BMC Medical Genomics最新文献

{"title":"Influence of genetic factors of humans, mosquitoes and parasites, on the evolution of Plasmodium falciparum infections, malaria transmission and genetic control methods: a review of the literature.","authors":"Seni Nikiema, Issiaka Soulama, Gifty Dufie Ampofo, Moustapha Nikiema, Abdou Azaque Zouré, Salif Sombié, Salam Sawadogo, Nicolas Ouedraogo, Samuel Sindie Sermé, Haffsatou Sawadogo, Raïssa Ily, Guillène Y N Tibiri, Djamila O A Zouré, Nassandba Julien Yanogo, Farida C A Kaboré, Chanolle Tchekounou, Adama Zida, Issoufou Tao, Oumarou Ouedraogo, Dramane Zongo, Florencia Wendkuuni Djigma, Alfred B Tiono, Sodiomon B Sirima, Athanase Badolo, Jacques Simporé","doi":"10.1186/s12920-025-02165-w","DOIUrl":"10.1186/s12920-025-02165-w","url":null,"abstract":"<p><p>Despite significant progress, malaria remains a public health problem in many regions, particularly in sub-Saharan Africa. This situation is partly explained by the mosquito's resistance to insecticides and the emergence of parasite resistance to antimalarial drugs. Indeed, in spite of the various vectors' controls, insecticide resistance emerges from multi-generational selection and poses worldwide concern. In parallel, artemisinin resistance unfortunately emerged independently in multiple countries in eastern Africa. Since 2014, artemisinin resistance has been observed in 6 countries in Africa and, more concerningly, the evidence from longitudinal molecular surveys in these countries suggests that it is spreading. While phenotypic evidence of treatment failure is still limited, the increasing reports of validated artemisinin resistance mutations are alarming. Unlike the emergence of artemisinin resistance in South-East Asia, our understanding of the genetic determinants of artemisinin resistance and our ability to sequence and map the spread of resistance are significantly greater. In addition to mosquito and parasite genetics affecting malaria evolution, many human individual variants have been identified that are associated with malaria protection, but the most important of all relates to the structure or function of red blood cells, the classical polymorphisms that causes sickle cell trait, α-thalassaemia, G6PD deficiency, and the major red cell blood group variants. In that biological complex context, there is a need to characterize the various genetic factors in Plasmodium falciparum, humans and mosquitoes that are potentially associated with resistance to antimalarial drugs and insecticides, and their involvement in the evolution, severity and transmission of malaria. In this direction, A comprehensive literature review was conducted to capture the objectives highlighted above. The advances in genomic surveillance and emerging genetic control strategies, such as gene drive technology were also considered in this review. We used search engines such as PubMed and Google scholar to retrieve articles useful to the objective of this paper and information on the knowledge of genetic factors and methods that contributed to malaria control were synthesized.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"100"},"PeriodicalIF":2.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207542","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":"CCDC22 mutations that impair COMMD binding cause attenuated 3C/Ritscher-Schinzel syndrome.","authors":"Amika Singla, Carolyn Rogers, Mary-Joe Touma, Yassin El-Najjar, Alison Colley, Daniel J Boesch, Daniel D Billadeau, Jozef Gecz, Baoyu Chen, Ezra Burstein","doi":"10.1186/s12920-025-02168-7","DOIUrl":"10.1186/s12920-025-02168-7","url":null,"abstract":"<p><p>The CCC complex, composed of CCDC22, CCDC93, and ten proteins of the COMMD family, coordinates several critical steps required to recycle internalized plasma membrane proteins from endosomes to the cell surface. CCC interacts with Retriever, a trimeric cargo recognition complex comprising VPS35L, VPS26C, and VPS29, and works closely with the WASH complex, a crucial regulator of branched actin polymerization at endosomal membranes. Mutations in genes encoding subunits of these three complexes, CCDC22, VPS35L, and WASHC5, have been linked with a developmental syndrome known as 3 C (cranio-cerebello-cardiac) or Ritscher-Schinzel syndrome. Here, we report a new CCDC22 missense mutation, p.E208K, that results in attenuated 3 C syndrome, without cardiac or neuroanatomical abnormalities. We show that this mutation impairs CCC complex assembly by disrupting a conserved interaction surface required for CCDC22-COMMD4 binding. We also review previously described cases and identify that CCDC22 p.P172R has a similar attenuated phenotype and impairs complex assembly in a similar fashion as p.E208K. The characterization of these mutations adds to our understanding of the clinical and molecular spectrum of these disorders.