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Bill Pak: reflections on mentoring. Bill Pak:关于指导的思考。
IF 1.8 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2024-07-08 DOI: 10.1080/01677063.2024.2374054
Martin G Burg
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引用次数: 0
Personal essay of a rookie's journey with Bill Pak and his legacy: tales and perspectives on PI-PLC, NorpA and cyclophilin, NinaA - William L. Pak, PhD., 1932-2023: in memoriam. 白威廉博士(William L. Pak, PhD.,1932-2023:悼念)的个人随笔:一个菜鸟与比尔-白及其遗产的旅程:关于 PI-PLC、NorpA 和环嗜血素 NinaA 的故事和观点。
IF 1.8 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2024-06-24 DOI: 10.1080/01677063.2024.2366455
Paulo A Ferreira

The neurogenetics and vision community recently mourned William L. Pak, PhD, whose pioneering work spearheaded the genetic, electrophysiological, and molecular bases of biological processes underpinning vision. This essay provides a historical background to the daunting challenges and personal experiences that carved the path to seminal findings. It also reflects on the intellectual framework, mentoring philosophy, and inspirational legacy of Bill Pak's research. An emphasis and perspectives are placed on the discoveries and implications to date of the phosphatidylinositol-specific phospholipase C (PI-PLC), NorpA, and the cyclophilin, NinaA of the fruit fly, Drosophila melanogaster, and their respective mammalian homologues, PI-PLCβ4, and cyclophilin-related protein, Ran-binding protein 2 (Ranbp2) in critical biological processes and diseases of photoreceptors and other neurons.

神经遗传学和视觉学界最近悼念了威廉-L-帕克(William L. Pak)博士,他的开创性工作是视觉生物过程的遗传学、电生理学和分子基础的先驱。这篇文章介绍了白威廉在取得开创性发现的道路上所面临的艰巨挑战和个人经历的历史背景。文章还反思了比尔-帕克研究的知识框架、指导理念和鼓舞人心的遗产。文章重点论述了迄今为止发现的磷脂酰肌醇特异性磷脂酶 C(P IP LC)、NorpA 和环纤蛋白、果蝇的 NinaA 以及它们各自的哺乳动物同源物 P I-P LCβ4 和环纤蛋白相关蛋白 Ran 结合蛋白 2(Ranbp2)在感光器和其他神经元的关键生物过程和疾病中的作用和影响。
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引用次数: 0
The pioneering use of the PDA phenotype by Bill Pak for screening a network of phototransduction genes and the associated signaling pathways. Bill Pak 率先利用 PDA 表型筛选光传导基因网络和相关信号通路。
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2024-06-19 DOI: 10.1080/01677063.2024.2335146
Baruch Minke
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引用次数: 0
Tribute to Dr. William L. Pak. 向白威廉博士致敬。
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2024-06-19 DOI: 10.1080/01677063.2024.2366468
Hiroyuki Matsumoto
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引用次数: 0
Carbamazepine responsive episodic dystonia and hallucination due to pyruvate dehydrogenase E2 (DLAT) gene mutation. 丙酮酸脱氢酶E2(DLAT)基因突变导致的卡马西平反应性发作性肌张力障碍和幻觉。
IF 1.8 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2024-06-01 Epub Date: 2024-07-15 DOI: 10.1080/01677063.2024.2372496
Jasmine Policherla, Fatema J Serajee, Salman Rashid, A H M Mahbubul Huq

Pyruvate Dehydrogenase (PDH) E2 deficiency due to Dihydrolipoamide acetyltransferase (DLAT) mutations is a very rare condition with only nine reported cases to date. We describe a 15-year-old girl with mild intellectual disability, paroxysmal dystonia and bilateral basal ganglia signal abnormalities on brain magnetic resonance imaging (MRI). Additionally, neurophysiological, imaging, metabolic and exome sequencing studies were performed. Routine metabolite testing, and GLUT1 and PRRT2 mutation analysis were negative. A repeat brain MRI revealed 'Eye-of-the-tiger-sign'. Exome sequencing identified homozygous valine to glycine alteration at amino acid position 157 in the DLAT gene. Bioinformatic and family analyses indicated that the alteration was likely pathogenic. Patient's dystonia was responsive to low-dose carbamazepine. On weaning carbamazepine, patient developed hallucinations which resolved after carbamazepine was restarted. PDH E2 deficiency due to DLAT mutation has a more benign course compared to common forms of PDH E1 deficiency due to X-linked PDHA1 mutations. All known cases of PDH E2 deficiency due to DLAT mutations share the features of episodic dystonia and intellectual disability. Our patient's dystonia and hallucinations responded well to low-dose carbamazepine.

