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Adaptation of ACMG/AMP Guidelines for Clinical Classification of BMPR2 Variants in Pulmonary Arterial Hypertension Resolves Variants of Unclear Pathogenicity in ClinVar 适应ACMG/AMP肺动脉高压BMPR2变异临床分类指南解决了ClinVar致病性不明确的变异
IF 3.3 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2025-07-07 DOI: 10.1155/humu/2475635
Christina A. Eichstaedt, Gabriel Maldonado-Velez, Rajiv D. Machado, Stefan Gräf, Dennis Dooijes, Srimmitha Balachandar, Florence Coulet, Kristina Day, Melanie Eyries, Daniela Macaya, Memoona Shaukat, Laura Southgate, Jair Tenorio-Castano, Wendy K. Chung, Carrie L. Welch, Micheala A. Aldred

Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by pathogenic variants, most frequently in the bone Morphogenetic Protein Receptor Type 2 (BMPR2) gene. We formed a ClinGen variant curation expert panel to devise guidelines for the clinical interpretation of BMPR2 variants identified in PAH patients. The general ACMG/AMP variant classification criteria were refined for PAH and adapted to BMPR2 following ClinGen procedures. Subsequently, these specifications were tested independently by three members of the curation expert panel on 28 representative BMPR2 variants selected from ClinVar and then presented and discussed in the plenum. Application of the final BMPR2 variant specifications resolved six of nine variants (66%) where multiple ClinVar classifications included a variant of uncertain significance, with all six being reclassified as Benign or Likely Benign. Four splice site variants underwent clinically consequential reclassification based on the presence or absence of supporting mRNA splicing data. These variant specifications provide an international framework and a valuable tool for BMPR2 variant classification that can be applied to increase confidence and consistency in BMPR2 interpretation for diagnostic laboratories, clinical providers, and patients.

肺动脉高压(PAH)是一种罕见的疾病,可由致病变异引起,最常见的是骨形态发生蛋白受体2型(BMPR2)基因。我们成立了一个ClinGen变异管理专家小组,为PAH患者中发现的BMPR2变异的临床解释制定指南。根据ClinGen程序,对PAH的一般ACMG/AMP变体分类标准进行了改进,并适用于BMPR2。随后,这些规范由策展专家小组的三名成员对从ClinVar中选出的28个具有代表性的BMPR2变体进行了独立测试,然后在全体会议上提出并讨论。最终BMPR2变体规范的应用解决了9个变体中的6个(66%),其中多个ClinVar分类包括一个不确定意义的变体,所有6个变体都被重新分类为良性或可能良性。基于是否存在支持mRNA剪接数据,四个剪接位点变异进行了临床相应的重新分类。这些变异规范为BMPR2变异分类提供了一个国际框架和有价值的工具,可用于提高诊断实验室、临床提供者和患者对BMPR2解释的信心和一致性。
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引用次数: 0
Identification of Enzalutamide-Related Genes for Prognosis and Immunotherapy in Prostate Adenocarcinoma 恩杂鲁胺与前列腺癌预后及免疫治疗相关基因的鉴定
IF 3.3 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2025-07-04 DOI: 10.1155/humu/9755727
Lian Fang, Zongming Jia, Tao Zou, Ouyang Song, Jun Ouyang, Yufeng Hou, Zhiyu Zhang, Xuefeng Zhang

Enzalutamide is classified as a novel antiandrogen medication; however, the majority of patients ultimately develop resistance to it. Consequently, conducting an in-depth investigation into potential targets of enzalutamide is essential for addressing the drug resistance observed in patients and for facilitating the discovery of new therapeutic targets. The SwissTargetPrediction database was used to identify targets linked to enzalutamide and to assess these targets in the prostate adenocarcinoma (PRAD) dataset sourced from the TCGA database. By employing various datasets and applying different machine learning methods for clustering, researchers constructed and validated both diagnostic and prognostic models for PRAD. A correlation analysis with the androgen receptor revealed TDP1 as the gene most significantly associated with enzalutamide. In addition, this study examined the relationship between TDP1 and immune infiltration. The expression levels of TDP1 and its prognostic correlation in PRAD patients were validated through immunofluorescence staining of 60 PRAD tissue specimens. Cluster analysis revealed a notable correlation among the 24 genes related to enzalutamide with regard to both prognosis and immune infiltration in PRAD patients. The diagnostic model, which incorporates various machine learning techniques, exhibits robust predictive ability for PRAD diagnosis, while the prognostic model employing the LASSO algorithm has also shown encouraging outcomes. Among the various prognostic genes linked to enzalutamide, TDP1 stands out as an important indicator of prognosis. Furthermore, immunofluorescence experiments confirmed that an increased expression of TDP1 is associated with a worse prognosis in patients with PRAD. Our results underscore the substantial potential of TDP1 as a novel diagnostic and prognostic biomarker for individuals diagnosed with PRAD.