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"98"},"PeriodicalIF":2.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186380","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":"Defining three dimensional chromatin structures of pediatric and adolescent B cells using primary B cell and EBV-immortalized B cell reference genomes.","authors":"Kaiyu Jiang, Yao Fu, Jennifer A Kelly, Patrick M Gaffney, Lucy C Holmes, James N Jarvis","doi":"10.1186/s12920-025-02166-9","DOIUrl":"10.1186/s12920-025-02166-9","url":null,"abstract":"<p><strong>Background/purpose: </strong>Knowledge of the 3D genome is essential to elucidate genetic mechanisms driving autoimmune diseases. The 3D genome is distinct for each cell type, and it is uncertain whether cell lines faithfully recapitulate the 3D architecture of primary human cells or whether developmental aspects of the pediatric immune system require use of pediatric samples. We undertook a systematic analysis of B cells and B cell lines to compare 3D genomic features encompassing risk loci for juvenile idiopathic arthritis (JIA), systemic lupus (SLE), and type 1 diabetes (T1D).</p><p><strong>Methods: </strong>We isolated B cells from four healthy individuals, ages 9-17. HiChIP was performed using a CTCF antibody, and CTCF peaks were called within each sample separately. Peaks observed in all four samples were identified. CTCF loops were called within the pediatric samples using three CTCF peak datasets: 1) self-called CTCF consensus peaks called within the pediatric samples, 2) ENCODE's publicly available GM12878 CTCF ChIP-seq peaks, and 3) ENCODE's primary B cell CTCF ChIP-seq peaks from two adult females. Differential looping was assessed within the pediatric samples and each of the three peak datasets.</p><p><strong>Results: </strong>The number of consensus peaks called in the pediatric samples was similar to that identified in ENCODE's GM12878 and primary B cell datasets. We observed < 1% of loops that demonstrated significantly differential looping between peaks called within the pediatric samples themselves and when called using ENCODE GM12878 peaks. Significant looping differences were even fewer when comparing loops of the pediatric called peaks to those of the ENCODE primary B cell peaks. When querying loops found in juvenile idiopathic arthritis, type 1 diabetes, or systemic lupus erythematosus risk haplotypes, we observed significant differences in only 2.2%, 1.0%, and 1.3% loops, respectively, when comparing peaks called within the pediatric samples and ENCODE GM12878 dataset. The differences were even less apparent when comparing loops called with the pediatric vs ENCODE adult primary B cell peak datasets.</p><p><strong>Conclusion: </strong>The 3D chromatin architecture in B cells is similar across pediatric, adult, and EBV-transformed cell lines. This conservation of 3D structure includes regions encompassing autoimmune risk haplotypes. Thus, even for pediatric autoimmune diseases, publicly available adult B cell and cell line datasets may be sufficient for assessing effects exerted in the 3D genomic space.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"97"},"PeriodicalIF":2.1,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12117681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172507","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":"Different mutations in TBL1XR1 lead to diverse phenotypes of neurodevelopmental disorder: two case reports.","authors":"Linlin Wei, Yonghui Yang, Tiejia Jiang, Chaolang Zhang, Cuiying Chen, Mingwei Huang, Nannan Li, Huachun Xiong, Feng Gao","doi":"10.1186/s12920-025-02169-6","DOIUrl":"10.1186/s12920-025-02169-6","url":null,"abstract":"<p><p>The TBL1XR1 gene (Transducin beta-like 1X-linked receptor 1) is responsible for encoding the TBL1XR1 protein, an important component of the NCoR and SMRT corepressor complexes. 