Genes

14 pages, 2514 KiB

Open AccessArticle

The Transcriptional Coactivator DEAD/H Box 5 (DDX5) Gene Is a Target of the Transcription Factor E2F1 Deregulated from the Tumor Suppressor pRB

by Rinka Nakajima, Yaxuan Zhou, Mashiro Shirasawa, Mariana Fikriyanti, Ritsuko Iwanaga, Andrew P. Bradford, Kenta Kurayoshi, Keigo Araki and Kiyoshi Ohtani

Genes 2025, 16(8), 929; https://doi.org/10.3390/genes16080929 (registering DOI) - 1 Aug 2025

Abstract

Background: DEAD/H box 5 (DDX5) serves as a transcriptional coactivator for several transcription factors including E2F1, the primary target of the tumor suppressor pRB. E2F1 physiologically activated by growth stimulation activates growth-related genes and promotes cell proliferation. In contrast, upon loss of pRB [...] Read more.

Background: DEAD/H box 5 (DDX5) serves as a transcriptional coactivator for several transcription factors including E2F1, the primary target of the tumor suppressor pRB. E2F1 physiologically activated by growth stimulation activates growth-related genes and promotes cell proliferation. In contrast, upon loss of pRB function due to oncogenic changes, E2F1 is activated out of restraint by pRB (deregulated E2F1) and stimulates tumor suppressor genes such as ARF, which activates the tumor suppressor p53, to suppress tumorigenesis. We have recently reported that DDX5 augments deregulated E2F1 activity to induce tumor suppressor gene expression and apoptosis. During the analyses, we noted that over-expression of E2F1 increased DDX5 expression, suggesting a feed forward loop in E2F1 activation through DDX5. Objective: We thus examined whether the DDX5 gene is a target of deregulated E2F1. Method: For this purpose, we performed promoter analysis and ChIP assay. Result: The DDX5 promoter did not possess typical E2F binding consensus but contained several GC repeats observed in deregulated E2F1 targets. Insertion of point mutations in these GC repeats decreased responsiveness to deregulated E2F1 induced by over-expression of E2F1, but scarcely affected responsiveness to growth stimulation. ChIP assays showed that deregulated E2F1 induced by over-expression of E2F1 or expression of E1a, which binds pRB and releases E2F1, bound to the DDX5 gene, while physiological E2F1 induced by growth stimulation did not. Conclusions: These results suggest that the DDX5 gene is a target of deregulated E2F1, generating a feed forward loop mediating tumor suppressive E2F1 activity. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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20 pages, 1318 KiB

Open AccessReview

A Genetically-Informed Network Model of Myelodysplastic Syndrome: From Splicing Aberrations to Therapeutic Vulnerabilities

by Sanghyeon Yu, Junghyun Kim and Man S. Kim

Genes 2025, 16(8), 928; https://doi.org/10.3390/genes16080928 (registering DOI) - 1 Aug 2025

Abstract

Background/Objectives: Myelodysplastic syndrome (MDS) is a heterogeneous clonal hematopoietic disorder characterized by ineffective hematopoiesis and leukemic transformation risk. Current therapies show limited efficacy, with ~50% of patients failing hypomethylating agents. This review aims to synthesize recent discoveries through an integrated network model and [...] Read more.

