Human Mutation最新文献

{"title":"Genetic Causal Relationship Between Systemic Lupus Erythematosus and Malignant Tumors of the Female Reproductive System: A GWAS Analysis in European Populations","authors":"Jianbin Li,&nbsp;Zhuo Tang,&nbsp;Lei Zhang,&nbsp;Ning Tan,&nbsp;Wei Liu","doi":"10.1155/humu/7447886","DOIUrl":"https://doi.org/10.1155/humu/7447886","url":null,"abstract":"<p><b>Background:</b> Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that primarily affects women of reproductive age. Existing studies have demonstrated complex associations between SLE and various diseases, but its genetic relationship with malignant tumors of the female reproductive system has not been fully elucidated. This study is aimed at exploring the potential genetic associations and shared molecular basis between SLE and female reproductive system malignancies using genome-wide association studies (GWASs) and cross-trait analysis.</p><p><b>Methods:</b> We selected genetic variants significantly associated with SLE (<i>p</i> &lt; 5 × 10⁻⁸) from large-scale GWAS databases as genetic instruments and applied various statistical methods to analyze the associations between SLE and cervical cancer, endometrial cancer, ovarian cancer, vulvar cancer, vaginal cancer, and uterine cancer. The primary analysis was conducted using inverse variance weighting (IVW), supplemented by Egger regression, weighted median, and weighted mode methods. To control for potential confounders, we performed multivariable analysis while including BMI, estradiol, and CRP as covariates. Additionally, cross-trait analysis using the association analysis based on subset (ASSET) method was employed to identify shared genetic variants and their effect directions between SLE and uterine cancer.</p><p><b>Results:</b> Genetic association analysis showed a significant negative association between SLE and endometrial cancer (OR = 0.972, 95% CI [0.946–0.998], <i>p</i> = 0.038), suggesting that SLE may be associated with a reduced risk of endometrial cancer. For uterine cancer, the weighted median method also indicated a marginally significant negative association (OR = 0.955, 95% CI [0.912–1.000], <i>p</i> = 0.049). Multivariable analysis further confirmed that the protective association between SLE and endometrial cancer remained significant after controlling for BMI, estradiol, and CRP (OR = 0.96, 95% CI [0.93–0.99], <i>p</i> = 0.014). However, no significant association was observed between SLE and cervical cancer, ovarian cancer, vulvar cancer, or vaginal cancer. Cross-trait analysis identified 193 shared genetic variants between SLE and endometrial cancer and 71 shared variants between SLE and uterine cancer, with rs2442719 and rs3131004 showing consistent effect directions in both comparisons.</p><p><b>Conclusion:</b> This study provides genetic epidemiological evidence suggesting that SLE may have a protective effect against endometrial and uterine cancers and identifies potential shared genetic bases. These findings offer new insights into the relationship between SLE and gynecological tumors and may provide references for the prevention and treatment of related diseases.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/7447886","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Functional Analysis of Complex Structural and Splice-Altering Variants in the ARSB Gene Towards the Personalized Antisense-Based Therapy for Mucopolysaccharidosis Type VI Patients”","authors":"","doi":"10.1155/humu/9764070","DOIUrl":"https://doi.org/10.1155/humu/9764070","url":null,"abstract":"<p>I. Bychkov, A. Filatova, G. Baydakova, N. Sikora, E. Garifullina, A. Bykova, V. Tabakov, A. Skretnev, M. Skoblov, E. Zakharova, “Functional Analysis of Complex Structural and Splice-Altering Variants in the ARSB Gene Towards the Personalized Antisense-Based Therapy for Mucopolysaccharidosis Type VI Patients,” <i>Human Mutation</i>, 2025, https://doi.org/10.1155/humu/2250030</p><p>Additionally, the disclosure statement incorrectly cites reference 37. The disclosure statement should read</p><p>“Some of the results of this work were presented earlier in the form of a preprint [38].”</p><p>The authors apologize for these errors.