二氢脂酰胺乙酰转移酶(DLAT)突变导致的丙酮酸脱氢酶(PDH)E2缺乏症是一种非常罕见的疾病,迄今仅有九例报道。我们描述了一名患有轻度智力障碍、阵发性肌张力障碍和脑磁共振成像(MRI)双侧基底节信号异常的 15 岁女孩。此外,还进行了神经电生理、成像、代谢和外显子组测序研究。常规代谢物检测、GLUT1 和 PRRT2 基因突变分析均为阴性。重复脑部核磁共振成像检查发现了 "虎眼征象"。外显子组测序发现,DLAT基因第157位氨基酸发生了从缬氨酸到甘氨酸的同源性改变。生物信息学和家族分析表明,该改变很可能是致病性的。患者的肌张力障碍对小剂量卡马西平有反应。在停用卡马西平后,患者出现幻觉,但在重新开始服用卡马西平后幻觉消失。与常见的由X连锁PDHA1突变导致的PDH E1缺乏症相比,由DLAT突变导致的PDH E2缺乏症的病程更为良性。所有已知的因DLAT突变导致的PDH E2缺乏症病例都具有发作性肌张力障碍和智力残疾的特征。我们患者的肌张力障碍和幻觉对小剂量卡马西平反应良好。
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引用次数: 0
Exploring the evidence for mitochondrial dysfunction and genetic abnormalities in the etiopathogenesis of tropical ataxic neuropathy. 探索热带共济失调性神经病发病机制中线粒体功能障碍和基因异常的证据。
IF 1.8 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2024-06-01 Epub Date: 2024-07-08 DOI: 10.1080/01677063.2024.2373363
Shivani Sharma, Anita Mahadevan, Gayathri Narayanappa, Monojit Debnath, Periyasamy Govindaraj, Sumanth Shivaram, Doniparthi V Seshagiri, Ramesh Siram, Akhilesh Shroti, Parayil S Bindu, Yasha T Chickabasaviah, Arun B Taly, Madhu Nagappa

Tropical ataxic neuropathy (TAN) is characterised by ataxic polyneuropathy, degeneration of the posterior columns and pyramidal tracts, optic atrophy, and sensorineural hearing loss. It has been attributed to nutritional/toxic etiologies, but evidence for the same has been equivocal. TAN shares common clinical features with inherited neuropathies and mitochondrial disorders, it may be hypothesised that genetic abnormalities may underlie the pathophysiology of TAN. This study aimed to establish evidence for mitochondrial dysfunction by adopting an integrated biochemical and multipronged genetic analysis. Patients (n = 65) with chronic progressive ataxic neuropathy with involvement of visual and/or auditory pathways underwent deep phenotyping, genetic studies including mitochondrial DNA (mtDNA) deletion analysis, mtDNA and clinical exome sequencing (CES), and respiratory chain complex (RCC) assay. The phenotypic characteristics included dysfunction of visual (n = 14), auditory (n = 12) and visual + auditory pathways (n = 29). Reduced RCC activity was present in 13 patients. Mitochondrial DNA deletions were noted in five patients. Sequencing of mtDNA (n = 45) identified a homoplasmic variant (MT-ND6) and a heteroplasmic variant (MT-COI) in one patient each. CES (n = 45) revealed 55 variants in nuclear genes that are associated with neuropathy (n = 27), deafness (n = 7), ataxia (n = 4), and mitochondrial phenotypes (n = 5) in 36 patients. This study provides preliminary evidence that TAN is associated with a spectrum of genetic abnormalities, including those associated with mitochondrial dysfunction, which is in contradistinction from the prevailing hypothesis that TAN is related to dietary toxins. Analysing the functional relevance of these genetic variants may improve the understanding of the pathogenesis of TAN.