Background/Objectives: Myelodysplastic syndrome (MDS) is a heterogeneous clonal hematopoietic disorder characterized by ineffective hematopoiesis and leukemic transformation risk. Current therapies show limited efficacy, with ~50% of patients failing hypomethylating agents. This review aims to synthesize recent discoveries through an integrated network model and examine translation into precision therapeutic approaches. Methods: We reviewed breakthrough discoveries from the past three years, analyzing single-cell multi-omics technologies, epitranscriptomics, stem cell architecture analysis, and precision medicine approaches. We examined cell-type-specific splicing aberrations, distinct stem cell architectures, epitranscriptomic modifications, and microenvironmental alterations in MDS pathogenesis. Results: Four interconnected mechanisms drive MDS: genetic alterations (splicing factor mutations), aberrant stem cell architecture (CMP-pattern vs. GMP-pattern), epitranscriptomic dysregulation involving pseudouridine-modified tRNA-derived fragments, and microenvironmental changes. Splicing aberrations show cell-type specificity, with SF3B1 mutations preferentially affecting erythroid lineages. Stem cell architectures predict therapeutic responses, with CMP-pattern MDS achieving superior venetoclax response rates (>70%) versus GMP-pattern MDS (<30%). Epitranscriptomic alterations provide independent prognostic information, while microenvironmental changes mediate treatment resistance. Conclusions: These advances represent a paradigm shift toward personalized MDS medicine, moving from single-biomarker to comprehensive molecular profiling guiding multi-target strategies. While challenges remain in standardizing molecular profiling and developing clinical decision algorithms, this systems-level understanding provides a foundation for precision oncology implementation and overcoming current therapeutic limitations. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

11 pages, 1707 KiB

Open AccessArticle

Genetic Variant of the Canine FGF5 Gene for the Hair Length Trait in the Akita: Utility for Hair Coat Variations and Welfare in Conservation Breeding

by Shinichiro Maki, Md Shafiqul Islam, Norio Kansaku, Nanami Arakawa, Akira Yabuki, Tofazzal Md Rakib, Abdullah Al Faruq and Osamu Yamato

Genes 2025, 16(8), 927; https://doi.org/10.3390/genes16080927 (registering DOI) - 1 Aug 2025

Abstract

Background/Objectives: Variations in hair length are observed in many dog breeds, as determined by the canine FGF5 gene. Long-haired Akitas, which are disqualified under breeding standards of Akitas, are sometimes born to short-haired parents and may have been subjected to treatments compromising [...] Read more.

Background/Objectives: Variations in hair length are observed in many dog breeds, as determined by the canine FGF5 gene. Long-haired Akitas, which are disqualified under breeding standards of Akitas, are sometimes born to short-haired parents and may have been subjected to treatments compromising animal welfare. Here, we aimed to identify an FGF5 variant associated with hair coat variations in Akitas in Japan, and to assess how welfare of this breed can be improved by carefully planned breeding. Methods: DNA samples were obtained from 60 Akitas in 2021 (modern Akitas) and 73 Akitas in the 1970s and the 1980s (classic Akitas). Sanger sequencing was performed on all exons and exon–intron junctions of the FGF5 gene to determine the causative variant of long hair in Akitas. A real-time PCR assay was developed to genotype FGF5:c.578C>T in modern and classic Akitas. Using 54 dogs from modern Akitas, scores (1 to 10) of hair length were compared among the three genotypes (C/C, C/T, and T/T). Results: Sanger sequencing revealed that the canine FGF5:c.578C>T variant was associated with long hair in Akitas in Japan. Genotyping revealed that the frequency of the mutant T allele was 0.350 in modern Akitas, which was significantly higher (p < 0.001) than in classic Akitas (0.212). The three genotypes were not in Hardy–Weinberg equilibrium (HWE) in modern Akitas but were in HWE in classic Akitas. There were significant differences in hair length scores among the three genotypes (p < 0.001) and between the C/C and C/T genotypes (p < 0.005). There was no significant difference in the scores between male and female dogs. Conclusions: This study revealed that a causative variant that determines the long hair trait of Akitas in Japan was the FGF5:c.578C>T variant, which was inherited in an incompletely dominant manner. Akita dog breeders were more likely to select heterozygous C/T dogs based on the appearance of the hair coat for breeding dogs with an ideal fluffy hair coat. This might result in a high mutant T allele frequency and the production of undesired long-haired Akitas with T/T, which may create welfare problems. Genetic testing for this variant is necessary to improve welfare and conserve the Akita breed. Full article

(This article belongs to the Special Issue Genetics in Canines: From Evolution to Conservation)