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/9764070","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-Cell RNA-Seq Recognized Key Genes for Metastasis and Macrophage Infiltration in Colorectal Cancer","authors":"Juan Shi,&nbsp;Peiming Zheng,&nbsp;Libo Ouyang,&nbsp;Facai Cui","doi":"10.1155/humu/9488531","DOIUrl":"https://doi.org/10.1155/humu/9488531","url":null,"abstract":"<p>Colorectal cancer (CRC) is one of the most common malignancies in the world. However, the main causes of metastasis and immune cell infiltration in CRC are still unclear. This experiment was conducted to identify the key genes of metastasis and macrophage infiltration in CRC according to single-cell sequencing (scRNA-seq) data. By analyzing the data of GSE261012 and GSE234804 in the Gene Expression Omnibus (GEO) database, the key node genes for the stages of tumorigenesis, epithelial–mesenchymal transition, and metastasis of CRC were found. These genes were modeled by lasso regression by The Cancer Genome Atlas (TCGA) database, and ZFAND2A was identified as a key gene for metastasis and macrophage infiltration in CRC. Finally, the specific function of ZFAND2A in cancer cell activity was explored in vitro by qRT-PCR, WB analysis, CCK-8, and transwell assay. The specific function of ZFAND2A in macrophage polarization was explored in vitro by qRT-PCR, ELISA, and flow cytometry. We identified crucial gene expression in the entire process of CRC tumor progression, including tumorigenesis, epithelial–mesenchymal transition, and metastasis. Ten thousand six hundred and thirty-seven genes were determined as genes associated with tumor progression and metastasis. Among them, six genes were identified to be related to CRC prognosis. The results of TCGA data indicated that ZFAND2A showed lower expression in tumors and was related to a good prognosis of CRC. Overexpression of ZFAND2A inhibits the proliferation and migration of CRC cells. Additionally, there was a correlation between ZFAND2A expression and macrophage infiltration. Increasing ZFAND2A promotes M1 polarization in macrophages. Our findings provide new potential biomarkers for the metastatic mechanisms and prognosis of CRC. In addition, ZFAND2A is expected to become a potential therapeutic target for CRC.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/9488531","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-Cell and Spatial Transcriptomics Explore Purine Metabolism–Related Prognostic Risk Model and Tumor Immune Microenvironment Modulation in Ovarian Cancer","authors":"Yinglei Liu,&nbsp;Rui Geng,&nbsp;Songyun Zhao,&nbsp;Jinjin Yang,&nbsp;Jinhui Liu,&nbsp;Yanli Zheng,&nbsp;Weichun Tang","doi":"10.1155/humu/5530325","DOIUrl":"https://doi.org/10.1155/humu/5530325","url":null,"abstract":"<p><b>Background:</b> Ovarian cancer (OC) ranks as the second leading cause of gynecological cancer–related deaths in women globally. Single-cell and spatial transcriptomics could precisely describe the heterogeneity of OC that affect the clinical treatment.</p><p><b>Methods:</b> Single-cell sequencing and spatial transcriptomics information were from different public datasets. A pseudotime analysis of cellular developmental pathways, score single-cell gene sets, and cell activity ratings in each metabolic pathway were performed. A prognostic model was created using univariate regression analysis, LASSO, and multivariate regression analysis. Finally, the immune microenvironment and immunotherapeutic effects were analyzed for their association with purine metabolism activity. Finally, RT-qPCR was used to estimate the mRNA level of OC in cell lines.</p><p><b>Results:</b> We observed a higher purine metabolism score by a signature of 12 purine metabolism–related gene in tumor cells. When compared with fibroblasts, epithelial cells with high scores displayed more intense TGF-<i>β</i> signaling pathway activity. Forty-four differentially expressed purine metabolism–related genes were identified to be substantially expressed in the tumor’s core region and were closely linked to purine and pyrimidine metabolic activities. Low-risk population had higher immune infiltration level and immunotherapy results. The NME6+ epithelial cell high-expression group had a greater prognosis and showed a negative connection with the tumor immune dysfunction and exclusion score and cancer-associated fibroblast cell concentration.