BMC Medical Genomics最新文献

{"title":"The miR-4512/PDZK1IP1 axis in hepatocellular carcinoma: clinical significance, diagnostic value, and functional validation.","authors":"Xiang Chen, Gui Zhou, Lihang Cen, Shuang Qin, Meiyu Dai","doi":"10.1186/s12920-026-02399-2","DOIUrl":"10.1186/s12920-026-02399-2","url":null,"abstract":"<p><strong>Background: </strong>PDZK1IP1 is implicated in various cancers, but its role in hepatocellular carcinoma (HCC) remains unclear.</p><p><strong>Aim: </strong>To investigate the expression, clinical significance, and biological function of the miR-4512/PDZK1IP1 axis in HCC.</p><p><strong>Methods: </strong>Serum samples from 56 HCC patients, 57 cirrhosis patients, and 68 healthy controls were analyzed by qRT-PCR. Diagnostic and prognostic values were assessed by ROC curves and Kaplan-Meier/Cox regression analyses, respectively. The regulatory relationship was validated by dual-luciferase assay. Functional roles and downstream mechanisms were examined via cellular assays and Western blotting.</p><p><strong>Results: </strong>Serum miR-4512 was significantly downregulated while PDZK1IP1 was upregulated in HCC patients, showing a negative correlation. Both markers served as independent prognostic factors for overall survival and disease-free survival. A triple diagnostic combination (miR-4512 + PDZK1IP1 + AFP) achieved an outstanding AUC of 0.988. Dual-luciferase assay confirmed miR-4512 directly targeted the 3'UTR of PDZK1IP1. Functionally, miR-4512 overexpression or PDZK1IP1 silencing suppressed HCC cell proliferation, migration, and invasion. Mechanistically, Western blot revealed that miR-4512 suppressed the Akt/mTOR signaling pathway and glycolysis, which was robustly reversed by PDZK1IP1 overexpression.</p><p><strong>Conclusion: </strong>The miR-4512/PDZK1IP1 axis regulates HCC progression via the Akt/mTOR and glycolysis pathways. Both molecules demonstrate significant potential as robust diagnostic and prognostic biomarkers for HCC.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13483619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148203835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Angiotensin-Converting Enzyme 1 (ACE1) gene polymorphisms in pediatric patients with COVID-19: impact on disease severity and outcomes.","authors":"Shima Mahmoudi, Reihaneh Hosseinpour Sadeghi, Babak Pourakbari, Mostafa Teymuri, Setareh Mamishi","doi":"10.1186/s12920-026-02408-4","DOIUrl":"10.1186/s12920-026-02408-4","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Angiotensin-converting enzyme 1 (ACE1) gene polymorphisms have been suggested to influence susceptibility to and severity of coronavirus disease 2019 (COVID-19) through dysregulation of the renin-angiotensin system. Despite considerable research on COVID-19, the influence of genetic factors, particularly polymorphisms in the ACE gene, on disease severity in pediatric populations remains inadequately understood. Therefore, the present study aimed to investigate the association of ACE1 insertion/deletion (I/D) polymorphism and ACE1 variants rs4341 and rs4343 with clinical manifestations, laboratory findings, and disease severity in hospitalized children with COVID-19.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This study included 100 hospitalized pediatric patients with confirmed COVID-19 infection. Demographic characteristics, including age and sex, clinical manifestations, comorbidities, disease severity, laboratory findings, ICU hospitalization, and mortality outcomes were recorded. Genotyping of the ACE1 I/D polymorphism was performed using PCR-based methods, while rs4341 (C/G) and rs4343 (A/G) polymorphisms were analyzed using PCR-restriction fragment length polymorphism (PCR-RFLP) assays.