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11 pages, 1419 KiB

Open AccessArticle

Genetic Evidence of Yersinia pestis from the First Pandemic

by Swamy R. Adapa, Karen Hendrix, Aditya Upadhyay, Subhajeet Dutta, Andrea Vianello, Gregory O’Corry-Crowe, Jorge Monroy, Tatiana Ferrer, Elizabeth Remily-Wood, Gloria C. Ferreira, Michael Decker, Robert H. Tykot, Sucheta Tripathy and Rays H. Y. Jiang

Genes 2025, 16(8), 926; https://doi.org/10.3390/genes16080926 (registering DOI) - 31 Jul 2025

Abstract

Background/Objectives: The Plague of Justinian marked the beginning of the First Pandemic (541–750 CE), yet no genomic evidence of Yersinia pestis has previously been recovered from the Eastern Mediterranean, where the outbreak was first recorded. This study aimed to determine whether Y. pestis [...] Read more.

Background/Objectives: The Plague of Justinian marked the beginning of the First Pandemic (541–750 CE), yet no genomic evidence of Yersinia pestis has previously been recovered from the Eastern Mediterranean, where the outbreak was first recorded. This study aimed to determine whether Y. pestis was present in a mid-6th to early 7th century mass grave in Jerash, Jordan, and to characterize its genome within the broader context of First Pandemic strains. Methods: We analyzed samples from multiple individuals recovered from the Jerash mass grave. Initial screening for potential pathogen presence was conducted using proteomics. Select samples were subjected to ancient DNA extraction and whole genome sequencing. Comparative genomic and phylogenetic analyses were conducted to assess strain identity and evolutionary placement. Results: Genomic sequencing recovered Y. pestis DNA from five individuals, revealing highly similar genomes. All strains clustered tightly with other First Pandemic lineages but were notably recovered from a region geographically close to the pandemic’s historical epicenter for the first time. The near-identical genomes across diverse individuals suggest an outbreak of a single circulating lineage at the time of this outbreak. Conclusions: This study provides the first genomic evidence of Y. pestis in the Eastern Mediterranean during the First Pandemic, linking archaeological findings with pathogen genomics near the origin point of the Plague of Justinian. Summary Sentence: Genomic evidence links Y. pestis to the First Pandemic in an ancient city. Full article

(This article belongs to the Section Microbial Genetics and Genomics)

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14 pages, 1096 KiB

Open AccessArticle

Unveiling the Spectrum: Clinical and Molecular Insights from a Spanish Pediatric Cohort with Hypermobility Disorders and Ehlers-Danlos Syndrome

by David Foz Felipe, Dídac Casas-Alba, Sara H. Sadok, Marina Toral Fernández, Lourdes Vega-Hanna, Laura Plaza, Asunción Vicente Villa, Judith Armstrong, Encarna Guillén-Navarro and Antonio F. Martínez-Monseny

Genes 2025, 16(8), 925; https://doi.org/10.3390/genes16080925 (registering DOI) - 31 Jul 2025

Abstract

Diagnosing hypermobility disorders and Ehlers-Danlos syndrome (EDS) in children is challenging due to overlapping features with generalized joint hypermobility (GJH) and the lack of biomarkers. Background/Objectives: This study aims to describe the clinical and genetic features of pediatric EDS patients and identify [...] Read more.

Diagnosing hypermobility disorders and Ehlers-Danlos syndrome (EDS) in children is challenging due to overlapping features with generalized joint hypermobility (GJH) and the lack of biomarkers. Background/Objectives: This study aims to describe the clinical and genetic features of pediatric EDS patients and identify key comorbidities and correlations. Methods: This is a single-center observational study of patients under 18 diagnosed with suspicion of EDS (2018–2024) at a tertiary pediatric hospital. Diagnoses were made using 2017 criteria. Results: Forty-one patients (46% female; mean age 11.1 ± 2.8 years) were included. Based on 2017 criteria, 61% had hypermobile EDS (hEDS)/hypermobility spectrum disorder (HSD), 22% classical EDS, 7.3% vascular, and 9.7% other subtypes. Musculoskeletal (90.2%), cutaneous (68.3%), and psychiatric (56.1%) symptoms were most frequent. Significant associations included older age with psychiatric symptoms (p = 0.029), Beighton score with dislocations (p = 0.026), and less atrophic scarring in hEDS (p < 0.008). Genetic testing (73% performed) confirmed pathogenic variants (11 novel) in EDS with a known molecular cause. Conclusions: This study proposes a clinically guided approach and diagnostic algorithm for youth hypermobility, emphasizing precision medicine principles, while highlighting the urgent need for further research to identify hEDS biomarkers. Full article

