Human molecular genetics最新文献_第8页

Characterization of a novel GRHL2 mutation reveals molecular mechanisms underlying autosomal dominant hearing loss (DFNA28): insights from structural and functional studies. 新型GRHL2突变的特征揭示了常染色体显性听力损失（DFNA28）的分子机制：来自结构和功能研究的见解。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-04-17 DOI: 10.1093/hmg/ddaf013

Dominika Oziębło, Natalia Bałdyga, Marcin L Leja, Adam Jarmuła, Tomasz Wilanowski, Henryk Skarżyński, Monika Ołdak

{"title":"Characterization of a novel GRHL2 mutation reveals molecular mechanisms underlying autosomal dominant hearing loss (DFNA28): insights from structural and functional studies.","authors":"Dominika Oziębło, Natalia Bałdyga, Marcin L Leja, Adam Jarmuła, Tomasz Wilanowski, Henryk Skarżyński, Monika Ołdak","doi":"10.1093/hmg/ddaf013","DOIUrl":"10.1093/hmg/ddaf013","url":null,"abstract":"The GRHL2 gene, encoding the Grainyhead-like 2 transcription factor, is essential for various biological processes. While GRHL2 has a complex role in cancer biology, its genetic variants have been also implicated in different forms of hearing loss (HL), including autosomal dominant non-syndromic hearing loss (DFNA28). Here, we report a novel c.1061C>T, p.(Ala354Val) mutation within the DNA binding domain (DBD) of GRHL2 that was identified in a three-generation HL family using a targeted multi-gene panel covering 237 HL-related genes. Unlike the previously reported DFNA28-causing variants that result in protein truncation, the impact of the p.(Ala354Val) missense change cannot be attributed to GRHL2 transcript level or composition, but to an alteration in protein function. Molecular dynamics simulations revealed destabilization of the p.(Ala354Val) mutant GRHL2 dimer interface and an altered DNA binding dynamics, leading to chaotic interaction patterns despite increased binding affinity to DNA. Functional assays demonstrated that the p.(Ala354Val) mutation and other DFNA28-related mutations in the DBD lead to loss of GRHL2 transcriptional transactivation activity, while the p.(Arg537Profs*11) mutation in the dimerization domain results in a gain-of-function effect. The findings indicate that both GRHL2 haploinsufficiency and gain-of-function contribute to HL and underscore the complex regulatory role of GRHL2 in maintaining proper function of the auditory system. Our study emphasizes the need to consider structural and functional aspects of gene variants to better understand their pathogenic potential. As GRHL2 is involved in a multitude of cellular processes, the data gathered here can be also applicable to other conditions.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"765-776"},"PeriodicalIF":3.1,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

HHIP protein interactions in lung cells provide insight into COPD pathogenesis. 肺细胞中hip蛋白的相互作用为COPD的发病机制提供了新的思路。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-04-17 DOI: 10.1093/hmg/ddaf016

Dávid Deritei, Hiroyuki Inuzuka, Peter J Castaldi, Jeong Hyun Yun, Zhonghui Xu, Wardatul Jannat Anamika, John M Asara, Feng Guo, Xiaobo Zhou, Kimberly Glass, Wenyi Wei, Edwin K Silverman

