Human Mutation最新文献

{"title":"Multiomics Analysis of Nucleotide Metabolism Highlights the Important Role of Adenylate Kinase 4 in Pancreatic Cancer.","authors":"Jun Li, Yiqun Yao, Wei Zhang, Dianlong Zhang","doi":"10.1155/humu/7729933","DOIUrl":"https://doi.org/10.1155/humu/7729933","url":null,"abstract":"<p><p>Nucleotide metabolism significantly influences tumor cell proliferation, yet its specific profile in pancreatic cancer remains inadequately understood. This study was aimed at characterizing the nucleotide metabolic profile in pancreatic cancer and assessing the contribution of the key gene adenylate kinase (AK) 4. Multiomics data, including transcriptomic, single-cell sequencing, spatial transcriptomic, and metabolomics datasets, were obtained from publicly accessible platforms. The impact of AK4, a key gene of nucleotide metabolism, on the proliferation and migration of pancreatic cancer cells was investigated using various molecular biological techniques. Nucleotide pathway-related metabolites exhibited marked differences in abundance between pancreatic cancer tissues and normal pancreatic tissues. Single-cell sequencing analysis identified MKI67⁺ and myeloid cells as subsets with overactive nucleotide metabolism. Immune cells from tumor tissues had a higher score of nucleotide metabolism than those from the normal pancreas. Spatial transcriptomics revealed spatial features of nucleotide metabolism in pancreatic cancer. Pancreatic cancer patients displayed distinct clinical heterogeneity in nucleotide metabolism, with elevated nucleotide signaling correlating with poorer patient prognosis. Furthermore, tumor subtypes showed variations in immune microenvironment features and immune checkpoint expression, which may explain their differential prognoses. A nucleotide metabolic-derived prognostic panel had the potential to predict the clinical outcomes of patients with pancreatic cancer. The AK4 gene played a central role in nucleotide metabolism, and its overexpression in clinical pancreatic cancer samples was frequently linked to adverse patient outcomes. Cell-based experiments revealed that AK4 knockdown suppressed pancreatic cancer cell proliferation and migration. Abnormal nucleotide metabolism pathways are implicated in pancreatic cancer onset and progression.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 ","pages":"7729933"},"PeriodicalIF":3.7,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837286","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":"Ubiquitination-Associated Ductal-Fibroblast Crosstalk Shapes Tumor Progression and Prognosis in Pancreatic Ductal Adenocarcinoma.","authors":"Yiping Fu, Xin Zhou, Lai Jiang, Shengke Zhang, Yuheng Gu, Ziye Zhuang, Gang Huang, Zhulin Xu, Pei Xu, Xiaolin Zhong","doi":"10.1155/humu/1665552","DOIUrl":"https://doi.org/10.1155/humu/1665552","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by a complex tumor microenvironment. Ubiquitination regulates key oncogenic processes and microenvironmental remodeling; however, its cell type-specific activity and spatial organization within the PDAC microenvironment remain poorly understood.</p><p><strong>Materials and methods: </strong>Single-cell RNA sequencing, spatial transcriptomics, and bulk RNA-seq datasets of PDAC were integrated for multiomics analysis. Ubiquitination activity was quantified using gene-set scoring algorithms, followed by cell-communication and spatial interaction analyses. Prognostic models were constructed using bulk cohorts, and key findings were validated through gene-silencing functional assays.</p><p><strong>Results: </strong>Ubiquitination activity was significantly increased in PDAC tissues compared with adjacent normal tissues, with ductal epithelial cells and fibroblasts showing the most prominent elevation. High ubiquitination states were associated with enhanced ductal-fibroblast interactions and distinct spatial patterns linked to invasion-associated tumor regions. Integration of ubiquitination-associated gene signatures identified a robust prognostic model, highlighting an extracellular matrix-related factor consistently overexpressed in tumors and associated with poor survival. Functional assays demonstrated that suppression of this factor inhibited proliferation, migration, invasion, and survival of pancreatic cancer cells.</p><p><strong>Conclusion: </strong>Ubiquitination organizes ductal-fibroblast crosstalk within the PDAC microenvironment and links spatial tumor ecology with disease aggressiveness and patient prognosis. Targeting ubiquitination-associated microenvironmental programs may offer new strategies for prognostic stratification and therapeutic intervention.