热带共济失调性神经病(TAN)的特征是共济失调性多神经病、后柱和锥体束变性、视神经萎缩和感音神经性听力损失。该病被归因于营养/毒性病因,但相关证据并不明确。TAN 与遗传性神经病和线粒体疾病具有共同的临床特征,因此可以假设遗传异常可能是 TAN 病理生理学的基础。本研究旨在通过综合生化和多管齐下的遗传分析,确定线粒体功能障碍的证据。患有慢性进行性共济失调性神经病并累及视觉和/或听觉通路的患者(n = 65)接受了深度表型分析和遗传学研究,包括线粒体 DNA(mtDNA)缺失分析、mtDNA 和临床外显子组测序(CES)以及呼吸链复合物(RCC)检测。表型特征包括视觉(14 例)、听觉(12 例)和视觉+听觉通路(29 例)功能障碍。13 名患者的 RCC 活性降低。5 名患者的线粒体 DNA 存在缺失。mtDNA 测序(n = 45)在一名患者中分别发现了同质变异体(MT-ND6)和异质变异体(MT-COI)。CES(n = 45)揭示了核基因中的 55 个变体,这些变体与 36 名患者的神经病变(n = 27)、耳聋(n = 7)、共济失调(n = 4)和线粒体表型(n = 5)有关。这项研究提供了初步证据,证明 TAN 与一系列基因异常有关,包括与线粒体功能障碍有关的基因异常。对这些遗传变异的功能相关性进行分析,可提高对 TAN 发病机制的认识。
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引用次数: 0
SORDD: mutation frequency and phenotype in predominantly axonal Charcot-Marie-Tooth disease of undefined genetic cause. SORDD:遗传原因不明的主要轴索型夏科-玛丽-牙病的突变频率和表型。
IF 1.8 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2024-06-01 Epub Date: 2024-07-08 DOI: 10.1080/01677063.2024.2374898
Annabelle Arlt, Esra Akova-Öztürk, Anja Schirmacher, Bernhard Schlüter, Stephan Rust, Gerd Meyer Zu Hörste, Heinz Wiendl, Sarah Wiethoff

Pathogenic, biallelic variants in SORD were identified in 2020 as a novel cause for autosomal-recessive Charcot-Marie-Tooth disease (CMT) type 2, an inherited neuropathy. SORD codes for the enzyme sorbitol dehydrogenase. Loss of this enzyme's activity leads to an increase of sorbitol in serum. We retrospectively screened 166 patients with axonal neuropathy (predominantly CMT type 2, but including intermediate form of CMT and distal hereditary motor neuropathy (dHMN)) without identified genetic etiology for SORD mutations at a single large German neuromuscular center. Clinical and electrophysiology exam findings were analyzed for genotype-phenotype correlation. Five patients of the total cohort of 166 patients harbored pathogenic variants in SORD (3%). The homozygous frameshift variant c.757delG (p.Ala253Glnfs*27) was the most common (4/5). One additional case carried this variant on one allele only and an additional pathogenic missense variant c.458C > A (p.Ala153Asp) on the other allele. Age of onset ranged from early infancy to mid-twenties, and phenotypes comprised axonal CMT (4) and dHMN (1). Our findings strengthen the importance of screening for pathogenic variants in SORD, especially in patients with genetically unconfirmed axonal neuropathy, especially CMT type 2 and dHMN.

2020 年,SORD 的致病性双倍拷贝变体被确定为常染色体隐性夏科-玛丽-牙病(CMT)2 型(一种遗传性神经病)的新病因。SORD 编码山梨醇脱氢酶。这种酶活性的丧失会导致血清中山梨醇的增加。我们在德国一家大型神经肌肉中心对 166 名轴索神经病患者(主要是 CMT 2 型,也包括中间型 CMT 和远端遗传性运动神经病 (dHMN))进行了回顾性筛查,未发现 SORD 基因突变的遗传病因。对临床和电生理学检查结果进行了基因型与表型相关性分析。在166名患者中,有5名患者携带SORD致病变异(3%)。其中最常见的是同基因框移变异 c.757delG(p.Ala253Glnfs*27)(4/5)。另有一个病例仅在一个等位基因上携带该变异,另一个等位基因上携带致病性错义变异 c.458C > A (p.Ala153Asp)。发病年龄从婴儿期到二十多岁不等,表型包括轴索型 CMT(4 例)和 dHMN(1 例)。我们的研究结果加强了筛查 SORD 致病变体的重要性,尤其是在遗传学上未经证实的轴索神经病患者中,特别是 CMT 2 型和 dHMN 患者。
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引用次数: 0
Global research landscape on the contribution of de novo mutations to human genetic diseases over the past 20 years: bibliometric analysis 过去 20 年全球关于新发基因突变对人类遗传疾病影响的研究概况:文献计量分析
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2024-04-22 DOI: 10.1080/01677063.2024.2335171
Jing Guan, Xiaonan Wu, Jiao Zhang, Jin Li, Hongyang Wang, Qiuju Wang
As the contribution of de novo mutations (DNMs) to human genetic diseases has been gradually uncovered, analyzing the global research landscape over the past 20 years is essential. Because of the l...
随着新发基因突变(DNM)对人类遗传疾病的影响逐渐被发现,对过去 20 年的全球研究状况进行分析至关重要。由于新基因突变对人类遗传疾病的贡献逐渐被发现,分析过去 20 年的全球研究状况至关重要。
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引用次数: 0
Meta-analysis of the association between C9orf72 repeats and neurodegeneration diseases. C9orf72重复序列与神经变性疾病相关的元分析。
IF 1.8 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2024-03-01 Epub Date: 2024-05-20 DOI: 10.1080/01677063.2024.2343672
Pingfei Jin, Yong Li, Yao Li