恩杂鲁胺被归类为一种新型抗雄激素药物;然而,大多数患者最终会产生耐药性。因此,深入研究enzalutamide的潜在靶点对于解决在患者中观察到的耐药性和促进发现新的治疗靶点至关重要。SwissTargetPrediction数据库用于识别与enzalutamide相关的靶标,并在来自TCGA数据库的前列腺腺癌(PRAD)数据集中评估这些靶标。通过使用不同的数据集和应用不同的机器学习方法进行聚类,研究人员构建并验证了PRAD的诊断和预后模型。与雄激素受体的相关性分析显示TDP1是与enzalutamide最显著相关的基因。此外,本研究还探讨了TDP1与免疫浸润的关系。通过60例PRAD组织标本的免疫荧光染色,验证TDP1在PRAD患者中的表达水平及其与预后的相关性。聚类分析显示,24个与恩杂鲁胺相关的基因与PRAD患者的预后和免疫浸润均有显著的相关性。该诊断模型结合了各种机器学习技术,显示出对PRAD诊断的强大预测能力,而采用LASSO算法的预后模型也显示出令人鼓舞的结果。在与enzalutamide相关的众多预后基因中,TDP1作为预后的重要指标尤为突出。此外,免疫荧光实验证实,TDP1表达升高与PRAD患者预后较差有关。我们的研究结果强调了TDP1作为一种新的PRAD诊断和预后生物标志物的巨大潜力。
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引用次数: 0
Management of Paediatric Cancers Associated With Bloom Syndrome 与布鲁姆综合征相关的儿科癌症的处理
IF 3.3 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2025-07-03 DOI: 10.1155/humu/7065233
Camille Pacaud, Charlotte Nazon, Mélanie Pages, Jérémie Rouger, Pascale Berthet, Sarah Winter, Éric Thebault, Cécile Faure-Conter, Claire Berger, Catherine Paillard

Bloom syndrome (BS) is a rare genetic disorder associated with an elevated risk of cancer. In a national multicentre study, nine paediatric patients with BS and cancer were analysed. Median age at cancer diagnosis was 12 years. Four of the nine patients were diagnosed with BS prior to cancer detection. Six presented with solid tumours, whilst three had haematological malignancies. Six received polychemotherapy, often with dose reductions. Complications included prolonged aplasia, sepsis and early treatment discontinuation. Two patients received radiotherapy. Four relapsed, and four died, including one toxic death. However, five achieved remission, highlighting the possibility of curative treatment despite significant toxicities.

布卢姆综合征(BS)是一种罕见的遗传性疾病,与癌症风险升高有关。在一项国家多中心研究中,对9名患有BS和癌症的儿科患者进行了分析。癌症诊断时的中位年龄为12岁。9名患者中有4名在癌症检测前被诊断为BS。6例为实体瘤,3例为血液学恶性肿瘤。其中6人接受综合化疗,通常减少剂量。并发症包括延长发育不全,败血症和早期停止治疗。2例患者接受放疗。四人复发,四人死亡,其中一人中毒死亡。然而,5例患者获得缓解,这表明尽管存在显著的毒性,但仍有治愈性治疗的可能性。
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引用次数: 0
A Novel Missense Variant in Ultrarare SLC35A1-CDG Alters Cellular Glycosylation, Lipid, and Energy Metabolism Without Affecting CDG Serum Markers 一种新的SLC35A1-CDG错义变体在不影响CDG血清标志物的情况下改变细胞糖基化、脂质和能量代谢
IF 3.3 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2025-06-26 DOI: 10.1155/humu/6290620
Kristina Falkenstein, Lukas Hoeren, Frauke Kikul, Gernot Poschet, Christian Lüchtenborg, Ines B. Brecht, Ruth Falb, Darja Gauck, Tobias Haack, Andreas Hecker, Nastassja Himmelreich, Jürgen G. Okun, Britta Brügger, Christian Thiel

