Search Results (84)

ANKRD26-related thrombocytopenia (ANKRD26-RT) is characterized by lifelong mild to moderate thrombocytopenia. Patients suffer from an increased susceptibility to acute or chronic myeloid leukemia, myelodysplastic syndrome, or chronic lymphocytic leukemia. We described here a patient with inherited thrombocytopenia initially misdiagnosed as immune thrombocytopenic purpura. A chromosomal deletion involving the ANKRD26 gene was identified. Gene and protein expression analyses suggest an alternative pathogenic mechanism of altered megakaryopoiesis: the synthesis of a chimeric protein with aberrant expression due to the unregulated action of a promoter from a gene located upstream of ANKRD26. This study highlights the importance of advanced genetic testing and functional analysis of patients’ primary cells in the case of the detection of previously unrecognized structural variants in order to understand pathogenic mechanisms. These investigations provided a definitive diagnosis for the patient and facilitated the development of a tailored clinical management strategy, especially concerning the potential for myeloid transformation. Full article

Background and Clinical Significance: Inherited thrombocytopenia (IT) is a heterogeneous group of disorders caused by mutations in over 45 genes. Among these, ANKRD26-related thrombocytopenia (ANKRD26-RT) accounts for a notable subset and is associated with variable bleeding tendencies and an increased risk of myeloid malignancies. However, the extent of this oncogenic risk appears to vary between specific gene variants. Understanding the genotype–phenotype relationship is essential for patient counseling and management. This report presents a multigenerational family carrying the rare c.−118C > G variant in the 5′ untranslated region of ANKRD26, contributing to the discussion on variant-specific cancer predisposition. Case Presentation: Two sisters aged 57 and 60 presented with lifelong bleeding diathesis and moderate thrombocytopenia. Their symptoms included easy bruising, menorrhagia, and excessive postoperative bleeding. Genetic testing confirmed heterozygosity for the ANKRD26 c.−118C > G variant. Bone marrow analysis revealed abnormal megakaryopoiesis without evidence of dysplasia or somatic mutations. One sister underwent major surgery without complications when managed with prophylactic hemostatic therapy. Their family history included multiple female relatives with similar symptoms, although formal testing was limited. Notably, none of the affected individuals developed hematologic malignancy, and only one developed esophageal cancer, with no current evidence linking this variant to solid tumors. Conclusions: This case underscores the importance of distinguishing between ANKRD26 variants when assessing malignancy risk. While ANKRD26-RT is associated with myeloid neoplasms, the c.−118C > G variant may confer a lower oncogenic potential. Variant-specific risk stratification and genetic counseling are crucial for optimizing surveillance and avoiding unnecessary interventions in low-risk individuals. Full article

This study aimed to identify genetic variants using a customized next-generation sequencing (NGS) panel for pediatric myelodysplastic syndrome (pMDS) and to explore their associations with cytogenetic and clinical characteristics. Cytogenetic analyses were conducted using G-banding and fluorescence in situ hybridization. NGS was performed with the Ion Torrent Personal Genome Machine for the following genes: GATA2, RUNX1, CEBPA, ANKRD26, ETV6, SAMD9, SAMD9L, PTPN11, NRAS, SETBP1, DDX41, TP53, FLT3, SRP72, and JAK3. Analyses were performed with Ion Reporter 5.20.8.0 software. Genetic variants were classified using the dbSNP, 1000 Genomes, COSMIC, and Varsome databases. We analyzed 25 cases of pMDS; 15 presented abnormal karyotypes, and 19 showed genetic variants. Among the 29 variants identified across 12/15 genes, 27% were pathogenic and 14% were likely pathogenic, with NRAS and GATA2 most frequently associated with disease progression. A new somatic variant of uncertain significance in SETBP1 was detected in seven patients showing heterogeneous clinical outcomes. Genetic variants were found in 7/10 patients with normal karyotypes, indicating that submicroscopic alterations can shed light on disease biology. Our results highlight the critical role of a targeted NGS panel in identifying molecular alterations associated with pMDS pathogenesis, thereby enhancing diagnostic precision, prognosis, and aiding in treatment selection. Full article