{"title":"HHIP protein interactions in lung cells provide insight into COPD pathogenesis.","authors":"Dávid Deritei, Hiroyuki Inuzuka, Peter J Castaldi, Jeong Hyun Yun, Zhonghui Xu, Wardatul Jannat Anamika, John M Asara, Feng Guo, Xiaobo Zhou, Kimberly Glass, Wenyi Wei, Edwin K Silverman","doi":"10.1093/hmg/ddaf016","DOIUrl":"10.1093/hmg/ddaf016","url":null,"abstract":"Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. The primary causes of COPD are environmental, including cigarette smoking; however, genetic susceptibility also contributes to COPD risk. Genome-Wide Association Studies (GWASes) have revealed more than 80 genetic loci associated with COPD, leading to the identification of multiple COPD GWAS genes. However, the biological relationships between the identified COPD susceptibility genes are largely unknown. Genes associated with a complex disease are often in close network proximity, i.e. their protein products often interact directly with each other and/or similar proteins. In this study, we use affinity purification mass spectrometry (AP-MS) to identify protein interactions with HHIP, a well-established COPD GWAS gene which is part of the sonic hedgehog pathway, in two disease-relevant lung cell lines (IMR90 and 16HBE). To better understand the network neighborhood of HHIP, its proximity to the protein products of other COPD GWAS genes, and its functional role in COPD pathogenesis, we create HUBRIS, a protein-protein interaction network compiled from 8 publicly available databases. We identified both common and cell type-specific protein-protein interactors of HHIP. We find that our newly identified interactions shorten the network distance between HHIP and the protein products of several COPD GWAS genes, including DSP, MFAP2, TET2, and FBLN5. These new shorter paths include proteins that are encoded by genes involved in extracellular matrix and tissue organization. We found and validated interactions to proteins that provide new insights into COPD pathobiology, including CAVIN1 (IMR90) and TP53 (16HBE). The newly discovered HHIP interactions with CAVIN1 and TP53 implicate HHIP in response to oxidative stress.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"777-789"},"PeriodicalIF":3.1,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143407352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A replication study of novel fetal hemoglobin-associated genetic variants in sickle cell disease-only cohorts. 镰状细胞病队列中新的胎儿血红蛋白相关遗传变异的复制研究

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-04-06 DOI: 10.1093/hmg/ddaf015

Yann Ilboudo, Nicolas Brosseau, Ken Sin Lo, Hicham Belhaj, Stéphane Moutereau, Kwesi Marshall, Marvin Reid, Abdullah Kutlar, Allison E Ashley-Koch, Marilyn J Telen, Philippe Joly, Frédéric Galactéros, Pablo Bartolucci, Guillaume Lettre

{"title":"A replication study of novel fetal hemoglobin-associated genetic variants in sickle cell disease-only cohorts.","authors":"Yann Ilboudo, Nicolas Brosseau, Ken Sin Lo, Hicham Belhaj, Stéphane Moutereau, Kwesi Marshall, Marvin Reid, Abdullah Kutlar, Allison E Ashley-Koch, Marilyn J Telen, Philippe Joly, Frédéric Galactéros, Pablo Bartolucci, Guillaume Lettre","doi":"10.1093/hmg/ddaf015","DOIUrl":"10.1093/hmg/ddaf015","url":null,"abstract":"Sickle cell disease (SCD) is the most common monogenic disease in the world and is caused by mutations in the β-globin gene (HBB). Notably, SCD is characterized by extreme clinical heterogeneity. Inter-individual variation in fetal hemoglobin (HbF) levels strongly contributes to this patient-to-patient variability, with high HbF levels associated with decreased morbidity and mortality. Genetic association studies have identified and replicated HbF levels-associated variants at three loci: BCL11A, HBS1L-MYB, and HBB. In SCD patients, genetic variation at these three loci accounts for ~ 50% of HbF heritability. Genome-wide association studies (GWAS) in non-anemic and SCD patients of multiple ancestries have identified 20 new HbF-associated variants. However, these genetic associations have yet to be replicated in independent SCD cohorts. Here, we validated the association between HbF levels and variants at five of these new loci (ASB3, BACH2, PFAS, ZBTB7A, and KLF1) in up to 3740 SCD patients. By combining CRISPR inhibition and single-cell transcriptomics, we also showed that sequences near non-coding genetic variants at BACH2 (rs4707609) and KLF1 (rs2242514, rs10404876) can control the production of the β-globin genes in erythroid HUDEP-2 cells. Finally, we analyzed whole-exome sequence data from 1354 SCD patients but could not identify rare genetic variants of large effect on HbF levels. Together, our results confirm five new HbF-associated loci that can be functionally studied to develop new strategies to induce HbF expression in SCD patients.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"699-710"},"PeriodicalIF":3.1,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143065356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Whole-genome sequencing reveals the impact of lipid pathway and APOE genotype on brain amyloidosis. 全基因组测序揭示了脂质途径和APOE基因型对脑淀粉样变性的影响。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-04-06 DOI: 10.1093/hmg/ddaf017