SLC35A1-CDG is a very rare type of congenital disorders of glycosylation (CDG) with only five cases known to date. Here, we review the literature and present new data from a sixth patient carrying the uncharacterized variant c.133A>G; p.Thr45Ala in the SLC35A1 gene. In addition to known clinical symptoms of SLC35A1-CDG, the patient presents with failure to thrive, short stature, café-au-lait spot, and preauricular ear tag. Even though examination of CDG markers transferrin (Tf), alpha-1-antitrypsin (A1AT), and apolipoprotein CIII (ApoCIII) revealed no abnormalities in serum, the patient’s fibroblasts showed significant alterations of protein expression or glycosylation of ICAM1, GP130, and TGN46 as well as differences in staining signals of lectins MAL-I, RCAI, and SNA and deviations in LC-MS analysis of total cellular N-glycans. Transfection of CRISPR/Cas9 generated SLC35A1 HEK293 knockout cells with either wild-type SLC35A1 or the c.133A>G variant restored the cellular CMP-Neu5Ac to wild-type levels, making a direct effect of p.Thr45Ala on the function of the transporter unlikely. Instead, our results imply that the residual transporter activity of 65% is caused by a decreased stability of the mutated SLC35A1 protein. Since O-GlcNAcylation was affected as well, energy and lipid homeostasis were analyzed and found to be significantly altered. Notably, proliferation and glycosylation of the SLC35A1-deficient patient fibroblasts were enhanced by supplementation of the cell culture medium with 10 mM GlcNAc.

SLC35A1-CDG是一种非常罕见的先天性糖基化疾病(CDG),目前已知只有5例。在这里,我们回顾了文献,并提供了来自第六位携带未表征变异c.133A>;G;p.Thr45Ala在SLC35A1基因中。除了已知的SLC35A1-CDG临床症状外,该患者还表现为发育不全、身材矮小、卡萨莫-奥-拉斑和耳前耳标。尽管检测CDG标记物转铁蛋白(Tf)、α -1抗胰蛋白酶(A1AT)和载脂蛋白CIII (ApoCIII)在血清中未发现异常,但患者的成纤维细胞显示ICAM1、GP130和TGN46蛋白表达或糖基化的显著改变,以及凝集素mal -1、RCAI和SNA染色信号的差异,以及细胞总n -聚糖的LC-MS分析的偏差。转染CRISPR/Cas9产生的SLC35A1 HEK293敲除细胞,无论是野生型SLC35A1还是c.133A>;G变体,都能使细胞CMP-Neu5Ac恢复到野生型水平,这使得p.s thr45ala不太可能直接影响转运体的功能。相反,我们的研究结果表明,65%的剩余转运蛋白活性是由突变的SLC35A1蛋白稳定性下降引起的。由于o - glcnac酰化也受到了影响,我们分析了能量和脂质稳态,发现它们发生了显著的改变。值得注意的是,添加10 mM GlcNAc的细胞培养基可以增强slc35a1缺陷患者成纤维细胞的增殖和糖基化。
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引用次数: 0
Exploring Therapeutic Targets for Preventing Cardiac Arrest by Modulating Dyslipidemia and 25-Hydroxyvitamin D Metabolism: A Mendelian Randomization Study 通过调节血脂异常和25-羟基维生素D代谢来探索预防心脏骤停的治疗靶点:一项孟德尔随机研究
IF 3.3 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2025-06-19 DOI: 10.1155/humu/5536318
Xinya Jia, Keke Du, Yuanting Zhu, Liuyang Xie, Tangjuan Zhang, Liu Yang, Yuepeng Hu, Chao Lan, Qiang Zhang