(This article belongs to the Special Issue Pediatric Rare Diseases: Genetics and Diagnosis)

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13 pages, 668 KiB

Open AccessReview

Optical Genome Mapping: A New Tool for Cytogenomic Analysis

by Brynn Levy, Rachel D. Burnside and Yassmine Akkari

Genes 2025, 16(8), 924; https://doi.org/10.3390/genes16080924 (registering DOI) - 31 Jul 2025

Abstract

Background/Objectives: Optical genome mapping (OGM) has recently emerged as a new technology in the clinical cytogenomics laboratories. This methodology has the ability to detect balanced and unbalanced structural rearrangements using ultra-high molecular weight DNA. This article discusses the uses of this new technology [...] Read more.

Background/Objectives: Optical genome mapping (OGM) has recently emerged as a new technology in the clinical cytogenomics laboratories. This methodology has the ability to detect balanced and unbalanced structural rearrangements using ultra-high molecular weight DNA. This article discusses the uses of this new technology in both constitutional and somatic settings, its advantages as well as opportunity for improvements. Methods: We reviewed the medical and scientific literature for methodology and current clinical uses of OGM. Results: OGM is a recent addition to the methods used in cytogenomics laboratories and can detect a wide range of structural and copy number variations across a plethora of diseases. Conclusions: Clinical cytogenomics is an important laboratory specialty for which various technologies have been validated over the last several decades to improve detection of copy number and structural variations and their association to human disease. OGM has proven to be a powerful tool in the arsenal of clinical laboratories and provides a unified workflow for the detection of chromosomal aberrations across a wide range of diseases. Full article

(This article belongs to the Special Issue Clinical Cytogenetics: Current Advances and Future Perspectives)

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18 pages, 300 KiB

Open AccessReview

Genetic Dissection of Energy Deficiency in Autism Spectrum Disorder

by John Jay Gargus

Genes 2025, 16(8), 923; https://doi.org/10.3390/genes16080923 (registering DOI) - 31 Jul 2025

Abstract

Background/Objectives: An important new consideration when studying autism spectrum disorder (ASD) is the bioenergetic mechanisms underlying the relatively recent rapid evolutionary expansion of the human brain, which pose fundamental risks for mitochondrial dysfunction and calcium signaling abnormalities and their potential role in [...] Read more.

Background/Objectives: An important new consideration when studying autism spectrum disorder (ASD) is the bioenergetic mechanisms underlying the relatively recent rapid evolutionary expansion of the human brain, which pose fundamental risks for mitochondrial dysfunction and calcium signaling abnormalities and their potential role in ASD, as recently highlighted by insights from the BTBR mouse model of ASD. The rapid brain expansion taking place as Homo sapiens evolved, particularly in the parietal lobe, led to increased energy demands, making the brain vulnerable to such metabolic disruptions as are seen in ASD. Methods: Mitochondrial dysfunction in ASD is characterized by impaired oxidative phosphorylation, elevated lactate and alanine levels, carnitine deficiency, abnormal reactive oxygen species (ROS), and altered calcium homeostasis. These dysfunctions are primarily functional, rather than being due to mitochondrial DNA mutations. Calcium signaling plays a crucial role in neuronal ATP production, with disruptions in inositol 1,4,5-trisphosphate receptor (ITPR)-mediated endoplasmic reticulum (ER) calcium release being observed in ASD patient-derived cells. Results: This impaired signaling affects the ER–mitochondrial calcium axis, leading to mitochondrial energy deficiency, particularly in high-energy regions of the developing brain. The BTBR mouse model, with its unique Itpr3 gene mutation, exhibits core autism-like behaviors and metabolic syndromes, providing valuable insights into ASD pathophysiology. Conclusions: Various interventions have been tested in BTBR mice, as in ASD, but none have directly targeted the Itpr3 mutation or its calcium signaling pathway. This review presents current genetic, biochemical, and neurological findings in ASD and its model systems, highlighting the need for further research into metabolic resilience and calcium signaling as potential diagnostic and therapeutic targets for ASD. Full article