Maulikkumar Patel, Cyril Pottier, Kang-Hsien Fan, Arda Cetin, Matthew Johnson, Muhammad Ali, Menghan Liu, Priyanka Gorijala, John Budde, Ruyu Shi, Ann D Cohen, James T Becker, Beth E Snitz, Howard Aizenstein, Oscar L Lopez, John C Morris, M Ilyas Kamboh, Carlos Cruchaga

{"title":"Whole-genome sequencing reveals the impact of lipid pathway and APOE genotype on brain amyloidosis.","authors":"Maulikkumar Patel, Cyril Pottier, Kang-Hsien Fan, Arda Cetin, Matthew Johnson, Muhammad Ali, Menghan Liu, Priyanka Gorijala, John Budde, Ruyu Shi, Ann D Cohen, James T Becker, Beth E Snitz, Howard Aizenstein, Oscar L Lopez, John C Morris, M Ilyas Kamboh, Carlos Cruchaga","doi":"10.1093/hmg/ddaf017","DOIUrl":"10.1093/hmg/ddaf017","url":null,"abstract":"Amyloid-PET imaging tracks the accumulation of amyloid beta (Aβ) deposits in the brain. Amyloid plaques accumulation may begin 10 to 20 years before the individual experiences clinical symptoms associated with Alzheimer's diseases (ad). Recent large-scale genome-wide association studies reported common risk factors associated with brain amyloidosis, suggesting that this endophenotype is driven by genetic variants. However, these loci pinpoint to large genomic regions and the functional variants remain to be identified. To identify new risk factors associated with brain amyloid deposition, we performed whole-genome sequencing on a large cohort of European descent individuals with amyloid PET imaging data (n = 1,888). Gene-based analysis for coding variants was performed using SKAT-O for amyloid PET as a quantitative endophenotype that identified genome-wide significant association for APOE (P = 2.45 × 10-10), and 26 new candidate genes with suggestive significance association (P < 5. 0 × 10-03) including SCN7A (P = 7.31 × 10-05), SH3GL1 (P = 7.56 × 10-04), and MFSD12 (P = 8.51 × 10-04). Enrichment analysis highlighted the lipid binding pathways as associated with Aβ deposition in brain driven by PITPNM3 (P = 4.27 × 10-03), APOE (P = 2.45 × 10-10), AP2A2 (P = 1.06 × 10-03), and SH3GL1 (P = 7.56 × 10-04). Overall, our data strongly support a connection between lipid metabolism and the deposition of Aβ in the brain. Our study illuminates promising avenues for therapeutic interventions targeting lipid metabolism to address brain amyloidosis.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"739-748"},"PeriodicalIF":3.1,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973900/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

BMP4-GPX4 can improve the ferroptosis phenotype of retinal ganglion cells and enhance their differentiation ability after retinal stem cell transplantation in glaucoma with high intraocular pressure. BMP4-GPX4可改善高眼压青光眼视网膜干细胞移植后视网膜神经节细胞的铁下垂表型，增强其分化能力。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-04-06 DOI: 10.1093/hmg/ddaf011

Chuankai Fang, Di He, Yafen Qian, Xiaomei Shen

引用次数: 0

Decomposing the genetic background of chronic back pain. 分解慢性背痛的遗传背景。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-04-06 DOI: 10.1093/hmg/ddae195

Elizaveta E Elgaeva, Irina V Zorkoltseva, Arina V Nostaeva, Dmitrii A Verzun, Evgeny S Tiys, Anna N Timoshchuk, Anatoliy V Kirichenko, Gulnara R Svishcheva, Maxim B Freidin, Frances M K Williams, Pradeep Suri, Yurii S Aulchenko, Tatiana I Axenovich, Yakov A Tsepilov