Cardiac arrest (CA) prevention continues to be a substantial hurdle for global public health. Although dyslipidemia and 25-hydroxyvitamin D (25(OH)D) insufficiency are recognized contributing factors for cardiovascular disease (CVD), their causal relationship with CA risk is still uncertain. Here, we explored these correlations and pinpointed possible therapeutic targets for CA prevention though Mendelian randomization (MR). Both two-sample and multivariable MR analysis methods were conducted to assess how serum lipid traits and 25(OH)D influence the susceptibility to develop CA. Nine thousand nine hundred eighty-eight participants in total from the National Health and Nutrition Examination Survey (NHANES) engaged in validating the relationship between the concentrations of 25(OH)D and cardiovascular mortality in individuals with dyslipidemia. The integration of MR with expression quantitative trait locus (eQTL) analysis enabled the identification of druggable targets, and molecular docking was used to screen small molecules, which were subsequently validated in animal models. The MR results revealed that both elevated levels of low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (ApoB), as well as triglycerides (TGs), significantly contributed to an increased CA risk (p < 0.05). Conversely, higher amounts of apolipoprotein A1 (ApoA1), high-density lipoprotein cholesterol (HDL-C), and 25(OH)D were causally contributing to a decreased risk of CA (p < 0.05). A bidirectional causal relationship was observed among LDL-C, TG, ApoB, and 25(OH)D levels. Mediation MR suggests that dyslipidemia and low 25(OH)D status could potentially elevate the CA risk through pathways involving myocardial infarction, diabetes, and hypertension. NHANES data confirmed that higher 25(OH)D were tied to decreased risks of all-cause and CVD death among those with dyslipidemia (p < 0.01). Notably, chromobox 6 (CBX6), negatively associated with CA risk (OR = 0.87, 95% CI: 0.78–0.99, p = 0.029), was determined to be a target of both sanguinarine and lycorine, which improved lipid profiles and 25(OH)D in mice. In conclusion, dyslipidemia and low 25(OH)D status are causally related to CA risk, they appear to interact, and their coexistence may confer a higher risk of CVD mortality. Compounds targeting specific genes can both improve dyslipidemia and elevate 25(OH)D levels, thereby exhibiting potential therapeutic effects for preventing CA. Overall, this study enhances our understanding of the underlying mechanisms linking dyslipidemia, 25(OH)D deficiency, and CA and offers new perspectives for prevention.

预防心脏骤停仍然是全球公共卫生的一个重大障碍。虽然血脂异常和25-羟基维生素D (25(OH)D)不足是公认的心血管疾病(CVD)的诱因,但它们与CA风险的因果关系仍不确定。在这里,我们探讨了这些相关性,并通过孟德尔随机化(MR)确定了预防CA的可能治疗靶点。采用双样本和多变量磁共振分析方法来评估血脂特征和25(OH)D如何影响患CA的易感性。来自全国健康与营养检查调查(NHANES)的共九千九百八十八名参与者参与了验证25(OH)D浓度与血脂异常个体心血管死亡率之间关系的研究。将MR与表达数量性状位点(eQTL)分析相结合,确定可药物靶点,并利用分子对接筛选小分子,随后在动物模型中进行验证。磁共振结果显示,低密度脂蛋白胆固醇(LDL-C)和载脂蛋白B (ApoB)以及甘油三酯(TGs)水平的升高都显著增加了CA风险(p <;0.05)。相反,较高含量的载脂蛋白A1 (ApoA1)、高密度脂蛋白胆固醇(HDL-C)和25(OH)D是导致CA风险降低的原因(p <;0.05)。LDL-C、TG、ApoB和25(OH)D水平之间存在双向因果关系。介导性磁共振提示,血脂异常和低25(OH)D状态可能通过心肌梗死、糖尿病和高血压等途径潜在地提高CA的风险。NHANES数据证实,在血脂异常患者中,较高的25(OH)D与全因死亡和心血管疾病死亡风险降低有关(p <;0.01)。值得注意的是,染色体盒6 (CBX6)与CA风险呈负相关(OR = 0.87, 95% CI: 0.78-0.99, p = 0.029),被确定为血碱和石油碱的靶点,可以改善小鼠的脂质谱和25(OH)D。总之,血脂异常和低25(OH)D状态与CA风险有因果关系,它们似乎是相互作用的,它们的共存可能会增加CVD死亡的风险。针对特定基因的化合物既可以改善血脂异常,又可以提高25(OH)D水平,从而显示出预防CA的潜在治疗效果。总的来说,本研究增强了我们对血脂异常、25(OH)D缺乏和CA之间潜在机制的理解,并为预防CA提供了新的视角。
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引用次数: 0
Phenotypic Characterization of ALS-Causing SOD1 Mutations Affecting Polypeptide Length als致SOD1突变影响多肽长度的表型特征
IF 3.3 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2025-06-16 DOI: 10.1155/humu/9792233
Mariusz Berdyński, Krzysztof Safranow, Peter M. Andersen, Cezary Żekanowski