</p><p><b>Conclusion:</b> Purine metabolism was a predictor for OC patients’ prognosis. The presence of positive NME6 expression in epithelial cells emerges as a protective factor for OC patients, presenting a possible therapeutic target for personalized treatment.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/5530325","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deletion Testing of the DEGS1 Gene Should Be Part of the Diagnostic Pipeline for Hypomyelinating Leukodystrophy (HLD18)","authors":"Mariateresa Zanobio,&nbsp;Francesca Nardecchia,&nbsp;Gerarda Cappuccio,&nbsp;Maria Elena Onore,&nbsp;Pasquale Di Letto,&nbsp;Sarah Iffat Rahman,&nbsp;Gaetano Terrone,&nbsp;Lorenzo Ugga,&nbsp;Agnese De Giorgi,&nbsp;Michele Dei Cas,&nbsp;Marco Trinchera,&nbsp;Vincenzo Leuzzi,&nbsp;Giulio Piluso,&nbsp;Vincenzo Nigro,&nbsp;Nicola Brunetti-Pierri,&nbsp;TUDP consortium,&nbsp;Annalaura Torella","doi":"10.1155/humu/3531508","DOIUrl":"https://doi.org/10.1155/humu/3531508","url":null,"abstract":"<p>Hypomyelinating leukodystrophies are a heterogeneous group of disorders characterized by abnormal myelin formation in the central nervous system. Thanks to the increased use of NGS, a growing number of pathogenic single nucleotide variants in <i>DEGS1</i> have recently been reported to be responsible for hypomyelinating leukodystrophy 18 (HLD18), a rare and severe autosomal recessive form. <i>DEGS1</i> is a small gene (4 exons and 17 kb) encoding <i>Δ</i>4-dihydroceramide desaturase, which catalyzes the final step in ceramide biosynthesis. Here, we present two patients from unrelated families affected by severe and progressive white matter disease with developmental delay with or without regression and severe intellectual disability. Trio exome sequencing (ES) revealed in both probands two homozygous missense variants in the <i>DEGS1</i> gene, p.Asp16His and p.Asn255Ser, both inherited from their heterozygous healthy mothers and with a noncarrier father. This curious finding of inconsistent segregation data raises the need for further testing. There is no MLPA test available for this gene, as no deletions have been reported. However, we tried a customized high-resolution 1 M CGH array, which was surprisingly positive in both cases: a 63-kb heterozygous deletion encompassing the entire gene in one proband and a 7-kb heterozygous deletion of Exons 2–3 in the second case. Previously reported cases of HLD18 have all been found to carry single nucleotide pathogenic variants in <i>DEGS1</i>, and the two patients described here are the first to carry whole or partial microdeletions involving <i>DEGS1</i> that unmask pathogenic missense variants on the other allele. These two cases report the first examples of microdeletions of <i>DEGS1</i> that unmask recessive allele pathogenic variants, underscoring the importance of considering whole or partial gene deletions in the diagnostic pipeline.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/3531508","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering the Mutational Background in Citrin Deficiency Through a Nationwide Study in Japan and Literature Review","authors":"Jun Kido,&nbsp;Keishin Sugawara,&nbsp;Sotiria Tavoulari,&nbsp;Georgios Makris,&nbsp;Véronique Rüfenacht,&nbsp;Kimitoshi Nakamura,&nbsp;Edmund R. S. Kunji,&nbsp;Johannes Häberle","doi":"10.1155/humu/9326326","DOIUrl":"https://doi.org/10.1155/humu/9326326","url":null,"abstract":"<p>Citrin deficiency (CD) is an autosomal recessive disorder caused by the absence or dysfunction of the mitochondrial transporter citrin, resulting from mutations in <i>SLC25A13</i>. The disease presents with age-dependent clinical manifestations: neonatal intrahepatic cholestasis caused by CD (NICCD), failure to thrive and dyslipidemia by CD (FTTDCD), and an adult-onset form (formerly called Type II citrullinemia, CTLN2, recently renamed to “adolescent and adult citrin deficiency,” AACD). We performed this study to compile known genotypes found in CD patients and investigate their impact on the clinical course. Through a nationwide survey in Japan as well as a literature review, we collected information regarding 68 genetic variants of a total of 345 patients with CD (285 NICCD, 19 post-NICCD, and 41 AACD). In this cohort, the pathogenic