Weight traits serve as key economic indicators for assessing growth performance and commercial quality in the mud crab Scylla paramamosain, yet the genetic basis of these traits remains poorly characterized. Here, we performed whole-genome resequencing on 323 individuals and conducted genome-wide association studies (GWAS) on five weight-related traits: (1) body-related traits, including body weight (BW), trunk weight (TruW), and weight excluding chelae (WEC); (2) appendage-related traits, containing appendage weight (AppW) and cheliped weight (CheW). Significantly associated SNPs were primarily enriched on chromosomes 15, 22, 25, and 36. For body-related traits, we identified 45 shared candidate SNPs and 175 common candidate genes; appendage-related traits revealed 71 shared candidate SNPs, and 229 common genes were identified; and across all five traits, there were 9 shared candidate SNPs and 49 common genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that shared functional terms/pathways among the five traits were mainly related to metabolism, development, and immunity. Body-related traits exhibited more unique GO terms and KEGG pathways associated with metabolism and immunity, whereas appendage-related traits showed some unique GO terms and KEGG pathways involved in development and morphogenesis. Among the candidate genes, we identified multiple genes associated with growth and development, metabolism, and immune responses. For example, the CCHa1R gene, common to carapace-related traits, is linked to feeding; the DCX-EMA gene, which is common to appendage-related traits, is connected to movement, and the MSTO1 gene is pertinent to muscle development. Among the candidate genes shared by all five traits, there are a series of genes concerning growth and development (such as NVD, CYP307A1, FGF1, NF2, ANKRD52) and immune responses (RGS10). These findings advance our understanding of the genetic architecture underlying decapod crustacean growth and provide valuable insights for optimizing sustainable breeding strategies in S. paramamosain. Full article

This study aimed to investigate the spatial heterogeneity of molecular signature in the muscle of juvenile dermatomyositis (JDM) patients before and after treatment. Unsupervised reference-free deconvolution of spatial transcriptomics and standardized morphometry were performed in two JDM muscle biopsies with different clinical severity at disease onset and compared to healthy muscle. Identified signatures were scored in two additional JDM muscle biopsies from the same patient before and after remission. Disappearance of the normal muscle signature mostly corresponding to mitochondrial biology was observed in JDM. Three pathological transcriptomic signatures were isolated, related to “myofibrillar stress”, “muscle remodeling” and “interferon signaling” signatures. The “myofibrillar stress signature” was prominent in the most severe biopsy while the “muscle remodeling” signature was mostly present in the biopsy from the patient with good outcome. These signatures unveiled genes not previously associated with JDM including ANKRD1 and FSLT1 for “myofibrillar stress” and “muscle remodeling” signatures, respectively. Post-treatment analysis of muscle after two years remission showed a persistence of pathological signatures. This pilot study of JDM muscle identified spatially distributed pathological signatures that persist after remission. This work paves the way for a better understanding of the pathophysiology in affected muscle and the identification of biomarkers that predict relapse. Full article

Background/Objectives: Finding single nucleotide polymorphisms (SNPs) and candidate genes that influence the expression of key traits is essential for genomic selection and helps improve the efficiency of poultry production. Here, we aimed to conduct a genome-wide association study (GWAS) for egg production traits in an F₂ resource population of chickens (Gallus gallus). Methods: The examined F₂ population was produced by crossing two divergently selected breeds with contrasting phenotypes for egg performance traits, namely Russian White (of higher egg production) and Cornish White (of lower egg production). Sampled birds (n = 142) were genotyped using the Illumina Chicken 60K SNP iSelect BeadChip. Results: In the course of the GWAS analysis, we were able to clarify significant associations with phenotypic traits of interest and economic value by using 47,432 SNPs after the genotype dataset was filtered. At the threshold p < 1.06 × 10⁻⁶, we found 23 prioritized candidate genes (PCGs) associated with egg weight at the age of 42–52 weeks (FGF14, GCK), duration of egg laying (CNTN4), egg laying cycle (SAMD12) and egg laying interval (PHF5A, AKR1B1, CALD1, ATP7B, PIK3R4, PTK2, PRKCE, FAT1, PCM1, CC2D2A, BMS1, SEMA6D, CDH13, SLIT3, ATP10B, ISCU, LRRC75A, LETM2, ANKRD24). Moreover, two SNPs were co-localized within the FGF14 gene. Conclusions: Based on our GWAS findings, the revealed SNPs and candidate genes can be used as genetic markers for egg weight and other performance characteristics in chickens to attain genetic enhancement in production and for further genomic selection. Full article