Background: Some 234 mutations in the small SOD1 gene have been reported to cause amyotrophic lateral sclerosis. However, the pathogenic mechanisms, particularly of those mutations affecting polypeptide length, are contested. It is presently unknown whether all reported nonsense mutations in SOD1 are causative for ALS. The emergence of promising new anti-SOD1 drugs has made it imperative to gain further insight into clinical–genetic aspects of ALS for deciding which patients to treat in clinical practice and include in drug trials.

Objective: This study is aimed at comprehensively analyzing the clinical phenotypes associated with ALS-causing SOD1 mutations that alter the polypeptide length. The specific focus is on the age at which symptoms manifest and the survival duration.

Methods: Data were collected from web databases, published reports, conference presentations, and personal communications up to November 2023. The clinical endpoints, including age at symptom onset and age at death, were subjected to survival analysis. Comparative analyses were performed between frameshift and nonframeshift variants.

Results: A cohort of 146 ALS patients harboring 38 different nonmissense SOD1 variants was analyzed. The mean age of disease onset was 46.9 years, with a mean survival duration of 49 months. Significant heterogeneity was observed in clinical outcomes, with earlier disease onset and reduced survival associated with specific mutations. Notably, frameshift mutations proximal to the N-terminus showed a higher risk of early ALS onset compared to more distal mutations.

Conclusions: The clinical phenotypes of ALS patients with nonmissense SOD1 mutations are highly variable and dependent on the specific mutation. These findings underscore the necessity of including diverse SOD1 mutation carriers in therapeutic trials and suggest that both loss-of-function and gain-of-function mechanisms may contribute to ALS pathology.

背景:据报道,大约234个SOD1小基因突变可引起肌萎缩性侧索硬化症。然而,致病机制,特别是那些影响多肽长度的突变,是有争议的。目前尚不清楚是否所有报道的SOD1无义突变都是ALS的病因。有希望的新型抗sod1药物的出现,使得进一步了解ALS的临床遗传学方面成为必要,以决定在临床实践中治疗哪些患者并将其纳入药物试验。目的:本研究旨在全面分析与als引起的SOD1突变改变多肽长度相关的临床表型。具体的重点是症状出现的年龄和生存时间。方法:数据收集自截至2023年11月的网络数据库、已发表的报告、会议演讲和个人通信。临床终点,包括症状出现时的年龄和死亡时的年龄,进行生存分析。在移码和非移码变体之间进行了比较分析。结果:对146例ALS患者进行了38种不同的非错义SOD1变异分析。平均发病年龄46.9岁,平均生存期49个月。在临床结果中观察到显著的异质性,与特定突变相关的疾病早期发病和生存率降低。值得注意的是,与远端突变相比,n端近端移码突变显示出更高的早期ALS发病风险。结论:SOD1非错义突变ALS患者的临床表型具有高度的可变性,并依赖于特异性突变。这些发现强调了在治疗试验中纳入多种SOD1突变携带者的必要性,并表明功能丧失和功能获得机制都可能导致ALS病理。
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引用次数: 0
ACOCMPMI: An Ant Colony Optimization Algorithm Based on Composite Multiscale Part Mutual Information for Detecting Epistatic Interactions ACOCMPMI:一种基于复合多尺度部分互信息的蚁群优化算法,用于上位交互检测
IF 3.3 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2025-06-13 DOI: 10.1155/humu/7656300
Yan Sun, Jing Wang, Yaxuan Zhang, Junliang Shang, Jin-Xing Liu