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Among the 100 enrolled patients, 76% had mild/moderate disease and 24% had severe disease. The ACE1 D/D genotype was identified in 76% of patients, whereas the ACE1 I/I genotype was detected in only 3% of cases. In the analysis of the rs4341 polymorphism, among 77 successfully genotyped patients, the C/C genotype was predominant and identified in 56 out of 77 (73.7%) individuals, while the C/G genotype was observed in 20 out of 77 (26.3%) patients. Severe disease was observed in 34 out of 56 (61%) individuals carrying the rs4341 C/C genotype compared with 8 out of 20 (40%) individuals with the C/G genotype; however, the difference was not statistically significant (P = 0.12). Patients carrying the rs4343 A/A genotype exhibited significantly higher white blood cell counts [8.2 (5.7-11.9) ×10⁹ cells/L vs. 5.5 (4.2-7.8) ×10⁹ cells/L, P = 0.008], platelet counts [269 (220.2-332) ×10⁹ cells/L vs. 206 (161.5-300) ×10⁹ cells/L, P = 0.041], and lactate dehydrogenase levels [555.5 (494.8-601.7) U/L vs. 461 (403-593.7) U/L, P = 0.011] compared with rs4343 A/G carriers.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;In conclusion, although the ACE1 D/D genotype was highly prevalent among pediatric COVID-19 patients, it was not significantly associated with disease severity or ICU hospitalization. Similarly, no significant associations were identified between rs4341 or rs4343 polymorphisms and overall clinical outcomes. However, rs4343 variants were associated with differences in laboratory parameters, including WBC count, platelet count, and LDH levels, suggesting a possible role in host inflammatory responses during SARS-CoV-2 infection. These findings should be interpreted cautiously due to the relatively small sample size and","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13483549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148203821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing SMN1 hybrid and deletion alleles using large-scale SNP array-based SMA carrier screening.","authors":"Noemi Vidal-Folch, Christian Stout, Jennifer Winters, Devin Oglesbee, Linda Hasadsri, Sara L Cook","doi":"10.1186/s12920-026-02406-6","DOIUrl":"10.1186/s12920-026-02406-6","url":null,"abstract":"<p><strong>Background: </strong>Most spinal muscular atrophy (SMA) carrier screening assays quantify SMN1 exon 7 copy number, providing limited information about the prevalence or structure of SMN1-SMN2 hybrid alleles generated through gene conversion. As long-read sequencing (LRS) studies begin to resolve these alleles at high resolution, typically in modest cohorts, large population-scale data remain essential for defining the broader allele-frequency context in which such structural signatures occur.</p><p><strong>Methods: </strong>We evaluated SMN1 exon 7 and exon 8 copy number in 18,015 individuals undergoing expanded carrier screening using a SNP-based array. Carriers were classified by deletion pattern, and representative cases underwent droplet digital PCR (ddPCR) to distinguish contiguous deletions from gene-conversion-derived hybrid alleles based on coordinated SMN1/SMN2 exon and intron copy number profiles.</p><p><strong>Results: </strong>Among 457 carriers (2.5%), exon 7-only deletions accounted for ~ 53%, while exon 7 + 8 deletions comprised ~ 47%. ddPCR showed that exon 7-only deletions predominantly represented SMN1-SMN2 hybrid alleles, whereas exon 7 + 8 deletions reflected contiguous loss of both exons. Isolated exon 8 deletions were rare (~ 0.05%) and likewise exhibited hybrid architecture. This distribution contrasts with earlier population studies reporting a predominance of exon 7 + 8 deletions and indicates that hybrid alleles constitute a substantial proportion of SMN1 deletion alleles in the general population.</p><p><strong>Conclusions: </strong>While hybrid resolution is not required for routine SMA carrier detection, the unexpectedly high prevalence of hybrid alleles highlights an important category of SMN1 structural variation that merits deeper investigation. These population-scale data provide a framework to guide and contextualize future LRS-based analyses aimed at resolving SMN1 gene-conversion tracts, allele structures, and potential modifier variants relevant to SMA pathogenesis and therapeutic response. Together, these findings support a more comprehensive understanding of SMN1 allele diversity as genomic technologies advance toward high-resolution characterization of the SMN locus.</p><p><strong>Trial registration: </strong>Clinical trial number: not applicable.