Ankyrin repeat domain 1 (Ankrd1), a transcriptional target of Yes-associated protein (YAP), is linked to cardiomyopathy. However, its role in cancer, particularly in clear cell renal cell carcinoma (ccRCC), remains vague. In this study, we examined the expression, regulation, and function of Ankrd1 in ccRCC. High Ankrd1 expression was related to poor prognosis in patients with ccRCC in The Cancer Genome Atlas cohort. Ankrd1 expression was regulated by YAP in all ccRCC cell lines examined and also by ERK5 in a subset of ccRCC cell lines. Moreover, silencing of Ankrd1 in ccRCC cell lines resulted in decreased cell motility, whereas its overexpression increased the cell motility. Ankrd1 colocalized with F-actin in lamellipodia upon phorbol ester stimulation. Ankrd1 silencing resulted in alterations in the shape of RCC cells and caused a decrease in lamellipodia formation. Ankrd1 also colocalized with talin-1 in lamellipodia. Ankrd1 depletion repressed talin-1-mediated activation of the integrin pathway. Immunohistochemical examination of surgical specimens revealed high expression of Ankrd1 in metastatic RCC tissues compared with that in primary RCC tissues from the same patients. Collectively, these findings suggest that Ankrd1 plays a critical role in the motility of ccRCC cells through lamellipodia formation. Full article

Background/Objectives: Human-driven selection has shaped modern horse breeds into highly specialized athletes, particularly in racing. Arabian horses, renowned for their endurance, provide an excellent model for studying molecular adaptations to exercise. This study aimed to identify genes commonly influenced by physical exertion in the gluteus medius muscle and whole blood of Arabian horses during their first year of race training. Methods: RNA sequencing of sixteen pure-breed Arabian horses was used to analyze transcriptomic changes at three key training stages. Differentially expressed genes (DEGs) were identified to explore their role in endurance and metabolic adaptation. Results: Seven genes—RCHY1, PIH1D1, IVD, FABP3, ANKRD2, USP13, and CRYAB—were consistently deregulated across tissues and training periods. These genes are involved in muscle remodeling, metabolism, oxidative stress response, and protein turnover. ANKRD2 was associated with mechanosensing and muscle adaptation, FABP3 with fatty acid metabolism, and USP13 with ubiquitination-related pathways crucial for muscle recovery and energy regulation. The transcriptomic overlap between muscle and blood suggests potential systemic biomarkers for athletic performance and endurance. Conclusions: Our findings highlight the importance of multi-tissue transcriptomic profiling in understanding exercise-induced molecular adaptations. The identified genes warrant further investigation as potential molecular markers for monitoring training progression and athletic potential in endurance horses. This study contributes to the growing field of equine sports genetics and may offer translational insights into human sports performance. Full article

Ankrd2, a mechanoresponsive protein primarily studied in muscle physiology, is emerging as a player in cancer progression. This study investigates the functional role of Ankrd2 in osteosarcoma cells, revealing its critical involvement in cell proliferation and response to chemotherapeutic drugs. We showed that Ankrd2 knockdown impairs the activation of PI3K/Akt and ERK1/2 pathways, reduces levels of cell cycle regulators including cyclin D1 and cyclin B, and counteracts the expression of nuclear lamin A and lamin B, disrupting nuclear morphology and DNA integrity. Strikingly, the loss of Ankrd2 enhances the sensitivity of osteosarcoma cells to doxorubicin and cisplatin, highlighting Ankrd2 potential as a therapeutic target to improve chemotherapeutic efficacy. Defining a novel mechanistic role for Ankrd2 in promoting tumor progression, we propose that Ankrd2 reduction could be exploited as an adjuvant strategy to enhance the efficacy of chemotherapy, offering new therapeutic opportunities for OS treatment. Full article