Epistatic interaction detection plays a pivotal role in understanding the genetic mechanisms underlying complex diseases. The effectiveness of epistatic interaction detection methods primarily depends on their interaction quantification measures and search strategies. In this study, a two-stage ant colony optimization algorithm based on composite multiscale part mutual information (ACOCMPMI) is proposed for detecting epistatic interactions. In the first stage, composite multiscale part mutual information is developed to quantify epistatic interactions, and an improved ant colony optimization algorithm incorporating filter and memory strategies is employed to search for potential epistatic interactions. In the second stage, an exhaustive search strategy and a Bayesian network score are adopted to further identify epistatic interactions within the candidate SNP set obtained in the first stage. ACOCMPMI is compared with five state-of-the-art methods, including epiACO, FDHE-IW, AntEpiSeeker, SIPSO, and MACOED, using simulation data generated from 11 epistatic interaction models. Furthermore, ACOCMPMI is applied to detect epistatic interactions in a real dataset of age-related macular degeneration. The experimental results show that ACOCMPMI is a promising method for epistatic interaction detection.

上位相互作用检测在理解复杂疾病的遗传机制中起着关键作用。上位交互检测方法的有效性主要取决于其交互量化措施和搜索策略。本文提出了一种基于复合多尺度部分互信息(ACOCMPMI)的两阶段蚁群优化算法来检测上位交互。第一阶段,利用复合多尺度部件互信息来量化上位性交互,并采用改进的蚁群优化算法结合滤波和记忆策略来搜索潜在的上位性交互。在第二阶段,采用穷举搜索策略和贝叶斯网络评分来进一步识别第一阶段获得的候选SNP集中的上位性相互作用。ACOCMPMI使用11个上位交互模型生成的仿真数据,比较了五种最先进的方法,包括epiACO、FDHE-IW、AntEpiSeeker、SIPSO和MACOED。此外,ACOCMPMI应用于检测年龄相关性黄斑变性真实数据集中的上位性相互作用。实验结果表明,ACOCMPMI是一种很有前途的上位相互作用检测方法。
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引用次数: 0
Functional Characterization of Variants in LARP7: Report of Three New Individuals With Alazami Syndrome and a Literature Review LARP7变异的功能特征:三例Alazami综合征新病例报告及文献综述
IF 3.3 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2025-06-12 DOI: 10.1155/humu/6490124
Anastasia Ambrose, Oana Caluseriu, Saadet Mercimek-Andrews

Introduction: Biallelic pathogenic variants in LARP7 result in Alazami syndrome, which is characterized by global developmental delay, cognitive dysfunction, and dysmorphic features. Cardiac and skeletal phenotypes are reported in about 30% of individuals. We report three new individuals with Alazami syndrome and functional characterization of LARP7 variants in this study.

Materials and Methods: We reviewed electronic patient charts. We applied the American College of Medical Genetics and Genomics and the Association for Molecular Pathology variant classification algorithms. We performed a 3D protein modeling tool for in silico prediction and functional characterization of LARP7 variants using qPCR gene expression experiments. We reviewed the medical literature for Alazami syndrome and LARP7.

Results: We report three individuals from two unrelated families with characteristic phenotypes suggestive of Alazami syndrome. We identified a homozygous novel missense LARP7 likely pathogenic variant (p.Asp54Val) in Family 1 and a homozygous novel pathogenic LARP7 variant (p.Lys219Glu∗) in Family 2 using clinical exome sequencing. 3D protein modeling showed large structural changes for both variants compared to wildtype. The functional characterization showed a statistically significant difference in LARP7 expression between affected individuals and wildtype control. We report phenotypic variability within the same family that the cardiac phenotype was only present in Family 1, Case 2. There were < 60 individuals with Alazami syndrome reported to date.

Conclusion: We report three new individuals with Alazami syndrome and two novel variants in LARP7. We report the first missense LARP7 variant associated with Alazami syndrome. We report the protein 3D structure of LARP7 variants. We show a relationship between the p.Asp54Val LARP7 variant and LARP7 expression levels. We think that this could be due to abnormal RNA binding of LARP7 as per the 3D protein modeling prediction tool.