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13483628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148194394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sporadic cone-rod dystrophy caused by a heterozygous RAB28 p.Ser23Phe pathogenic variant and a de novo 4p16.1p15.33 deletion.","authors":"Joonhong Park, Woori Jang, Yoojung Ahn, Haeng-Jin Lee","doi":"10.1186/s12920-026-02402-w","DOIUrl":"10.1186/s12920-026-02402-w","url":null,"abstract":"<p><strong>Background: </strong>Cone-rod dystrophy (CRD) is an inherited retinal dystrophy characterized by decreased visual acuity, color vision defects, and progressive loss of peripheral vision. RAB28-associated CRD is genetically homogeneous and results from pathogenic variants in the RAB28 gene, which is essential for photoreceptor function.</p><p><strong>Case presentation: </strong>Fundus examinations, optical coherence tomography, color vision tests, and full-field electroretinography (ERG) were performed in the proband. Genetic analysis, including clinical exome sequencing (CES), Sanger sequencing and chromosomal microarray (CMA), was conducted to determine the genetic cause in the proband. The patient exhibited significantly reduced visual acuity, severe color vision impairment, macular atrophy, and thinning of the photoreceptor layers. Full-field ERG revealed severely diminished cone responses, while rod responses were mildly reduced. Genetic analysis identified that the heterozygous RAB28 c.68 C > T/p.(Ser23Phe) pathogenic variant was inherited exclusively from the father. Additionally, a 3.4 Mb deletion on chromosome 4p16.1p15.33 was detected only in the proband. Four genes associated with Mendelian diseases, including CLNK (OMIM *611434), HS3ST1 (*603244), NKX3-2 (*602183), and RAB28 (*612994), are located within this deletion region.</p><p><strong>Conclusions: </strong>This case illustrates a rare combination of a heterozygous RAB28 c.68 C > T/p.(Ser23Phe) pathogenic variant and a de novo 4p16.1p15.33 deletion, which is associated with AR CRD. Although extremely rare, bi-allelic RAB28 pathogenic variants can result from one inherited allele and a de novo deletion in the other.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13455248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148148211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular diagnosis of non-syndromic hearing loss in seven Iranian families using whole-exome sequencing.","authors":"Fateme Zahedi Abghari, Emran Esmaeilzadeh, Sajjad Biglari, Hossein Ghasemi, Marzieh Mohseni, Narges Shahmohammad, Hamid Reza Khorram Khorshid, Reza Najafipour","doi":"10.1186/s12920-026-02403-9","DOIUrl":"10.1186/s12920-026-02403-9","url":null,"abstract":"<p><strong>Background: </strong>Congenital hearing loss is a common and genetically diverse sensory disorder. Non-syndromic forms are often inherited in an autosomal recessive pattern, with the types and frequencies of clinically relevant variants differing across populations. Studies of consanguineous families have been instrumental in identifying genes associated with autosomal recessive non-syndromic hearing loss (ARNSHL). The present study aimed to characterize candidate variants potentially underlying ARNSHL in seven unrelated Iranian families with consanguinity or from the same geographic region, as reported during genetic counseling.</p><p><strong>Methods: </strong>We conducted GJB2 screening, whole-exome sequencing (WES), and copy-number variation (CNV) analysis in seven probands with sensorineural hearing loss in the absence of additional phenotypes. Bioinformatic filtering, in silico analysis, and segregation studies were applied to determine the potential clinical relevance of candidate variants.</p><p><strong>Results: </strong>WES identified nine different candidate variants in five genes among the probands and their affected family members, including six missense variants, two affecting canonical splice sites, and one nonsense variant. Previously reported variants included TMC1 (NM_138691.3:c.100 C > T), SLC26A4 (NM_000441.2:c.1229 C > T, c.716T > A, c.2027T > A), MYO7A (NM_000260.4:c.247 C > T), LOXHD1 (NM_001384474.1:c.4940 C > A), and CABP2 (NM_016366.3:c.637 + 1G > T). Additionally, two novel variants were detected in two unrelated families: LOXHD1 (NM_001384474.1:c.1136T > A) and TMC1 (NM_138691.3:c.1567-1G > A).