variants, arising from nonsense, insertion/deletion, and splice site mutations, are expected to have severe functional or biogenesis defects. Of 82 alleles in patients with AACD, the two most common variants, c.852_855del and c.1177+1G&gt;A, accounted for 25 alleles (30.5%) and 15 alleles (18.3%), respectively. The c.852_855del variant, even when present as part of compound heterozygosity, often presented with hyperammonemia (≥ 180 μmol/L), cognitive impairment, short stature (&lt; -2SD), liver cirrhosis, and pancreatitis, with some patients requiring liver transplantation. In conclusion, certain <i>SLC25A13</i> genotypes are particularly frequent, especially those that result in severely truncated citrin proteins with often a significant impact on the clinical outcome of the patient. The most prevalent variant is c.852_855del, which was found in 42% (128/304) of NICCD/post-NICCD cases and 49% (20/41) of AACD patients.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/9326326","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143856908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Temperature as a Key Modulator: Investigating Phosphorylation Patterns of p.Asn666 PDGFRB Variants and Their Role in Downstream Signaling","authors":"Titas Gladkauskas,&nbsp;Ileana Cristea,&nbsp;Roya Mehrasa,&nbsp;Jean-Baptiste Demoulin,&nbsp;Bjørn Tore Gjertsen,&nbsp;Ove Bruland,&nbsp;Eyvind Rødahl,&nbsp;Cecilie Bredrup","doi":"10.1155/humu/6664372","DOIUrl":"https://doi.org/10.1155/humu/6664372","url":null,"abstract":"<p>Four different amino acid substitutions have been reported at the p.Asn666 position in platelet-derived growth factor receptor <i>β</i> (PDGFR<i>β</i>): p.Asn666Lys, p.Asn666Tyr, p.Asn666Ser, and p.Asn666His. All four substitutions result in strikingly different phenotypes, ranging from somatic infantile myofibromatosis in p.Asn666Lys and ocular pterygium–digital keloid dysplasia in p.Asn666Tyr to a severe form of Penttinen syndrome in p.Asn666Ser, while p.Asn666His is associated with a complex phenotype characterized by debilitating hand and foot contractures and facial coarseness. Here, we show that the p.Asn666Lys, p.Asn666Tyr, and p.Asn666His substitutions result in increased total PDGFR<i>β</i> phosphorylation at 32°C compared to 37°C. All four substitutions exhibit distinct activation patterns of specific PDGFR<i>β</i> tyrosine residues at both temperatures, indicating a unique activation of each variant. The temperature effect on downstream signaling is present across all substitutions, resulting in substitution-specific downstream signaling at both 37°C and 32°C. This complex interplay of downstream signaling proteins could be important for the clinical manifestations of p.Asn666 <i>PDGFRB</i> variants. Furthermore, variant-specific overactivation of tyrosine residues and downstream signaling at 32°C emphasize the importance of temperature as an environmental factor in the pathogenesis of this diverse group of disorders.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/6664372","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143856823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Monogenic, Polygenic, and Epigenetic Models of Common Variable Immunodeficiency","authors":"Tayebeh Ranjbarnejad,&nbsp;Hassan Abolhassani,&nbsp;Roya Sherkat,&nbsp;Mansoor Salehi,&nbsp;Fatemeh Ranjbarnejad,&nbsp;Nasimeh Vatandoost,&nbsp;Mohammadreza Sharifi","doi":"10.1155/humu/1725906","DOIUrl":"https://doi.org/10.1155/humu/1725906","url":null,"abstract":"<p>Common variable immunodeficiency (CVID) is the most frequent symptomatic inborn error of immunity (IEI). CVID is genetically heterogeneous and occurs in sporadic or familial forms with different inheritance patterns. Monogenic mutations have been found in a low percentage of patients, and multifactorial or polygenic inheritance may be involved in unsolved patients. In the complex disease model, the epistatic effect of multiple variants in several genes and environmental factors such as infections may contribute. Epigenetic modifications, such as DNA methylation changes, are also proposed to be involved in CVID pathogenesis. In general, the pathogenic mechanism and molecular basis of CVID disease are still unknown, and identifying patterns of association across the genome in polygenic models and epigenetic modification profiles in CVID requires more studies. Here, we describe the current knowledge of the molecular genetic basis of CVID from monogenic, polygenic, and epigenetic aspects.