简介:LARP7双等位致病变异可导致Alazami综合征,该综合征以整体发育迟缓、认知功能障碍和畸形为特征。心脏和骨骼表型在大约30%的个体中报告。在本研究中,我们报告了三例新的Alazami综合征患者和LARP7变异的功能特征。材料和方法:我们回顾了电子病历。我们应用了美国医学遗传学和基因组学学院和分子病理学协会的变异分类算法。我们使用qPCR基因表达实验进行了一个3D蛋白质建模工具,用于LARP7变异的计算机预测和功能表征。我们回顾了Alazami综合征和LARP7的医学文献。结果:我们报告了三个来自两个不相关家族的个体,他们的特征表型提示Alazami综合征。通过临床外显子组测序,我们在家族1中发现了一种纯合的新型错义LARP7可能致病变异(p.Asp54Val),在家族2中发现了一种纯合的新型致病性LARP7变异(p.Lys219Glu∗)。3D蛋白质模型显示,与野生型相比,这两种变体的结构都发生了巨大变化。功能鉴定显示LARP7在患病个体和野生型对照之间的表达差异有统计学意义。我们报告了同一家族内的表型变异性,即心脏表型仅存在于家族1,病例2中。迄今为止报告了60例Alazami综合征患者。结论:我们报告了3例新的Alazami综合征患者和2个新的LARP7变异。我们报告了与Alazami综合征相关的第一个错义LARP7变异。我们报道了LARP7变异的蛋白质三维结构。我们发现了p.Asp54Val LARP7变异与LARP7表达水平之间的关系。根据3D蛋白建模预测工具,我们认为这可能是由于LARP7的异常RNA结合。
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引用次数: 0
EPHB1 Protein Promoted the Progression of Prostate Adenocarcinoma Through Phosphorylating GSK3B and Activating EPHB1-GSK3B-SMAD3 Pathway EPHB1蛋白通过磷酸化GSK3B,激活EPHB1-GSK3B- smad3通路,促进前列腺癌的进展
IF 3.3 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2025-06-12 DOI: 10.1155/humu/4961883
Bohan Xu, Shen Lin, Kai Yang

Background: The apoptosis affected the prostate adenocarcinoma (PRAD); we aimed to explore the potential pathogenesis of high-risk patients based on the apoptosis features.

Method: The RNA-seq data of patients and apoptosis genes were used for apoptosis score calculation via “GSVA” package; then, the weighted gene coexpression network analysis (WGCNA) and Lasso algorithm were performed for a RiskScore model. After that, the “maftools” package was applied for the somatic mutation analysis. By combining the Kaplan–Meier (KM) survival curves in order to compare the prognosis of different subgroups of patients, Cell Counting Kit-8 (CCK-8), EdU staining, and Transwell assays were performed. Protein expression was measured using western blotting. Finally, the activity of PRAD cells in macrophage polarization was detected using coculture and immunofluorescence assays.

Results: The PRAD samples had significantly lower apoptosis scores, and the RiskScore supported the risk stratification of patients. In somatic mutation analysis, EPHB1 and KIF13A from the top six mutant genes were overexpressed in 22RV1 and PC-3 tumor cells, and low levels of EPHB1 indicated a better prognosis. Overexpression or knockdown of EPHB1 affected cell viability, proliferation, and invasion. We found that high expression of EPHB1 interacting with GSK3B protein promoted the expression of p-SMAD3 in 22RV1 cells with high levels of antiapoptotic and invasion markers (BCL2, Snail, and N-CAD). Importantly, GSK3B and EPHB1 knockdown inhibited p-SMAD3 activation and promoted proapoptotic features, accompanied by a reduction in macrophage M2 polarization.

Conclusion: This study revealed that EPHB1 plays a pivotal role in activating the EPHB1-GSK3B-SMAD3 pathway to facilitate PRAD progression.