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 ","pages":"1665552"},"PeriodicalIF":3.7,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13129506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814094","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":"Pathophysiological Significance of Variants of the HAND1 Gene Promoter in Congenital Atrial Septal Defects: A Study in 632 Chinese Subjects.","authors":"Jia-Le Qi, Huan-Xin Chen, Hai-Tao Hou, Qin Yang, Guo-Wei He","doi":"10.1155/humu/8840490","DOIUrl":"https://doi.org/10.1155/humu/8840490","url":null,"abstract":"<p><strong>Background: </strong>Atrial septal defect (ASD) is a common congenital heart disease (CHD) and genetic variation in the HAND1 gene is associated with cardiac development. The variants in the promoter region of the HAND1 gene are unknown.</p><p><strong>Methods: </strong>We performed Sanger sequencing of DNA from 632 subjects (320 ASD patients and 312 healthy controls). The identified variants were also subjected to further cellular functional validation, electrophoretic mobility shift analysis (EMSA), and JASPAR database analysis.</p><p><strong>Results: </strong>A total of 12 variants were identified in the promoter region of HAND1 gene, seven of which were found only in 10 ASD patients (g.3658 T > C [rs1287904093], g.3689 A > G, g.3714 G > A [rs140545341], g.3771 C > T [rs2113306555], g.3961 T > G, g.4411 A > T [rs1034236730], and g.4512 G > T) and three of the variants (g.3689 A > G, g.3961 T > G, and g.4512 G > T) were newly discovered. Further cellular functional validation showed that these seven variants reduced the transcriptional activity of HAND1 gene promoter (p < 0.05). The results of EMSA and the analysis of the JASPAR database suggest that these variants may have altered a series of transcription factor binding sites (TFBs), leading to altered HAND1 protein expression as well as the development of ASD.</p><p><strong>Conclusions: </strong>Thus, the present study provides new insights into the role of the promoter region of HAND1 gene, which could lead to a better understanding of the genetic basis of ASD formation and potential treatments.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 ","pages":"8840490"},"PeriodicalIF":3.7,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13131053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814074","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":"X-Linked Hypophosphatemia Caused by a New Partial Insertion of LINE-1 in the <i>PHEX</i> Gene.","authors":"Dongmei Li, Wan Peng, Lu Kang, Jia Geng, Yu Lu, Jing Lu","doi":"10.1155/humu/3376327","DOIUrl":"https://doi.org/10.1155/humu/3376327","url":null,"abstract":"<p><p>X-linked hypophosphatemia (XLH), primarily caused by mutations of the <i>PHEX</i> gene, is the most common cause of genetic rickets. Pediatric cases of XLH typically present with elevated levels of serum fibroblast growth factor 23 (FGF23), hypophosphatemia, rickets, and impaired growth. Here, we report a 2-year-old boy diagnosed with XLH, presenting with short stature, genu varum, and hypophosphatemia. Sanger sequencing revealed a novel mutation of the <i>PHEX</i> gene, comprising a 62-bp poly-T and a 421-bp long interspersed element-1 (LINE-1) insertion into exon 22, which appears to induce the hypophosphatemia. This study presents the first documented case of XLH associated with a partial LINE-1 insertion in <i>PHEX</i>. We suggest that LINE-1 transposon element insertions be considered in XLH patients lacking other known mutations.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 ","pages":"3376327"},"PeriodicalIF":3.7,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13129501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814334","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":"Variant-to-Biomarker Pathways in Peripheral Artery Disease: Multiomics Integration and Clinical Translation.","authors":"Wanting Wang, Gang Zhao, Changxin Yang, Siyao Chang","doi":"10.1155/humu/1908331","DOIUrl":"https://doi.org/10.1155/humu/1908331","url":null,"abstract":"<p><p>Peripheral artery disease (PAD) is a prevalent, disabling manifestation of systemic atherosclerosis that carries high risks of major adverse cardiovascular and limb events, yet remains incompletely explained by conventional risk factors and haemodynamic indices. Although genome-wide association studies have nominated reproducible susceptibility