48 missense variants of the TBL1XR1 gene have been reported, which are associated with various phenotypes of neurodevelopmental disorders, including West syndrome, Pierpont syndrome, and others. However, given the important role of TBL1XR1 in neurological diseases, it is still necessary to further explore the variation of TBL1XR1. In this study, we present two patients with distinct variants and phenotypes. Patient 1 exhibits global developmental delay, intellectual disability, delayed language development, and seizures. While patient 2 displays mild facial dysmorphism, significant developmental delay, feeding difficulties, and increased muscle tone. Through trio whole-exome sequencing, two novel pathogenic variants in the TBL1XR1 gene were identified: A heterozygous NM_024665.6:c.940G > T (p.Val314Phe) variant in patient 1 and a heterozygous NM_024665.6:c.1387G > T (p.Asp463Tyr) in patient 2. Discovery of these two novel variant sites expands the mutation spectrum associated with the TBL1XR1 gene.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"96"},"PeriodicalIF":2.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12117794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144156195","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":"Comprehensive analysis of a novel LYST mutation in a Tunisian patient with Chediak-Higashi syndrome.","authors":"Yessine Amri, Saoussen Chouchene, Hajer Foddha, Amani Abderahmene, Ikbel Kooli, Adnen Toumi, Kawthar Hadj Khalifa, Rihem Mezrigui, Taieb Messaoud, Mohsen Hassine, Rym Dabboubi","doi":"10.1186/s12920-025-02145-0","DOIUrl":"10.1186/s12920-025-02145-0","url":null,"abstract":"<p><strong>Background: </strong>Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, recurrent infections, bleeding tendencies, and progressive neurological impairment. The syndrome is caused by mutations in the LYST gene, which plays a crucial role in lysosomal trafficking.</p><p><strong>Objective: </strong>This study aims to characterize the molecular basis of CHS in a Tunisian patient by identifying mutations in the LYST gene and analyzing their impact on the protein function, correlating these findings with the patient's clinical presentation.</p><p><strong>Methods: </strong>A comprehensive clinical assessment was conducted on the patient, followed by biochemical, hematological, and microbiological analyses. Additionally, LYST protein levels were quantified in the patient and their parents using an ELISA assay. Genomic DNA was extracted from the patient's blood, and Whole Exome Sequencing (WES) was performed to identify mutations in the LYST gene. The findings were confirmed through Sanger sequencing, and bioinformatic tools were employed to predict the functional consequences of the detected mutations.</p><p><strong>Results: </strong>The patient presented with classical symptoms of CHS, including silver hair, hypopigmented skin, recurrent infections, and neurological decline, with an unusually late onset at 18 years. ELISA results demonstrated significantly reduced LYST levels in the patient (1.8 ng/ml) compared to heterozygous parents (7.8 ng/ml and 8.1 ng/ml) and controls (9.2 ng/ml). Genetic analysis revealed a novel homozygous deletion, c.10269_10275del (p.Gly3424SerfsTer15), in the LYST gene, leading to a frameshift mutation and premature termination of the protein. Bioinformatic analysis demonstrated that this mutation leads to the deletion of five out of sven WD40 repeats in the protein's C-terminal region, which are critical for protein-protein interactions and lysosomal trafficking.</p><p><strong>Conclusion: </strong>The study identifies a novel LYST mutation in a Tunisian patient with CHS, expanding the spectrum of known genetic variants associated with the disease. The findings highlight the importance of genetic screening in populations with high consanguinity and underscore the need for targeted therapies to address the molecular defects in CHS.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"95"},"PeriodicalIF":2.