(This article belongs to the Section Neurogenomics)

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18 pages, 1580 KiB

Open AccessArticle

Metformin Reduces Oxidative Damage in RNASEH2-Mutant Aicardi-Goutières Cells

by Francesca Dragoni, Jessica Garau, Bartolo Rizzo, Simona Orcesi, Costanza Varesio, Rosalinda Di Gerlando, Matteo Bordoni, Eveljn Scarian, Cristina Cereda, Orietta Pansarasa and Stella Gagliardi

Genes 2025, 16(8), 922; https://doi.org/10.3390/genes16080922 (registering DOI) - 30 Jul 2025

Abstract

Background: Aicardi-Goutières Syndrome (AGS) is a rare neuroinflammatory condition characterized by early-onset symptoms that extend outside the nervous system. Due to the rarity of the disease, the pathogenesis is not well understood, and its diagnosis and treatment remain elusive. We recently demonstrated mitochondrial [...] Read more.

Background: Aicardi-Goutières Syndrome (AGS) is a rare neuroinflammatory condition characterized by early-onset symptoms that extend outside the nervous system. Due to the rarity of the disease, the pathogenesis is not well understood, and its diagnosis and treatment remain elusive. We recently demonstrated mitochondrial abnormalities and increased reactive oxygen species (ROS) levels in lymphoblastoid cell lines (LCLs) derived from RNASEH2B- and RNASEH2A-mutated AGS patients. On this background, we turned our attention to metformin, the first-choice drug for type 2 diabetes, as a possible treatment acting on oxidative stress in RNASEH2-mutant AGS cells. Methods and Results: By means of flow cytometry, we found that metformin treatment significantly decreases ROS production in RNASEH2B- and RNASEH2A-mutated AGS LCLs. Of note, metformin treatment reduces the green JC-1 monomeric signal and, concurrently, increases the red JC-1 signal in both mutated LCLs, accounting for restoration of the mitochondrial membrane potential. Immunofluorescence staining shows a decrease in 8-oxoG levels only in RNASEH2B- mutated AGS LCLs. Finally, the significant upregulation of Forkhead Box O3 (FOXO3), cytochrome C somatic (CYCS), and superoxide dismutase 2 (SOD2) mRNA levels in RNASEH2B-mutated AGS LCLs after metformin treatment points to FOXO3 signaling as a possible mechanism to reduce oxidative stress. Conclusions: In conclusion, even if these pilot results need to be confirmed on a larger cohort, we shed light on metformin treatment as a valid approach to ameliorate oxidative stress-related inflammation in AGS patients. Full article

(This article belongs to the Section Cytogenomics)

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19 pages, 3826 KiB

Open AccessArticle

Circular RNA circ_0001591 Contributes to Melanoma Cell Migration Through AXL and FRA1 Proteins by Targeting miR-20a-3p and miR-34a-5p

by Elisa Orlandi, Elisa De Tomi, Francesca Belpinati, Marta Menegazzi, Macarena Gomez-Lira, Maria Grazia Romanelli and Elisabetta Trabetti

Genes 2025, 16(8), 921; https://doi.org/10.3390/genes16080921 - 30 Jul 2025

Abstract

Background/Objectives: Different risk factors are involved in the initiation and progression of melanoma. In particular, genetic and epigenetic pathways are involved in all stages of melanoma and are exploited in therapeutic approaches. This study investigated the role of circular RNA circ_0001591 in melanoma [...] Read more.