loci and high-throughput profiling has expanded the landscape of circulating, imaging, vascular and skeletal muscle biomarkers, most signals are noncoding, mechanistic attribution is often uncertain and few biomarkers have demonstrated durable incremental utility for risk stratification or therapeutic guidance in routine care. In this review, we summarise PAD-relevant genetic architectures and multiomics modalities-fine-mapped GWAS with tissue- and cell-resolved functional genomics, proteogenomic and metabolomic profiling and network-based integration across vascular, muscle and circulating compartments-and we appraise translational opportunities that span variant-anchored protein and metabolite prioritisation, composite biomarker panels for limb-specific ischaemic burden and residual atherothrombotic risk and biomarker-informed selection of antithrombotic, lipid-lowering, anti-inflammatory and revascularisation strategies. We also discuss enduring challenges-including ancestry-sensitive transferability of genetic instruments, limited access to disease-relevant tissues, cross-platform standardisation, confounding by disease stage and therapy and the need for prospective validation and trial-ready pharmacodynamic endpoints-that temper implementation. The purpose of this review is to delineate variant-to-biomarker pathways in PAD and specify integrative, clinically actionable solutions for discovery, validation and translation. We further distinguish diagnostic, prognostic, predictive/theragnostic and pharmacodynamic biomarker contexts of use, and emphasise that phenotype definition, sex, diabetes, exposure measurement and treatment effects all condition the interpretation and transferability of PAD multiomic signals.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 ","pages":"1908331"},"PeriodicalIF":3.7,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13127234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814279","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":"ILF3 Regulates Cell Proliferation and Metastasis by Competitively Antagonizing the Interaction Between HMGCL and USP38 in Hepatocellular Carcinoma.","authors":"Qingqing Luo, Lei Xiao, Ganlu Deng, Tan Deng, Wenchao Zhao, Rensheng Wang, Xueying Hu","doi":"10.1155/humu/2654435","DOIUrl":"https://doi.org/10.1155/humu/2654435","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is a major type of primary liver cancer. Previous studies have reported that interleukin enhancer-binding factor 3 (ILF3) is involved in the regulation of multiple cancers. This study investigated the molecular mechanisms whereby ILF3 promotes HCC progression.</p><p><strong>Methods: </strong>ILF3 expression levels were determined through immunohistochemistry (IHC) and Western blot (WB) analyses. The biological functions of ILF3 in HCC were evaluated using both in vitro assays and in vivo animal models. Co-immunoprecipitation (Co-IP) was carried out to identify HMGCL as a binding partner of ILF3. To clarify the potential molecular pathways underlying ILF3-mediated regulation of HCC malignant behaviors, protein stability assays and in vitro ubiquitination experiments were performed.</p><p><strong>Results: </strong>ILF3 was significantly upregulated in HCC. The patients with high expression of ILF3 showed poor prognosis in our cohort. ILF3 knockdown inhibited the proliferation and metastasis of HCC cells both in vitro and in vivo in this study. Mechanistically, ILF3 was found to be bound to HMGCL and to accelerate its protein degradation. Additionally, we found that ILF3 promotes HCC cell proliferation and metastasis through HMGCL. Overexpression of HMGCL in ILF3-upregulated HCC cells could significantly reverse the proliferation and invasion role of ILF3 on HCC cells. Moreover, USP38 was identified as a deubiquitinating enzyme that participates in promoting the stability of HMGCL. ILF3 disrupted the interaction between USP38 and HMGCL, thereby enhancing HMGCL ubiquitination and accelerating its degradation.</p><p><strong>Conclusion: </strong>ILF3 promotes the proliferation and metastasis of HCC by enhancing the ubiquitination of HMGCL by interfering with the interaction between the deubiquitinase USP38 and HMGCL.