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12117754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144156180","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":"A case of congenital heart defects and familial exudative vitreoretinopathy caused by activation of a cryptic splice donor in NOTCH1.","authors":"Joseph Farris, Camila Dergam-Larson, Madeline Lopour, Kahlen Darr, Lisa A Schimmenti, Brittni A Scruggs, Laura J Lambert, Eric W Klee","doi":"10.1186/s12920-025-02160-1","DOIUrl":"10.1186/s12920-025-02160-1","url":null,"abstract":"<p><strong>Background: </strong>NOTCH1 is associated with two disorders of vascular development, Adams-Oliver Syndrome 5 (AOS5) and aortic valve disease 1 (AOVD1). Here we report a disease-causing variant in NOTCH1 that has a previously undemonstrated effect on splicing. Additionally, we found that the proband has the optic phenotype of familial exudative vitreoretinopathy (FEVR) which has been reported for probands with pathogenic variants in genes in the notch signaling pathway, but never for NOTCH1.</p><p><strong>Case presentation: </strong>The proband presented with a ventricular septal defect, pulmonic stenosis, and ocular findings consistent with familial exudative vitreoretinopathy (FEVR), which NOTCH1 has not been associated with to date. Trio exome sequencing identified a paternally inherited variant of uncertain significance in NOTCH1:c.2153 A > G. We assessed the variant's effect using RT-PCR, finding an increased use of a cryptic donor compared to the control. On this basis, we were able to re-classify this variant as pathogenic.</p><p><strong>Conclusions: </strong>We expand the phenotypic spectrum of NOTCH1 and contribute to the building evidence that variants in NOTCH1 cause a spectrum of disorders of vascular development.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"94"},"PeriodicalIF":2.1,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12105292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148992","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":"RNAcare: integrating clinical data with transcriptomic evidence using rheumatoid arthritis as a case study.","authors":"Mingcan Tang, William Haese-Hill, Fraser Morton, Carl Goodyear, Duncan Porter, Stefan Siebert, Thomas D Otto","doi":"10.1186/s12920-025-02162-z","DOIUrl":"10.1186/s12920-025-02162-z","url":null,"abstract":"<p><strong>Background: </strong>Gene expression analysis is a crucial tool for uncovering the biological mechanisms that underlie differences between patient subgroups, offering insights that can inform clinical decisions. However, despite its potential, gene expression analysis remains challenging for clinicians due to the specialised skills required to access, integrate, and analyse large datasets. Existing tools primarily focus on RNA-Seq data analysis, providing user-friendly interfaces but often falling short in several critical areas: they typically do not integrate clinical data, lack support for patient-specific analyses, and offer limited flexibility in exploring relationships between gene expression and clinical outcomes in disease cohorts. Users, including clinicians with a general knowledge of transcriptomics, however, who may have limited programming experience, are increasingly seeking tools that go beyond traditional analysis. To overcome these issues, computational tools must incorporate advanced techniques, such as machine learning, to better understand how gene expression correlates with patient symptoms of interest.</p><p><strong>Results: </strong>Our RNAcare platform, addresses these limitations by offering an interactive and reproducible solution specifically designed for analysing transcriptomic data from patient samples in a clinical context. This enables researchers to directly integrate gene expression data with clinical features, perform exploratory data analysis, and identify patterns among patients with similar diseases. By enabling users to integrate transcriptomic and clinical data, and customise the target label, the platform facilitates the analysis of the relationships between gene expression and clinical symptoms like pain and fatigue. This allows users to generate hypotheses and illustrative visualisations/reports to support their research. As proof of concept, we use RNAcare to link inflammation-related genes to pain and fatigue in rheumatoid arthritis (RA) and detect signatures in the drug response group, confirming previous findings.</p><p><strong>Conclusion: </strong>We present a novel computational platform allowing the interpretation of clinical and transcriptomics data in real-time. The platform can be used for data generated by the user, such as the patient data presented here or using published datasets. The platform is available at https://rna-care.mvls.gla.ac.uk/ , and its source code is https://github.com/sii-scRNA-Seq/RNAcare/ .