</p><p><strong>Conclusion: </strong>This study contributes to the current understanding of the genetic spectrum of ARNSHL in a small cohort of Iranian families by identifying rare variants in known hearing loss genes, including a novel missense variant in LOXHD1 and a novel splice-site variant in TMC1. However, due to lack of functional validation, their clinical significance remains uncertain. Further functional and large-cohort studies are needed to confirm pathogenicity and clarify genotype-phenotype relationships.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13455336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148148001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SomaScan proteomics reveals novel biomarkers in the progression of liver cirrhosis to hepatocellular carcinoma.","authors":"Lingyu Huang, Junjun Guo, Wei Liu, Shenping Xie, Qiang Yan, Wenjun Pu, Zhipeng Zeng, Liusheng Lai, Baoyao Wang, Yong Dai, Donge Tang, Huaizhou Chen","doi":"10.1186/s12920-026-02398-3","DOIUrl":"10.1186/s12920-026-02398-3","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) typically develops from liver cirrhosis (LC), however early diagnosis is difficult due to a lack of reliable biomarkers. The goal of this study was to use SomaScan proteomics technology to find plasma protein profiles that differentiated LC and HCC from healthy controls in order to develop novel biomarkers for HCC early detection and targeted therapy.</p><p><strong>Methods: </strong>We used SomaScan technology to evaluate 10,893 plasma proteins from LC, HCC, and normal populations. Differentially expressed proteins (DEPs) were discovered and functionally annotated using HPA, GO/KEGG, and PPI networks. Venn analysis was used to identify DEPs that were expressed in both LC and HCC.</p><p><strong>Results: </strong>There were 402 DEPs in LC and 389 in HCC, with MAPK signaling and neutrophil extracellular trap generation being the primary dysregulated pathways in LC and HCC, respectively. In addition, 38 co-expressed DEPs (e.g., SSX7, HIP1R, SLC25A18) were discovered in LC and HCC, including 9 previously unknown potential DEPs. PPI network analysis revealed that FLT4 and PDGFA were key drivers of LC progression to HCC. ELISA experiments confirmed that FLT4 and PDGFA are consistently down-regulated in the progression of LC to HCC (P < 0.05).</p><p><strong>Conclusions: </strong>This investigation described the plasma proteomes of LC and HCC and identified FLT4 and PDGFA as possible early screening targets for HCC, establishing a scientific foundation for HCC detection in high-risk LC populations.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13435949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148136303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative single-cell and bulk transcriptomics define cell death patterns and ZDHHC22 in gastric cancer progression.","authors":"Jiaming Wu, Cong Chen, Guangjian Dou, Liyong Huang, Yi Zhu, Zhiheng Chen, Qile Mao, Jingyi Jia, Peter Wang, Jin Li","doi":"10.1186/s12920-026-02405-7","DOIUrl":"10.1186/s12920-026-02405-7","url":null,"abstract":"<p><p>INTRODUCTION‌: Gastric cancer remains a major global health burden with high incidence and mortality. Despite therapeutic advances, long-term survival remains unsatisfactory. Reliable biomarkers to predict therapeutic efficacy and clinical outcomes are urgently needed. This study aimed to elucidate the heterogeneity of gastric cancer using an integrative bioinformatics approach that combines single-cell RNA-sequencing (scRNA-seq) and bulk RNA-seq data. METHODS‌: scRNA-seq datasets were obtained from the GEO database, and bulk RNA-seq data were obtained from the TCGA. Cell communication, pseudotime analysis, and cell death scoring (cuproptosis, ferroptosis, autophagy, and pyroptosis) were performed on the basis of the scRNA-seq datasets. Stemness, survival, drug sensitivity and posttranslational modification (PTM) analyses were conducted using TCGA data. RESULTS‌: Cancer cells were clustered into three molecular subtypes with distinct molecular characteristics, pathway activation profiles and