To conduct a meta-analysis investigating the relationship between the chromosome 9 open reading frame 72 (C9orf72) GGGGCC (G4C2) and neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We searched the EMBASE, PubMed, Web of Science, and Cochrane databases. Twenty-seven case-control studies were included, comprising 7202 AD, 5856 PD, 644 MSA, 439 PSP, and 477 CBD cases. This study demonstrated that C9orf72 repeat expansions (>30) were associated with AD, MSA, PSP, and CBD (AD: OR = 4.88, 95% CI = 2.71-8.78; MSA: OR = 6.98, 95% CI = 1.48-33.01; PSP: OR =10.04, 95% CI = 2.72-37.10; CBD: OR = 28.04, 95% CI = 10.17-77.31). C9orf72 intermediate repeat expansions (20-30) were not associated with AD and MSA (AD: OR = 1.16, 95% CI = 0.39-3.45; MSA: OR = 5.65, 95% CI = 0.69-46.19), while C9orf72 repeat expansions (>30) were not associated with the risk of PD (OR = 1.51, 95% CI = 0.55-4.17), C9orf72 intermediate repeat expansions (20-30) were indeed associated with PD (OR = 2.43, 95% CI = 1.20-4.9). The pathological mechanism of C9orf72 G4C2 repeat expansions differs across various NDs due to the varying number of pathogenic expansions. Measuring the number of C9orf72 G4C2 repeats may be useful in the early-stage differential diagnosis of various NDs.

对 9 号染色体开放阅读框 72 (C9orf72) GGGGCC (G4C2) 与神经退行性疾病(NDs)(包括阿尔茨海默病(AD)、帕金森病(PD)、多系统萎缩(MSA)、进行性核上性麻痹(PSP)和皮质基底变性(CBD))之间的关系进行荟萃分析。我们检索了 EMBASE、PubMed、Web of Science 和 Cochrane 数据库。共纳入 27 项病例对照研究,包括 7202 例 AD、5856 例 PD、644 例 MSA、439 例 PSP 和 477 例 CBD 病例。该研究表明,C9orf72 重复扩增(>30)与 AD、MSA、PSP 和 CBD 相关(AD:OR = 4.88,95% CI = 2.71-8.78;MSA:OR=6.98,95% CI=1.48-33.01;PSP:OR=10.04,95% CI=2.72-37.10;CBD:或 = 28.04,95% CI = 10.17-77.31)。C9orf72 中间重复扩展(20-30)与 AD 和 MSA 无关(AD:OR = 1.16,95% CI = 0.39-3.45;MSA:OR = 5.65,95% CI = 0.69-46.19),而 C9orf72 中间重复扩展(20-30)与 AD 和 MSA 无关(AD:OR = 1.16,95% CI = 0.39-3.45;MSA:OR = 5.65,95% CI = 0.69-46.19)。19),而C9orf72重复扩增(>30)与PD风险无关(OR = 1.51,95% CI = 0.55-4.17),C9orf72中间重复扩增(20-30)确实与PD有关(OR = 2.43,95% CI = 1.20-4.9)。由于致病性扩增的数量不同,C9orf72 G4C2重复扩增在各种ND中的病理机制也不同。测量C9orf72 G4C2重复序列的数量可能有助于对各种ND进行早期鉴别诊断。
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引用次数: 0
Identification and bioinformatics analysis of a novel variant in the HERC2 gene in a patient with intellectual developmental disorder. 一名智力发育障碍患者的 HERC2 基因新型变异的鉴定和生物信息学分析。
IF 1.8 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2024-03-01 Epub Date: 2024-06-17 DOI: 10.1080/01677063.2024.2365634
Asal Asghari Sarfaraz, Neda Jabbarpour, Mortaza Bonyadi, Mohammad Khalaj-Kondory