{"title":"Decomposing the genetic background of chronic back pain.","authors":"Elizaveta E Elgaeva, Irina V Zorkoltseva, Arina V Nostaeva, Dmitrii A Verzun, Evgeny S Tiys, Anna N Timoshchuk, Anatoliy V Kirichenko, Gulnara R Svishcheva, Maxim B Freidin, Frances M K Williams, Pradeep Suri, Yurii S Aulchenko, Tatiana I Axenovich, Yakov A Tsepilov","doi":"10.1093/hmg/ddae195","DOIUrl":"10.1093/hmg/ddae195","url":null,"abstract":"Chronic back pain (CBP) is a disabling condition with a lifetime prevalence of 40% and a substantial socioeconomic burden. Because of the high heterogeneity of CBP, subphenotyping may help to improve prediction and support personalized treatment of CBP. To investigate CBP subphenotypes, we decomposed its genetic background into a shared one common to other chronic pain conditions (back, neck, hip, knee, stomach, and head pain) and unshared genetic background specific to CBP. We identified and replicated 18 genes with shared impact across different chronic pain conditions and two genes that were specific for CBP. Among people with CBP, we demonstrated that polygenic risk scores accounting for the shared and unshared genetic backgrounds of CBP may underpin different CBP subphenotypes. These subphenotypes are characterized by varying genetic predisposition to diverse medical conditions and interventions such as diabetes mellitus, myocardial infarction, diagnostic endoscopic procedures, and surgery involving muscles, bones, and joints.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"711-725"},"PeriodicalIF":3.1,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reciprocal and non-reciprocal effects of clinically relevant SETBP1 protein dosage changes. 临床相关SETBP1蛋白剂量变化的互反和非互反效应。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-04-06 DOI: 10.1093/hmg/ddaf003

Lilit Antonyan, Xin Zhang, Anjie Ni, Huashan Peng, Shaima Alsuwaidi, Peter Fleming, Ying Zhang, Amelia Semenak, Julia Macintosh, Hanrong Wu, Nuwan C Hettige, Malvin Jefri, Carl Ernst

{"title":"Reciprocal and non-reciprocal effects of clinically relevant SETBP1 protein dosage changes.","authors":"Lilit Antonyan, Xin Zhang, Anjie Ni, Huashan Peng, Shaima Alsuwaidi, Peter Fleming, Ying Zhang, Amelia Semenak, Julia Macintosh, Hanrong Wu, Nuwan C Hettige, Malvin Jefri, Carl Ernst","doi":"10.1093/hmg/ddaf003","DOIUrl":"10.1093/hmg/ddaf003","url":null,"abstract":"Many genes in the human genome encode proteins that are dosage sensitive, meaning they require protein levels within a narrow range to properly execute function. To investigate if clinically relevant variation in protein levels impacts the same downstream pathways in human disease, we generated cell models of two SETBP1 syndromes: Schinzel-Giedion Syndrome (SGS) and SETBP1 haploinsufficiency disease (SHD), where SGS is caused by too much protein, and SHD is caused by not enough SETBP1. Using patient and sex-matched healthy first-degree relatives from both SGS and SHD SETBP1 cases, we assessed how SETBP1 protein dosage affects downstream pathways in human forebrain progenitor cells. We find that extremes of SETBP1 protein dose reciprocally influence important signalling molecules such as AKT, suggesting that the SETBP1 protein operates within a narrow dosage range and that extreme doses are detrimental. We identified SETBP1 nuclear bodies as interacting with the nuclear lamina and suggest that SETBP1 may organize higher order chromatin structure via links to the nuclear envelope. SETBP1 protein doses may exert significant influence on global gene expression patterns via these SETBP1 nuclear bodies. This work provides evidence for the importance of SETBP1 protein dose in human brain development, with implications for two neurodevelopmental disorders.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"651-667"},"PeriodicalIF":3.1,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction to: Expression variation of long noncoding RNAs in dopaminergic cells-derived from stem cells and their MPP+ induced PD models. 更正：长链非编码rna在干细胞来源的多巴胺能细胞及其MPP+诱导PD模型中的表达变化。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-04-06 DOI: 10.1093/hmg/ddaf034