Background/Objectives: Different risk factors are involved in the initiation and progression of melanoma. In particular, genetic and epigenetic pathways are involved in all stages of melanoma and are exploited in therapeutic approaches. This study investigated the role of circular RNA circ_0001591 in melanoma cell migration. Methods: Three different melanoma cell lines were transfected with siRNA targeting circ_0001591 and with mimic or inhibitor molecules for miR-20a-3p and miR-34a-5p. Gene and protein expression levels were analyzed by RT-qPCR and Western blot, respectively. Dual luciferase reporter assays were performed to confirm the direct interaction of miR-20a-3p and miR-34a-5p with circ_0001591, as well as with the 3’UTRs of AXL (for both miRNAs) and FOSL1 (miR-34a-5p only). Wound healing assays were conducted to assess cell migration velocity. Results: The silencing of circ_0001591 significantly reduces the migration ability of melanoma cell lines. This downregulation was associated with an increased expression of miR-20a-3p and miR-34a-5p. Dual luciferase reporter assays confirmed the direct binding of both miRNAs to circ_0001591, supporting its role as a molecular sponge. The same assays also verified that miR-20a-3p directly targets the 3’UTR of AXL, while miR-34a-5p binds the 3’UTRs of both AXL and FOSL1. Western blot analysis showed that the modulation of this axis affects the expression levels of the AXL and FRA1 oncoproteins. Conclusions: Our findings demonstrate that circ_0001591 promotes melanoma migration by sponging miR-20a-3p and miR-34a-5p, thereby indirectly modulating the expression of AXL and FRA1 oncoprotein. Further investigations of this new regulatory network are needed to better understand its role in melanoma progression and to support the development of targeted therapies. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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22 pages, 1013 KiB

Open AccessReview

Genomic Alterations and Microbiota Crosstalk in Hepatic Cancers: The Gut–Liver Axis in Tumorigenesis and Therapy

by Yuanji Fu, Jenny Bonifacio-Mundaca, Christophe Desterke, Íñigo Casafont and Jorge Mata-Garrido

Genes 2025, 16(8), 920; https://doi.org/10.3390/genes16080920 - 30 Jul 2025

Abstract

Background/Objectives: Hepatic cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are major global health concerns due to rising incidence and limited therapeutic success. While traditional risk factors include chronic liver disease and environmental exposures, recent evidence underscores the significance of genetic alterations and [...] Read more.

Background/Objectives: Hepatic cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are major global health concerns due to rising incidence and limited therapeutic success. While traditional risk factors include chronic liver disease and environmental exposures, recent evidence underscores the significance of genetic alterations and gut microbiota in liver cancer development and progression. This review aims to integrate emerging knowledge on the interplay between host genomic changes and gut microbial dynamics in the pathogenesis and treatment of hepatic cancers. Methods: We conducted a comprehensive review of current literature on genetic and epigenetic drivers of HCC and CCA, focusing on commonly mutated genes such as TP53, CTNNB1, TERT, IDH1/2, and FGFR2. In parallel, we evaluated studies addressing the gut–liver axis, including the roles of dysbiosis, microbial metabolites, and immune modulation. Key clinical and preclinical findings were synthesized to explore how host–microbe interactions influence tumorigenesis and therapeutic response. Results: HCC and CCA exhibit distinct but overlapping genomic landscapes marked by recurrent mutations and epigenetic reprogramming. Alterations in the gut microbiota contribute to hepatic inflammation, genomic instability, and immune evasion, potentially enhancing oncogenic signaling pathways. Furthermore, microbiota composition appears to affect responses to immune checkpoint inhibitors. Emerging therapeutic strategies such as probiotics, fecal microbiota transplantation, and precision oncology based on mutational profiling demonstrate potential for personalized interventions. Conclusions: The integration of host genomics with microbial ecology provides a promising paradigm for advancing diagnostics and therapies in liver cancer. Targeting the gut–liver axis may complement genome-informed strategies to improve outcomes for patients with HCC and CCA. Full article

(This article belongs to the Special Issue Feature Papers in Microbial Genetics and Genomics)