</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"93"},"PeriodicalIF":2.1,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096495/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118733","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":"Deep clinical and genetic analysis of 17p13.3 region: 38 pediatric patients diagnosed using next-generation sequencing and literature review.","authors":"Xiaoshan Ji, Qiong Xu, Yulan Lu, Bo Liu, Feifan Xiao, Qi Ni, Suzhen Xu, Renchao Liu, Gang Li, Bingbing Wu, Shuizhen Zhou, Huijun Wang","doi":"10.1186/s12920-025-02155-y","DOIUrl":"10.1186/s12920-025-02155-y","url":null,"abstract":"<p><strong>Background: </strong>Chromosome 17p13.3 is a region of genomic instability associated with different neurodevelopmental diseases. The malformation spectrum of 17p13.3 microdeletions ranges from an isolated lissencephaly sequence to Miller-Dieker syndrome, while 17p13.3 microduplications result in autism, learning disabilities, microcephaly and other brain malformations. This study aims to provide a more comprehensive delineation of the clinical and genetic characteristics associated with 17p13.3 alterations.</p><p><strong>Methods: </strong>We retrospectively analyzed the next-generation sequencing (NGS) data of more than 40 thousand patients from January 2016 to December 2021 and identified 38 pediatric patients with copy-number variations (CNVs) or single-nucleotide variations (SNVs) in 17p13.3 region. Published patients with CNVs in the 17p13.3 region were also collected and we performed a Chi-square test to compare the phenotype spectrum of microdeletions and microduplications.</p><p><strong>Results: </strong>Among the 27 CNV patients, 20 patients with microdeletions and 7 patients with microduplications were found. PAFAH1B1 was the most frequently deleted gene and CRK was the most frequently duplicated gene. Affected genes in 11 SNV patients included PAFAH1B1 and PRPF8. Developmental delay was the most common abnormality detected in the 38 patients (29/38, 76.3%). Of note, Case 10 presented omphalocele and Case 23 presented scoliosis, webbed neck and bone cyst, all of which were unusual variant phenotypes in this region. The Chi-square test revealed that epilepsy, lissencephaly and short stature were statistically significant with microdeletions, while behavioral abnormalities and hand and foot abnormalities were significant with microduplications (p < 0.01).</p><p><strong>Conclusions: </strong>While PAFAH1B1, YWHAE and CRK are associated with major phenotypes of 17p13.3, RTN4RL1 may be involved in white matter changes and HIC1 might contribute to the occurrence of omphalocele. This study provided a comprehensive understanding of genetic information and phenotype spectrum of the 17p13.3 region.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"90"},"PeriodicalIF":2.1,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12090631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101319","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":"N⁶-methyladenosine RNA base modification regulates NKG2D-dependent and cytotoxic genes expression in natural killer cells.","authors":"Raghda A Elsabbagh, Ghada Abdelhady, Doris Urlaub, Mina Sandusky, Ola Khorshid, Mohamed Z Gad, Khaled Abou-Aisha, Carsten Watzl, Mona Rady","doi":"10.1186/s12920-025-02147-y","DOIUrl":"10.1186/s12920-025-02147-y","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer (BC) is the most commonly diagnosed cancer in women. N⁶-methyladenosine (m⁶A) is the most prevalent internal modification in mammalian mRNAs and plays a crucial role in various biological processes. However, its function in Natural killer (NK) cells in BC remains unclear. NK cells are essential for cancer immunosurveillance. This study aims to assess m⁶A levels in transcripts involved in the NKG2D cytotoxicity signaling pathway in NK cells of BC patients compared to controls and find out its impact on mRNA levels. Additionally, it evaluates how deliberately altering m⁶A levels in NK cells affects mRNA and protein expression of NKG2D pathway genes and NK cell functionality.