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/1725906","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intron Variant Cause DICER1 Syndrome With Pleuropulmonary Blastoma","authors":"Rujin Tian,&nbsp;Yixiao Li,&nbsp;Lin Zhong,&nbsp;Haozheng Zhang,&nbsp;Zhongtao Gai,&nbsp;Dong Wang,&nbsp;Li Song,&nbsp;Kaihui Zhang","doi":"10.1155/humu/8884636","DOIUrl":"https://doi.org/10.1155/humu/8884636","url":null,"abstract":"<p><i>DICER1</i> syndrome (OMIM 601200) is a rare autosomal dominant familial tumor susceptibility disorder with heterozygous <i>DICER1</i> germline mutations. The most common tumor in clinical practice is pleuropulmonary blastoma. Pleuropulmonary blastoma is a rare pediatric lung tumor that begins during fetal lung development and is part of an inherited tumor syndrome. We found a patient with pleuropulmonary blastoma in clinical practice and performed whole-exome testing on him and his parents. The mutation is located at <i>DICER1</i> gene, c. 1510-16G&gt;A. The tested person has a heterozygous variation at this locus. The tested person’s father has no variation at this locus, while the tested person’s mother has a heterozygous variation at this locus. According to the ACMG guidelines, this mutation has been preliminarily determined as clinically significant (uncertain) PM2_Supporting: The frequency of this supporting variation in the normal population database is unknown; there is no report of correlation for this locus in the literature database, and the ClinVar database does not feature this locus. In point pathogenicity analysis results, analysis of splicing was carried out by Sanger sequencing and RT-PCR from peripheral blood and a minigene splicing assay, both of which showed a deletion of exon 10 resulting from the c. 1510-16G&gt;A variant at the mRNA level. Bioinformatic analysis of the reported c. 1510-16G&gt;A variant suggests that the variant is pathogenic. Based on the clinical characteristics of the patient and the functional verification of the gene variants, our pediatricians have finally diagnosed the infant with pleuropulmonary blastoma (OMIM 601200). Our findings expand the mutation spectrum leading to <i>DICER1</i> deficiency-related diseases and provide accurate information for genetic counseling.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/8884636","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143749700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Splicing Analysis of Exonic TSC1 and TSC2 Gene Variants Causing Tuberous Sclerosis Complex","authors":"Qingqing You,&nbsp;Jingwei Liu,&nbsp;Ran Zhang,&nbsp;Zhi Wang,&nbsp;Bingying Zhang,&nbsp;Wencong Guo,&nbsp;Ning Xu,&nbsp;Irene Bottillo,&nbsp;Leping Shao","doi":"10.1155/humu/1497712","DOIUrl":"https://doi.org/10.1155/humu/1497712","url":null,"abstract":"<p>Tuberous sclerosis complex (TSC) is characterized by abnormalities in cell proliferation and migration, leading to the development of hamartomas, benign tumors, or malignant cancers, affecting both the skin and brain, as well as potentially impacting the heart, kidneys, lungs, and eyes, with varying patterns of involvement over a lifetime. It is primarily caused by mutations in the TSC1 and TSC2 genes. Aberrant splicing is a crucial factor in hereditary diseases. Alternative splicing is a key mechanism for expanding the diversity of the human proteome. Mutations disrupting canonical splice sites or splicing regulatory elements impede the utilization of splice sites, leading to exon skipping and intron retention. We comprehensively analyzed missense and nonsense mutations of TSC1 and TSC2 genes using bioinformatics tools and identified 10 candidate mutations affecting pre-mRNA splicing through minigene analysis. Mutations in TSC genes can lead to partial or complete exon skipping and/or intron retention through complex mechanisms. This study emphasizes the importance of evaluating their roles in the splicing of suspected pathogenic variants in TSC.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/1497712","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}