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16 pages, 6331 KiB

Open AccessArticle

Integrative Analysis of Iso-Seq and RNA-Seq Identifies Key Genes Related to Fatty Acid Biosynthesis and High-Altitude Stress Adaptation in Paeonia delavayi

by Qiongji He, Wenjue Yuan, Rui Wang, Wengao Yang, Guiqing He, Jinglong Cao, Yan Li, Lei Ye, Zhaoguang Li and Zhijiang Hou

Genes 2025, 16(8), 919; https://doi.org/10.3390/genes16080919 (registering DOI) - 30 Jul 2025

Abstract

Background/Objectives: Paeonia delavayi, a high-altitude-adapted medicinal and oil-producing plant, exhibits broad elevational distribution. Understanding how environmental factors regulate its growth across altitudes is critical for optimizing cultivation and exploiting its economic potential. Methods: In this study, we conducted a comprehensive Iso-Seq [...] Read more.

Background/Objectives: Paeonia delavayi, a high-altitude-adapted medicinal and oil-producing plant, exhibits broad elevational distribution. Understanding how environmental factors regulate its growth across altitudes is critical for optimizing cultivation and exploiting its economic potential. Methods: In this study, we conducted a comprehensive Iso-Seq and RNA-seq analysis to elucidate the transcriptional profile across diverse altitudes and three seed developmental stages. Results: Using Pacbio full-length cDNA sequencing, we identified 39,267 full-length transcripts, with 80.03% (31,426) achieving successful annotation. RNA-seq analysis uncovered 11,423 and 9565 differentially expressed genes (DEGs) in response to different altitude and developmental stages, respectively. KEGG analysis indicated that pathways linked to fatty acid metabolism were notably enriched during developmental stages. In contrast, pathways associated with amino acid and protein metabolism were significantly enriched under different altitudes. Furthermore, we identified 34 DEGs related to fatty acid biosynthesis, including genes encoding pivotal enzymes like biotin carboxylase, carboxyl transferase subunit alpha, malonyl-CoA-acyl carrier protein transacylase, 3-oxoacyl-ACP reductase, 3-hydroxyacyl-ACP dehydratase, and stearoyl-ACP desaturase enoyl-ACP reductase. Additionally, ten DEGs were pinpointed as potentially involved in high-altitude stress response. Conclusions: These findings provide insights into the molecular mechanisms of fatty acid biosynthesis and adaptation to high-altitude stress in peony seeds, providing a theoretical foundation for future breeding programs aimed at enhancing seed quality. Full article

(This article belongs to the Section Genes & Environments)

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16 pages, 636 KiB

Open AccessReview

The Gut–Endometriosis Axis: Genetic Mechanisms and Public Health Implications

by Efthalia Moustakli, Nektaria Zagorianakou, Stylianos Makrydimas, Emmanouil D. Oikonomou, Andreas Miltiadous and George Makrydimas

Genes 2025, 16(8), 918; https://doi.org/10.3390/genes16080918 - 30 Jul 2025

Abstract

Background/Objectives: Endometriosis is a chronic, estrogen-driven gynecological disorder affecting approximately 10% of reproductive-aged women worldwide, with significant physical, psychosocial, and socioeconomic impacts. Recent research suggests a possible involvement of the gut microbiome in endometriosis disease mechanisms through immune manipulation, estrogen metabolism, and [...] Read more.

Background/Objectives: Endometriosis is a chronic, estrogen-driven gynecological disorder affecting approximately 10% of reproductive-aged women worldwide, with significant physical, psychosocial, and socioeconomic impacts. Recent research suggests a possible involvement of the gut microbiome in endometriosis disease mechanisms through immune manipulation, estrogen metabolism, and inflammatory networks. This narrative review aims to summarize current evidence on gut microbiota changes in endometriosis patients, explore the mechanisms by which gut dysbiosis contributes to disease progression, and examine epidemiological links between gastrointestinal health and endometriosis risk. Methods: A narrative review was conducted to synthesize available literature on the compositional changes in gut microbiota associated with endometriosis. The review also evaluated studies investigating potential mechanisms and epidemiological patterns connecting gut health with endometriosis development and severity. Results: Alterations in gut microbiota composition were observed in endometriosis patients, suggesting roles in immune dysregulation, estrogen metabolism, and inflammation. Potential gut-oriented interventions, including dietary changes, probiotics, and lifestyle modifications, emerged as promising management options. However, methodological variability and research gaps remain barriers to clinical translation. Conclusions: Integrating gut microbiome research into endometriosis management holds potential for improving early diagnosis, patient outcomes, and healthcare system sustainability. The study emphasizes the need for further research to address existing challenges and to develop public health strategies that incorporate microbiome-based interventions in population-level endometriosis care. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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13 pages, 1323 KiB