</p><p><strong>Methods: </strong>m⁶A methylation in transcripts of NKG2D-pathway-related genes in BC patients and controls was determined using methylated RNA immunoprecipitation-reverse transcription-PCR (MERIP-RT-PCR). To deliberately alter m⁶A levels in primary cultured human NK cells, the m⁶A demethylases, FTO and ALKBH5, were knocked out using the CRISPR-CAS9 system, and FTO was inhibited using Meclofenamic acid (MA). The impact of m⁶A alteration on corresponding mRNA and protein levels was assessed using RT-qPCR and Western blot analysis or flow cytometry, respectively. Additionally, NK cell functionality was evaluated through degranulation and ⁵¹Cr release cytotoxicity assays.</p><p><strong>Results: </strong>Transcripts of NKG2D, an activating receptor that detects stressed non-self tumour cells, had significantly higher m⁶A levels in the 3' untranslated region (3'UTR) accompanied by a marked reduction in their corresponding mRNA levels in BC patients compared to controls. Conversely, transcripts of ERK2 and PRF1 exhibited significantly lower m⁶A levels escorted with higher mRNA expression in BC patients relative to controls. The mRNA levels of PI3K, PAK1 and GZMH were also significantly elevated in BC patients. Furthermore, artificially increasing transcripts' m⁶A levels via MA in cultured primary NK cells reduced mRNA levels of NKG2D pathway genes and death receptor ligands but did not affect protein expression or NK cell functionality.</p><p><strong>Conclusion: </strong>Transcripts with higher m⁶A levels in the 3'UTR region were less abundant, and vice versa. However, changes in mRNA levels of the target genes didn't impact their corresponding protein levels or NK cell functionality.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"91"},"PeriodicalIF":2.1,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12090489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101070","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":"Association of Calpain-10 gene polymorphisms with Type 2 diabetes mellitus: a case-control study from a tertiary care hospital in Pakistan.","authors":"Humaira Farooqi, Nakhshab Choudhry, Muhammad Nabeel Saddique, Samina Qamar, Rehma Dar, Salman Kazmi, Aamir Jamal Gondal, Nighat Yasmin, Hammad Javaid, Ursula Abu Nahla","doi":"10.1186/s12920-025-02152-1","DOIUrl":"10.1186/s12920-025-02152-1","url":null,"abstract":"<p><strong>Introduction: </strong>Type 2 diabetes mellitus (T2DM) is a major public health challenge, with rising prevalence in low- and middle-income countries such as Pakistan. Genetic susceptibility plays a critical role in its pathogenesis. Calpain-10 (CAPN-10), a gene implicated in insulin secretion and glucose homeostasis, has been studied for its potential involvement in T2DM. This study aimed to evaluate the association of CAPN-10 polymorphisms-SNP44 (rs2975760) and SNP43 (rs3792267)-with T2DM in a Pakistani cohort.</p><p><strong>Methods: </strong>This case-control study included 164 T2DM patients and 164 healthy controls (mean age ± SD: 57.2 ± 8.2 vs. 53.9 ± 6.3 years; age range: 41-82 years). The male-to-female ratio was 41.4-58.6% in cases and 37.2-62.8% in controls. Participants were enrolled using non-probability convenience sampling. Genomic DNA was extracted from whole blood, and genotyping of CAPN-10 SNPs (rs3792267 and rs2975760) was performed using PCR-RFLP. Genotype distributions were assessed for Hardy-Weinberg equilibrium. Associations with T2DM were evaluated using odds ratios (ORs) and 95% confidence intervals (CIs) via logistic regression. Chi-square tests were used for categorical comparisons, with p < 0.05 considered statistically significant. Analyses were conducted using SPSS version 26.</p><p><strong>Results: </strong>For SNP44, no significant association with T2DM was observed under dominant, heterozygous, or recessive models after Bonferroni correction (adjusted p > 0.05). Similarly, SNP43 showed no statistically significant association with T2DM in either dominant or recessive models (adjusted p > 0.05), although the AA genotype appeared more frequently among T2DM cases. These findings suggest no significant role of CAPN-10 polymorphisms in T2DM susceptibility in this population.</p><p><strong>Conclusion: </strong>CAPN-10 polymorphisms SNP44 and SNP43 showed no significant association with T2DM in this population, suggesting limited predictive value for disease susceptibility.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"89"},"PeriodicalIF":2.1,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101253","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}