Background: KBG syndrome is a multisystem developmental disorder characterized by macrodontia of the upper permanent incisors, distinctive facial features, a short stature, developmental delay, variable intellectual disability, and behavioral issues. Heterozygous chromosomal deletion encompassing the partial or entire ANKRD11 gene, as well as the loss of function mutations, result in haploinsufficiency of the gene, leading to KBG syndrome. This indicates that precise levels of ANKRD11 transcripts or protein are essential for human development. Clinical report: Here, we report three individuals who present with clinical features of KBG syndrome. These individuals carry microdeletions encompassing only the non-coding exon 1 of ANKRD11 and its upstream region. Our molecular analysis showed that this deletion leads to reduction in the ANKRD11 transcript and global transcriptome alterations similar to those seen in KBG syndrome patients. Conclusions: We concluded that microdeletions involving non-coding exon 1 of ANKRD11 lead to KBG syndrome. Our study suggests the utility of transcriptome analysis in aiding the interpretation of novel copy number variants in the non-coding genomic region of ANKRD11. Full article

Mutations in the genes ANKRD26, RUNX1, and ETV6 cause three clinically overlapping thrombocytopenias characterized by a predisposition to hematological neoplasms. The ANKRD26 gene, which encodes a protein involved in protein-protein interactions, is downregulated by RUNX1 during megakaryopoiesis. Mutations in 5′UTR of ANKRD26, leading to ANKRD26-RT, disrupt this regulation, resulting in the persistent expression of ANKRD26, which leads to impaired platelet biogenesis and an increased risk of leukemia. Although ANKRD26 and ETV6 exhibit inverse expression during megakaryopoiesis, ETV6 does not regulate the ANKRD26 expression. Hypothesizing an interplay between ETV6 and ANKRD26 through in vitro studies, we explored the interactions between the two proteins. In this study, we found that ANKRD26 interacts with ETV6 and retains it in the cytoplasm, phenocopying ETV6-RT-related mutants. We found that GPS2, a component of the NCoR complex, binds both ANKRD26 and ETV6, mediating this interaction. Furthermore, ANKRD26 overexpression deregulates ETV6 transcriptional repression, supporting a common pathogenic mechanism underlying ANKRD26-RT, FPD/AML, and ETV6-RT. Our results unveil a novel ANKRD26-ETV6-GPS2 axis, providing new insights to investigate the molecular mechanism underlying thrombocytopenias with a predisposition to myeloid neoplasms that need to be further characterized. Full article

A number of standard molecules are used for the molecular and histological characterization of lymphatic endothelial cells (LECs), including lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), Podoplanin (D2-40), VEGFR3, Prospero homeobox protein 1 (PROX1), and CD31. The number of molecules whose mutations cause lymphatic malformations or primary congenital lymphedema is considerable, but the majority of these diseases have not yet been characterized at the molecular level. Therefore, there is still considerable scope for molecular and functional studies of the lymphatic vasculature. Using RNASeq, we have previously characterized lymphatic endothelial cells (LECs) under normoxic and hypoxic conditions. We used this information to compare it with immunohistochemical data. We carried out some of the immunohistology ourselves, and systematically studied the Human Protein Atlas, a cell and tissue database based in Sweden. Here we describe molecules that are expressed at RNA and protein levels in LECs, hoping to stimulate future functional studies of these molecules. Full article