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 ","pages":"2654435"},"PeriodicalIF":3.7,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13125944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147813820","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":"A Tertiary Lymphoid Structure-Derived Prognostic Signature Integrates Immune Microenvironment and Mutational Landscapes in Clear Cell Renal Cell Carcinoma.","authors":"Xuanyu Zhou, Zhongwei Zhao, Kai Huang, Guangxin Ma","doi":"10.1155/humu/8446751","DOIUrl":"https://doi.org/10.1155/humu/8446751","url":null,"abstract":"<p><p>Tertiary lymphoid structures (TLSs) are increasingly recognized as important components of the tumor immune microenvironment, yet their prognostic and immunological implications in clear cell renal cell carcinoma (ccRCC) remain incompletely characterized. In this study, we performed an integrated bioinformatic and translational analysis to investigate TLS-associated molecular features in ccRCC. Using TCGA-KIRC transcriptomic data, we identified three TLS-related molecular subtypes with distinct survival outcomes and immune microenvironment characteristics. Based on prognostic TLS-associated genes, we developed a four-gene TLS-derived score (CSF2, CXCL13, IL1R2, and SGPP2) that stratified patients into groups with significantly different overall survival. The TLS score remained an independent prognostic factor after adjustment for clinical variables. Interestingly, higher TLS scores were associated with increased immune infiltration but poorer survival outcomes, suggesting that TLS-associated transcriptional patterns may reflect heterogeneous immune functional states rather than uniformly effective antitumor immunity. Computational analyses indicated potential differences in predicted immunotherapy response and mutation landscapes between TLS score groups. Limited experimental validation using fresh ccRCC specimens supported the feasibility of TLS score assessment and provided preliminary histopathological context for TLS-associated immune features. Overall, this study proposes a TLS-derived transcriptional signature that may help capture immune heterogeneity in ccRCC and may provide a complementary framework for prognostic assessment. Further studies are required to validate its biological and clinical relevance.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 ","pages":"8446751"},"PeriodicalIF":3.7,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13122255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147769988","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":"Targeting the Vim-PGI₂ Pathway Enhances CD8⁺ T Cell-Mediated Antitumor Immunity in Breast Cancer.","authors":"Hong Quan, Lujing Shao, Qi Li, Chunyan Dong","doi":"10.1155/humu/8880918","DOIUrl":"https://doi.org/10.1155/humu/8880918","url":null,"abstract":"<p><p>Breast cancer is the most prevalent malignancy in women, and the limited effectiveness of current treatments highlights the need for novel immune regulatory mechanisms to improve long-term survival. This study investigated the role of Vim in PGI₂ synthesis and its impact on tumor immune regulation. Multiomics profiling revealed molecular alterations following Vim deletion, which were validated in murine breast cancer models using RT-qPCR, Western blot, ELISA, and flow cytometry, with rescue experiments involving exogenous PGI₂. The findings showed that Vim deletion downregulated arachidonic acid metabolism, reduced PTGIS expression, and significantly lowered PGI₂ levels. Functional assays demonstrated that Vim deficiency enhanced T cell-mediated antitumor immunity, evidenced by an increased proportion of CD8⁺ T cells, upregulation of cytotoxic genes (<i>Ifng</i>, <i>Gzmb</i>, <i>Tnf</i>, and <i>Klrd1</i>), and activation of inflammation-related signaling pathways, as indicated by enhanced phosphorylation of ERK1/2 and p65. Both exogenous PGI₂ supplementation and ozagrel treatment reversed these effects. In conclusion, the Vim-PGI₂ axis is identified as a key regulator of CD8⁺ T cell immunity in breast cancer, representing a potential therapeutic target and a critical consideration in anticoagulant management during cancer immunotherapy.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 ","pages":"8880918"},"PeriodicalIF":3.7,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13122558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770138","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":"De Novo <i>TRIO</i> Missense Variants Disrupt Ras-GEF Domains and Cause Congenital Ventriculomegaly and Hydrocephalus.","authors":"Neel H Mehta, Evan Dennis, Garrett Allington, Kedous Y Mekbib, Andrew T Hale, William C Davalan, Phan Q Duy, Emmarose Zilla, Baojian Fan, Ekkehard M Kasper, Seth L Alper, Shozeb Haider, Kristopher T Kahle","doi":"10.1155/humu/8870037","DOIUrl":"https://doi.org/10.1155/humu/8870037","url":null,"abstract":"<p><p>Congenital hydrocephalus (CH), characterized by congenital ventriculomegaly (CV), affects approximately 0.5-1 per 1000 live births and is a common cause of pediatric neurosurgical intervention, yet its genetic architecture remains incompletely defined. We report a child with syndromic CH requiring cerebrospinal fluid diversion who harbored a pathogenic de novo missense variant in <i>TRIO</i> (c.3232C > T; p.