cell death patterns. Cell-cell communication analysis revealed subtype-specific regulatory interactions, whereas pseudotime and cell death scoring demonstrated dynamic cellular states. Bulk RNA-seq revealed five cell death patterns, among which \"cell death 2\" and high cuproptosis scores emerged as independent risk factors for poor prognosis. Genes such as LMF1-AS1, CAMKV, ERVW-1, ACLY, GAS2L2, RGS8, and RASSF8-AS1 were differentially expressed in the high-risk group. Samples with low stemness and elevated pyroptosis showed enhanced inferred drug resistance, particularly to LBH589. Additionally, ZDHHC22 was identified as a potential protective prognostic factor, and in vitro assays suggested its association with cell death modulation in gastric cancer. CONCLUSION‌: This study highlights the molecular heterogeneity of gastric cancer, demonstrating how distinct cell death patterns and PTM features shape prognosis and drug sensitivity. The identified biomarkers and resistance profiles may provide valuable guidance for personalized therapeutic strategies.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13435517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148101001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 serum miR‑320a in gestational diabetes mellitus for predicting macrosomia and in vitro mechanistic investigation.","authors":"Ruiping Yu, Xiaoyan Liu, Sai Zhang","doi":"10.1186/s12920-026-02401-x","DOIUrl":"10.1186/s12920-026-02401-x","url":null,"abstract":"<p><strong>Background: </strong>Gestational diabetes mellitus (GDM) significantly elevates the risk for a spectrum of adverse pregnancy outcomes. The expression pattern and regulatory mechanism of microRNA-320a (miR-320a) in GDM remain poorly elucidated.</p><p><strong>Methods: </strong>The study enrolled 40 GDM patients along with 40 healthy controls. Serum expression levels of miR-320a were quantified using reverse transcription quantitative polymerase chain reaction (RT-qPCR). ROC curve analysis and binary logistic regression were applied to evaluate its diagnostic performance for GDM and predictive value for fetal macrosomia, respectively. In HTR-8/SVneo trophoblast cells, CCK-8 assay and flow cytometry were used to assess the influence of miR-320a on cell proliferation and apoptosis. Dual-luciferase reporter assay validated the direct targeting relationship between miR-320a and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD). Western blot was performed to detect PIK3CD protein expression, and rescue experiments further explored the biological function of the miR-320a/PIK3CD axis in trophoblast proliferation and apoptosis.</p><p><strong>Results: </strong>Serum miR-320a was significantly downregulated in GDM patients and exhibited good diagnostic capability to distinguish GDM from healthy pregnancies. Lower miR-320a expression was correlated with a higher risk of fetal macrosomia. In addition, overexpression of miR-320a promoted cell proliferation and suppressed apoptosis in HTR‑8/SVneo cells. PIK3CD was identified as a direct downstream target of miR‑320a, and miR‑320a overexpression inhibited PIK3CD expression. Furthermore, the effects of miR‑320a on cell proliferation and apoptosis were markedly reversed by co‑transfection with pcDNA‑PIK3CD.</p><p><strong>Conclusions: </strong>Circulating miR-320a has promising potential for GDM diagnosis and fetal macrosomia prediction. Increased miR-320a expression facilitates proliferation and restricts apoptosis in HTR-8/SVneo trophoblast cells by directly targeting PIK3CD.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13374213/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148052126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early-onset hereditary spastic paraplegia type 56 (SPG56): clinical-molecular correlations and functional validation of CYP2U1 variants.","authors":"Eva Sustrova, Kamila Rihova, Petra Pokorna, Veronika Havlova, Marek Stiborek, Zdenek Simek, Jiri Damborsky, Ondrej Horak, Katerina Kozelkova, Eliska Hlouskova, Regina Demlova, Jana Kubatova, Ondrej Slaby, Katerina Slaba","doi":"10.1186/s12920-026-02394-7","DOIUrl":"10.1186/s12920-026-02394-7","url":null,"abstract":"<p><strong>Background: </strong>Hereditary spastic paraplegia type 56 (SPG56) is a rare autosomal recessive neurodegenerative disorder caused by biallelic variants in the CYP2U1 gene, which encodes a cytochrome P450 enzyme involved in fatty acid metabolism and mitochondrial function. The clinical spectrum includes progressive spasticity of the lower limbs, developmental delay or regression, cognitive impairment, and variable ophthalmological findings. Although several cases have been reported in recent years, the functional characterization of individual variants remains limited.