Background: Colorectal cancer (CRC) displays a complex pattern of inheritance. It is postulated that much of the missing heritability of CRC is enriched in high-impact rare alleles, which might play a crucial role in the etiology and susceptibility of CRC. Methods: In this study, an exome-wide association analysis was performed in 146 patients with high-risk CRC in the Middle East and 1395 healthy controls. The aim was to identify rare germline variants in coding regions and their splicing sites associated with high-risk CRC in the Middle Eastern population. Results: Rare inactivating variants (RIVs) in APC had the strongest association with high-risk CRC (6/146 in cases vs. 1/1395 in controls, OR = 59.7, p = 5.13 × 10⁻¹²), whereas RIVs in RIMS1, an RAS superfamily member, were significantly associated with high-risk CRC (5/146 case vs. 2/1395 controls, OR = 24.7, p = 2.03 × 10⁻⁸). Rare damaging variants in 17 genes were associated with high-risk CRC at the exome-wide threshold (p < 2.5 × 10⁻⁶). Based on the sequence kernel association test, nonsynonymous variants in six genes (TNXB, TAP2, GPSM3, ADGRG4, TMEM229A, and ANKRD33B) had a significant association with high-risk CRC. RIVs in APC—the most common high-penetrance genetic factor—were associated with patients with high-risk CRC in the Middle East. Individuals who inherited APC RIVs had an approximate 60-fold increased risk of developing CRC and were likely to develop the disease earlier. Conclusions: We identified new potential CRC predisposition variants in other genes that could play a role in CRC inheritance. However, large collaborative studies are needed to confirm the association of these variants with high-risk CRC. These results provide information for counseling patients with high-risk CRC and their families in our population. Full article

Depressive disorder contributes to the initiation and prognosis of patients with cancer, but the interaction between cancer and depressive disorder remains unclear. We generated a gastric adenocarcinoma patient-derived xenograft mice model, treated with chronic unpredictable mild stimulation. Based on the RNA-sequence from the mouse model, patient data from TCGA, and MDD-related (major depressive disorder) genes from the GEO database, 56 hub genes were identified by the intersection of differential expression genes from the three datasets. Molecular subtypes and a prognostic signature were generated based on the 56 genes. A depressive mouse model was constructed to test the key changes in the signatures. The signature was constructed based on the NDUFA4L2, ANKRD45, and AQP3 genes. Patients with high risk-score had a worse overall survival than the patients with low scores, consistent with the results from the two GEO cohorts. The comprehensive results showed that a higher risk-score was correlated with higher levels of tumor immune exclusion, higher infiltration of M0 macrophages, M2 macrophages, and neutrophils, higher angiogenetic activities, and more enriched epithelial–mesenchymal transition signaling pathways. A higher risk score was correlated to a higher MDD score, elevated MDD-related cytokines, and the dysfunction of neurogenesis-related genes, and parts of these changes showed similar trends in the animal model. With the Genomics of Drug Sensitivity in Cancer database, we found that the gastric adenocarcinoma patients with high risk-score may be sensitive to Pazopanib, XMD8.85, Midostaurin, HG.6.64.1, Elesclomol, Linifanib, AP.24534, Roscovitine, Cytarabine, and Axitinib. The gene signature consisting of the NDUFA4L2, ANKRD45, and AQP3 genes is a promising biomarker to distinguish the prognosis, the molecular and immune characteristics, the depressive risk, and the therapy candidates for gastric adenocarcinoma patients. Full article

Early detection and surgical excision of tumors have helped improve the survival rate of patients with breast cancer. However, patients with metastatic cancer typically have a poor prognosis. In this study, we propose that ANKRD1 promotes metastasis of breast cancer. ANKRD1 was found to be highly expressed in the MDA-MB-231 and MDA-LM-2 highly metastatic breast cancer cell lines compared to the non-metastatic breast cancer cell lines (MCF-7, ZR-75-30, T47D) and normal breast cancer cells (MCF-10A). Furthermore, high-grade tumors showed increased levels of ANKRD1 compared to low-grade tumors. Both in vitro and in vivo functional studies demonstrated the essential role of ANKRD1 in cancer cell migration and invasion. The previous studies have suggested a significant role of NF-κB and MAGE-A6 in breast cancer metastasis, but the upstream regulators of this axis are not well characterized. Our study suggests that ANKRD1 promotes metastasis of breast cancer by activating NF-κB as well as MAGE-A6 signaling. Our findings show that ANKRD1 is a potential therapeutic target and a diagnostic marker for breast cancer metastasis. Full article