引用次数: 0

A novel frameshift mutation of SOX10 identified in Waardenburg syndrome type 2. 在Waardenburg综合征2型中发现一种新的SOX10移码突变。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-04-06 DOI: 10.1093/hmg/ddaf010

Wenqing Han, Run Yang, Xin Chen, Ying Chen, Tianyu Zhang, Jing Ma

引用次数: 0

Sudden cardiac death, arrhythmogenic cardiomyopathy and intercalated disc pathology due to reduced filamin C protein levels: a matter of life and death. 由于纤维蛋白C水平降低引起的心源性猝死、心律失常性心肌病和嵌套性椎间盘病理：一个生死攸关的问题。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-04-06 DOI: 10.1093/hmg/ddaf014

Christian Holtzhausen, Lorena Heil, Karin Klingel, Henrik Fox, Jan Gummert, Anna Gärtner, Andreas Schmidt, Marcus Krüger, Gregor Kirfel, Peter F M van der Ven, Hendrik Milting, Christoph S Clemen, Rolf Schröder, Dieter O Fürst, Jens Tiesmeier

{"title":"Sudden cardiac death, arrhythmogenic cardiomyopathy and intercalated disc pathology due to reduced filamin C protein levels: a matter of life and death.","authors":"Christian Holtzhausen, Lorena Heil, Karin Klingel, Henrik Fox, Jan Gummert, Anna Gärtner, Andreas Schmidt, Marcus Krüger, Gregor Kirfel, Peter F M van der Ven, Hendrik Milting, Christoph S Clemen, Rolf Schröder, Dieter O Fürst, Jens Tiesmeier","doi":"10.1093/hmg/ddaf014","DOIUrl":"10.1093/hmg/ddaf014","url":null,"abstract":"Mutations in the human FLNC gene encoding filamin C (FLNc) cause a broad spectrum of sporadic and familial cardiomyopathies and myopathies. We report on the genetic, clinical, morphological and biochemical findings in a German family harboring an FLNC variant that leads to severe cardiac disease comprising sudden cardiac death and arrhythmogenic cardiomyopathy. Genetic analysis identified a novel heterozygous FLNC variant in exon 16 (NM_001458.4:c.2495_2498delAGTA, het; p.K832TfsX45) in i) the index patient suffering from dilated cardiomyopathy necessitating heart transplantation, ii) a son, who died from sudden cardiac death, iii) a second son, who survived an episode of sudden cardiac arrest and iv) a third son affected by isolated skeletal muscle myopathy. FLNc protein levels were markedly reduced in cardiac tissue obtained from the index patient, implying that the p.K832TfsX45 FLNc variant most probably caused nonsense-mediated decay of the corresponding mRNA. Morphological analysis of the diseased cardiac tissue revealed extensive fibrotic remodeling, and marked degenerative changes of the contractile apparatus of cardiomyocytes and severe structural alterations of intercalated discs. Connexin-43 signal intensity at intercalated discs was diminished and FLNc labelling of myofibrils was attenuated or even absent. Proteome analyses demonstrated complex alterations of extracellular matrix and intercalated disc proteins. Our findings demonstrate that this novel, truncating FLNC mutation likely leads to haploinsufficiency, thereby causing a deleterious sequence of degenerative changes of cardiac tissue with extensive fibrotic remodeling and intercalated disc pathology as the structural basis for FLNC-related cardiomyopathy with life-threatening cardiac arrhythmias.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"726-738"},"PeriodicalIF":3.1,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0