(Arg1078Trp)), a gene previously associated with autosomal dominant neurodevelopmental disorders featuring variable head circumference. This case prompted systematic evaluation of <i>TRIO</i> variation in our CV/CH cohort (2,697 patient-parent trios) using exome sequencing. We identified five additional unrelated probands with de novo <i>TRIO</i> variants, including two novel substitutions affecting the same residue within the Ras-GEF1 domain (p.(Glu1299Lys) and p.(Glu1299Gly)), yielding significant gene-level enrichment for protein-damaging de novo variants (adjusted <i>p</i> = 6.12 × 10^-5). All affected individuals exhibited CV, frequently accompanied by developmental delay and additional structural brain abnormalities. In silico structural modeling predicted that associated variants destabilize critical <i>TRIO</i> Ras-GEF domains required for Rho GTPase activation. Analysis of single-nucleus transcriptomic data from the developing human neocortex revealed enrichment of <i>TRIO</i> expression in multipotent progenitor populations. A systematic literature review identified six additional individuals with <i>TRIO</i> de novo variants and reported CV or CH, including an unrelated patient with the same p.(Arg1078Trp) substitution. Together, these findings expand the phenotypic spectrum associated with pathogenic <i>TRIO</i> variation to include CV/CH and support <i>TRIO</i> as a clinically relevant gene in the genetic evaluation of syndromic CV/CH patients.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 ","pages":"8870037"},"PeriodicalIF":3.7,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13115915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770052","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":"Identification of a Novel VLDLR Variant in the First Report of CAMRQ1 From Africa: Expanding the Spectrum of Cerebellar Ataxia Syndromes.","authors":"Aseel A Jawabri, Ainara Salazar-Villacorta, Henriette Senghor, Rokhaya Ndiaye, Alia Al-Mehrzi, Amadou Gallo Diop, Moustapha Ndiaye, Bassam R Ali, Pedro M Rodriguez Cruz","doi":"10.1155/humu/4661238","DOIUrl":"https://doi.org/10.1155/humu/4661238","url":null,"abstract":"<p><p>Cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ)-related disorders are rare, nonprogressive, autosomal recessive conditions primarily characterized by cerebellar ataxia, hypotonia, intellectual disability, delayed ambulation, and, in some cases, quadrupedal locomotion. Pathogenic variants in four disease genes, <i>VLDLR</i>, <i>CA8</i>, <i>WRD81</i>, and <i>ATP8A2,</i> have been linked to these disorders, with cases reported across various ethnic groups and geographic regions. However, no reports of CAMRQ1 (OMIM #224050) have been previously made from Africa. In this study, we report the first African family with four affected siblings exhibiting typical CAMRQ1 clinical features with varying levels of phenotypic severity. Genetic analysis revealed a novel missense homozygous variant (c.1694C > A; p.P565Q) in the <i>VLDLR</i> gene in all the affected individuals, with the parents being heterozygous. Biochemical analysis, including immunofluorescence and confocal laser microscopy, western blot, and endoglycosidase H sensitivity and resistance assay, demonstrated the retention of the p.(P565Q) VLDLR protein in the endoplasmic reticulum (ER), impairing its trafficking to the plasma membrane and thus confirming its pathogenic impact. This ER retention is expected to disrupt VLDLR-mediated signaling pathways, including reelin signaling, thereby affecting neuronal migration. Furthermore, due to its ER retention, the p.(P565Q) is expected to induce ER stress and activate the endoplasmic reticulum-associated degradation (ERAD) pathway. Our findings expand the genetic and geographical spectrum of CAMRQ1 and provide further functional insights into its underlying pathogenesis.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 ","pages":"4661238"},"PeriodicalIF":3.7,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13112595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770119","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}