背景:细胞凋亡对前列腺癌(PRAD)的影响;我们的目的是根据细胞凋亡的特点来探讨高危患者的潜在发病机制。方法:采用“GSVA”包装,利用患者RNA-seq数据及凋亡基因进行细胞凋亡评分计算;然后,对RiskScore模型进行加权基因共表达网络分析(WGCNA)和Lasso算法。之后,应用“maftools”包进行体细胞突变分析。结合Kaplan-Meier (KM)生存曲线比较不同亚组患者的预后,进行细胞计数试剂盒-8 (CCK-8)、EdU染色和Transwell检测。western blotting检测蛋白表达。最后,采用共培养和免疫荧光法检测PRAD细胞在巨噬细胞极化中的活性。结果:PRAD样本的细胞凋亡评分明显降低,RiskScore支持患者的风险分层。体细胞突变分析中,前6个突变基因中的EPHB1和KIF13A在22RV1和PC-3肿瘤细胞中过表达,低水平的EPHB1预示着更好的预后。过表达或敲低EPHB1影响细胞活力、增殖和侵袭。我们发现,在具有高水平抗凋亡和侵袭标志物(BCL2、Snail和N-CAD)的22RV1细胞中,EPHB1与GSK3B蛋白相互作用的高表达促进了p-SMAD3的表达。重要的是,GSK3B和EPHB1的敲低抑制了p-SMAD3的激活,促进了促凋亡的特征,并伴随着巨噬细胞M2极化的减少。结论:本研究揭示EPHB1在激活EPHB1- gsk3b - smad3通路促进PRAD进展中起关键作用。
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引用次数: 0
A Nomogram Combining Two Novel Biomarkers for Predicting Lung Adenocarcinoma in Ground-Glass Nodule Patients 结合两种新的生物标志物预测磨玻璃结节患者肺腺癌的Nomogram
IF 3.3 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2025-06-11 DOI: 10.1155/humu/8647969
Yameng Li, Qingxian Zhang

Objective: Combination of CT imaging and RNA sequencing techniques was used to explore the potential biomarkers specific to lung adenocarcinoma within pulmonary ground-glass nodules.

Method: The imaging and pathological data of patients with pulmonary ground-glass nodules who underwent chest CT scanning were confirmed through surgical procedures. Based on the pathological results, the patients were categorized into a benign nodule group and a malignant nodule group. Subsequently, RNA sequencing was conducted to analyze gene expression information in the pulmonary ground-glass nodules of these 16 patients.

Results: CT signs demonstrated statistical significance in both benign and malignant nodules. A total of 2080 upregulated genes and 1240 downregulated genes were identified through RNA sequencing in malignant nodules compared to benign nodules. CST1 exhibited increased expression among the upregulated genes in lung adenocarcinoma tissues compared to lung tissues. Among the downregulated genes, only GIMAP1-GIMAP5 showed decreased expression in lung adenocarcinoma tissues. Finally, we validated the clinical significance of CST1 and GIMAP1-GIMAP5 in patients with lung adenocarcinoma, particularly highlighting a strong correlation between GIMAP1-GIMAP5 expression levels and prognosis for patients. A visual nomogram predictive model for pulmonary ground-glass nodules was constructed (area under the receiver operating characteristic curve (AUC) > 0.8).

Conclusion: We constructed a nomogram combining CST1 and GIMAP1-GIMAP5 expression for predicting lung adenocarcinoma in ground-glass nodules in the context of COVID-19. This nomogram addresses the unique diagnostic challenges posed by COVID-19, where overlapping pulmonary imaging findings between viral pneumonia and early lung cancer necessitate robust molecular-aided discrimination.

目的:结合CT成像和RNA测序技术,探讨肺毛玻璃结节内潜在的肺腺癌特异性生物标志物。方法:对经胸部CT扫描的肺磨玻璃结节患者的影像学和病理资料进行手术确认。根据病理结果将患者分为良性结节组和恶性结节组。随后,对这16例肺磨玻璃结节进行RNA测序,分析其基因表达信息。结果:良、恶性结节的CT征象均有统计学意义。与良性结节相比,通过RNA测序在恶性结节中共鉴定出2080个上调基因和1240个下调基因。与肺组织相比,CST1在肺腺癌组织中的上调基因表达增加。在下调的基因中,只有GIMAP1-GIMAP5在肺腺癌组织中表达降低。最后,我们验证了CST1和GIMAP1-GIMAP5在肺腺癌患者中的临床意义,特别强调了GIMAP1-GIMAP5表达水平与患者预后的强相关性。建立了肺磨玻璃结节的视觉图预测模型(受者工作特征曲线下面积(AUC));0.8)。结论:我们构建了CST1与GIMAP1-GIMAP5联合表达的nomogram预测2019冠状病毒病背景下磨玻璃结节肺腺癌。该图解决了COVID-19带来的独特诊断挑战,其中病毒性肺炎和早期肺癌之间重叠的肺部影像学发现需要强有力的分子辅助鉴别。
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引用次数: 0
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Human Mutation
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