基底节区异常伴进行性脑/小脑萎缩。
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2021-03-01 Epub Date: 2020-11-20 DOI: 10.1080/01677063.2020.1833006
Ahmet Okay Caglayan, Kourosh Yaghouti, Tanyel Kockaya, Demet Kemer, Tufan Cankaya, Najim Ameziane, Ozgur Cogulu, Mahmut Coker, Cengiz Yalcinkaya

To date, less than 10 pedigrees have been reported with ZNF335 mutations since it was discovered in 2012 and little is known about ZNF335-related clinical spectrum. We describe a 12 years old male patient who is only child of nonconsanguineous Turkish parents. Trio whole genome sequencing identified previously unreported compound heterozygous variants in ZNF335, namely, c.3889T > A p.(Ser1297Thr) and c.758G > A p.(Arg253Gln) where transmitted by his father and mother, respectively. Patient' magnetic resonance imaging findings were overlapping to those observed in the previous cases with ZNF335 mutations. Here we report the oldest patient with biallelic ZNF335 mutations. We recommend screening for ZNF335 defects in patients with basal ganglia anomaly, secondary white matter abnormalities and microcephaly.

自2012年发现ZNF335突变以来,迄今为止,只有不到10个家系报道了ZNF335突变,并且对ZNF335相关的临床谱知之甚少。我们描述了一个12岁的男性患者谁是唯一的孩子非近亲土耳其父母。三人全基因组测序结果显示,ZNF335的复合杂合变异为c.3889T > A p.(Ser1297Thr)和c.758G > A p.(Arg253Gln),分别由父亲和母亲遗传。患者的磁共振成像结果与先前ZNF335突变病例的观察结果重叠。在这里,我们报告了年龄最大的双等位基因ZNF335突变患者。我们建议在基底神经节异常、继发性白质异常和小头畸形患者中筛查ZNF335缺陷。
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引用次数: 4
Analysis of whole genome sequenced cases and controls shows that the association of variants in TOMM40, BCAM, NECTIN2 and APOC1 with late onset Alzheimer's disease is driven by linkage disequilibrium with APOE ε2/ε3/ε4 alleles. 对全基因组测序病例和对照组的分析表明,TOMM40、BCAM、NECTIN2 和 APOC1 中的变异与晚发性阿尔茨海默病的关联是由与 APOE ε2/ε3/ε4 等位基因的连锁不平衡驱动的。
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2021-03-01 Epub Date: 2021-05-10 DOI: 10.1080/01677063.2020.1866569
David Curtis

Variants in APOE are associated with risk of late onset Alzheimer's disease (LOAD) but the magnitude of the effect has been reported to vary across ancestries. Also, other variants in the region have been reported to show association though it has been unclear whether this was secondary to their linkage disequilibrium with the APOE variants rs429358 and rs7412. Previous analyses of exome-sequenced samples have identified other genes in which rare variants impact risk of disease. In this study 2000 whole genome sequenced cases and controls with different ancestries were subjected to gene-based weighted burden analysis to identify risk genes. Additionally, individual variants in the APOE region were tested for association with LOAD. When using the APOE variants as covariates no individual genes showed statistically significant evidence for association after Bonferroni correction for multiple testing, which may well be a consequence of the modest sample size. Likewise, for those variants initially showing evidence of association with LOAD incorporating the APOE variants as covariates dramatically reduced the strength of association. These results demonstrate that the differential association of APOE across ancestries does not appear to be driven by another variant in the region. It seems likely that no other genes in the region have a direct effect on LOAD risk.

APOE 变异与晚发性阿尔茨海默病(LOAD)的风险有关,但据报道,不同血统的影响程度不同。此外,据报道该区域的其他变异也显示出相关性,但尚不清楚这是否与 APOE 变异 rs429358 和 rs7412 的连锁不平衡有关。以前的外显子组测序样本分析发现了罕见变异影响疾病风险的其他基因。在这项研究中,对 2000 个不同血统的全基因组测序病例和对照组进行了基于基因的加权负担分析,以确定风险基因。此外,还检测了 APOE 区域的单个变异与 LOAD 的关联。当使用 APOE 变体作为协变量时,经 Bonferroni 多重检验校正后,没有单个基因显示出统计学上显著的关联证据,这很可能是样本量不大的结果。同样,对于那些最初显示出与 LOAD 相关的变体,将 APOE 变体作为协变量大大降低了相关性的强度。这些结果表明,不同祖先间 APOE 的不同关联性似乎并不是由该区域的另一个变体驱动的。看来,该地区的其他基因很可能对 LOAD 风险没有直接影响。
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引用次数: 0
期刊
Journal of neurogenetics
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