HERC2-associated neurodevelopmental-disorders(NDD) encompass a cluster of medical conditions that arise from genetic mutations occurring within the HERC2 gene. These disorders can manifest a spectrum of symptoms that impact the brain and nervous system, including delayed psychomotor development, severe mental retardation, seizures and autistic features. Whole-Exome-Sequencing(WES) was performed on a ten-year-old male patient referred to the genetic center for genetic analysis. Blood samples were collected from the proband, his parents, and his sister to extract DNA. PCR-Sanger-sequencing was utilized to validate the findings obtained from WES. In order to obtain a more thorough understanding of the impact of the mutation, an extensive analysis was conducted using bioinformatics tools. WES data analysis identified a homozygous single nucleotide change(C > T) at position c14215 located in exon ninety-two of the HERC2 gene (NC_000015.10(NM_004667.6):c.14215C > T). The absence of this mutation among our cohort composed of four hundred normal healthy adults from the same ethnic group, and its absence in any other population database, confirms the pathogenicity of the mutation. This study revealed that the substitution of arginine with a stop codon within the Hect domain caused a premature stop codon at position 4739(p.Arg4739Ter). This mutation significantly results in the production of a truncated HERC2 protein with an incomplete HECT domain. In the final stage of ubiquitin attachment, HECT E3 ubiquitin ligases play a catalytic role by creating a thiolester intermediate using their conserved catalytic cysteine (Cys4762). This intermediate is formed before ubiquitin is transferred to a substrate protein. The truncation of the HERC2 protein is expected to disrupt its ability to perform this function, which could potentially hinder important regulatory processes related to the development and maintenance of synapses. The identification of a novel pathogenic variant, NC_000015.10(NM_004667.6):c.14215C > T, located within the ninety-two exon of the HERC2 gene, is notable for its association with an autosomal recessive inheritance pattern in cases of Intellectual Developmental Disorder(IDD). In the end, this variant could potentially play a part in the underlying mechanisms leading to the onset of intellectual developmental disorder.

HERC2 相关神经发育障碍(NDD)是由 HERC2 基因突变引起的一组疾病。这些疾病可表现出一系列影响大脑和神经系统的症状,包括精神运动发育迟缓、严重智力迟钝、癫痫发作和自闭症特征。为进行基因分析,遗传中心对一名十岁的男性患者进行了全基因组测序(WES)。研究人员采集了患者、其父母和姐姐的血液样本,提取 DNA。利用 PCR-Sanger 测序验证了 WES 的结果。为了更透彻地了解突变的影响,利用生物信息学工具进行了广泛的分析。WES 数据分析确定了位于 HERC2 基因第 92 号外显子 c14215 位的同源单核苷酸变化(C > T)(NC_000015.10(NM_004667.6):c.14215C > T)。在我们由四百名来自同一族群的正常健康成年人组成的队列中,没有发现这一突变,而在其他人群数据库中也没有发现,这证实了该突变的致病性。这项研究发现,在 Hect 结构域中,精氨酸与终止密码子的替换导致在 4739 位出现过早的终止密码子(p.Arg4739Ter)。这一突变极大地导致产生了具有不完整 HECT 结构域的截短 HERC2 蛋白。在泛素连接的最后阶段,HECT E3 泛素连接酶利用其保守的催化半胱氨酸(Cys4762)产生硫醇酯中间体,从而发挥催化作用。这种中间体是在泛素转移到底物蛋白质之前形成的。HERC2 蛋白的截短预计会破坏其执行这一功能的能力,从而有可能阻碍与突触的发育和维持有关的重要调节过程。在 HERC2 基因的九十二个外显子中发现了一个新的致病变体 NC_000015.10(NM_004667.6):c.14215C>T,该变体与智力发育障碍(IDD)病例的常染色体隐性遗传模式有关。最终,该变异有可能在导致智力发育障碍发病的潜在机制中扮演重要角色。
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引用次数: 0
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Journal of neurogenetics
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