</p><p><strong>Case presentation: </strong>Here we describe a male patient with early-onset SPG56 carrying two CYP2U1 missense variants, NM_183075.3:c.1376 C > T p.(Pro459Leu) and NM_183075.3:c.557G > A p.(Arg186His). Combined genomic, cellular, and in silico analyses confirmed loss of enzymatic activity and protein instability, supporting the pathogenic classification of both variants. Functional validation led to reclassification of the p.(Arg186His) variant from uncertain significance to pathogenic. Further, we link specific CYP2U1 missense changes to convergent molecular defects, thereby refining genotype-phenotype correlations. From a therapeutic perspective, we highlight the relevance of experimental interventions such as folinic acid supplementation and multimodal spasticity management, while emphasizing the future promise of gene therapy for SPG56 patients.</p><p><strong>Conclusions: </strong>Our findings highlight the value of integrating genomic, biochemical, and structural approaches in the diagnostic evaluation of rare neurogenetic disorders, and provide functional evidence that the identified CYP2U1 variants are damaging, consistent with the observed early-onset complex SPG56 phenotype.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13397756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148040488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HMGA1 promotes the proliferation, migration, and invasion of uveal melanoma cells via the PI3K/Akt/MMP-9 pathway.","authors":"Wanying Ren, Binhua Luo","doi":"10.1186/s12920-026-02387-6","DOIUrl":"10.1186/s12920-026-02387-6","url":null,"abstract":"<p><strong>Background: </strong>Uveal melanoma (UM) was prone to metastasis and had an extremely poor prognosis. High-mobility group protein A1 (HMGA1) was known to promote proliferation and invasion in various tumors, but its molecular mechanism in UM remained unclear.</p><p><strong>Objective: </strong>The effect of HMGA1 on the proliferation, migration, and invasion of UM cells was investigated, and whether it functioned through the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/matrix metalloproteinase-9 (MMP-9) pathway was explored.</p><p><strong>Methods: </strong>HMGA1 overexpression (OE) and knockdown (KD) models were established in two UM cell lines (C918, MUM-2B). Cell functions were assessed using MTT assay, EdU (5‑ethynyl‑2'‑deoxyuridine) incorporation assay, scratch wound healing assay, and Matrigel-Transwell assay. The expression of PI3K, phosphorylated PI3K (p-PI3K), Akt, phosphorylated Akt (p-Akt), and MMP-9 was detected by Western blot (WB). Pathway intervention was performed using the PI3K inhibitor LY294002.</p><p><strong>Results: </strong>Compared with the control group, HMGA1 overexpression significantly up-regulated the proliferation, migration, and invasion abilities of both cell lines, and led to a fold-dependent up-regulation of PI3K/Akt pathway activation and MMP-9 expression. In contrast, HMGA1 knockdown significantly down-regulated the above indicators. After treatment with LY294002, the tumor-promoting effects induced by HMGA1 overexpression were significantly reversed.</p><p><strong>Conclusion: </strong>HMGA1 significantly promoted the proliferation, migration, and invasion of UM cells from different origins (primary C918, metastatic MUM-2B) by activating the PI3K/Akt pathway and upregulating MMP-9 expression, suggesting its potential as a target for molecular targeted therapy in UM.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13377751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148004458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}