Open AccessArticle

Genotypic and Phenotypic Characterization of Axonal Charcot–Marie–Tooth Disease in Childhood: Identification of One Novel and Four Known Mutations

by Rojan İpek, Büşra Eser Çavdartepe, Sevcan Tuğ Bozdoğan, Erman Altunışık, Akçahan Akalın, Mahmut Yaman, Alper Akın and Sefer Kumandaş

Genes 2025, 16(8), 917; https://doi.org/10.3390/genes16080917 - 30 Jul 2025

Abstract

Background: Charcot–Marie–Tooth disease (CMT) is a genetically and phenotypically heterogeneous hereditary neuropathy. Axonal CMT type 2 (CMT2) subtypes often exhibit overlapping clinical features, which makes molecular genetic analysis essential for accurate diagnosis and subtype differentiation. Methods: This retrospective study included five pediatric patients [...] Read more.

Background: Charcot–Marie–Tooth disease (CMT) is a genetically and phenotypically heterogeneous hereditary neuropathy. Axonal CMT type 2 (CMT2) subtypes often exhibit overlapping clinical features, which makes molecular genetic analysis essential for accurate diagnosis and subtype differentiation. Methods: This retrospective study included five pediatric patients who presented with gait disturbance, muscle weakness, and foot deformities and were subsequently diagnosed with axonal forms of CMT. Clinical data, electrophysiological studies, neuroimaging, and genetic analyses were evaluated. Whole exome sequencing (WES) was performed in three sporadic cases, while targeted CMT gene panel testing was used for two siblings. Variants were interpreted using ACMG guidelines, supported by public databases (ClinVar, HGMD, and VarSome), and confirmed by Sanger sequencing when available. Results: All had absent deep tendon reflexes and distal muscle weakness; three had intellectual disability. One patient was found to carry a novel homozygous frameshift variant (c.2568_2569del) in the IGHMBP2 gene, consistent with CMT2S. Other variants were identified in the NEFH (CMT2CC), DYNC1H1 (CMT2O), and MPV17 (CMT2EE) genes. Notably, a previously unreported co-occurrence of MPV17 mutation and congenital heart disease was observed in one case. Conclusions: This study expands the clinical and genetic spectrum of pediatric axonal CMT and highlights the role of early physical examination and molecular diagnostics in detecting rare variants. Identification of a novel IGHMBP2 variant and unique phenotypic associations provides new insights for future genotype–phenotype correlation studies. Full article

(This article belongs to the Special Issue Genetics of Neuromuscular and Metabolic Diseases)

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23 pages, 3835 KiB

Open AccessArticle

Computational Saturation Mutagenesis Reveals Pathogenic and Structural Impacts of Missense Mutations in Adducin Proteins

by Lennon Meléndez-Aranda, Jazmin Moreno Pereyda and Marina M. J. Romero-Prado

Genes 2025, 16(8), 916; https://doi.org/10.3390/genes16080916 - 30 Jul 2025

Abstract

Background and objectives: Adducins are cytoskeletal proteins essential for membrane stability, actin–spectrin network organization, and cell signaling. Mutations in the genes ADD1, ADD2, and ADD3 have been linked to hypertension, neurodevelopmental disorders, and cancer. However, no comprehensive in silico saturation [...] Read more.

Background and objectives: Adducins are cytoskeletal proteins essential for membrane stability, actin–spectrin network organization, and cell signaling. Mutations in the genes ADD1, ADD2, and ADD3 have been linked to hypertension, neurodevelopmental disorders, and cancer. However, no comprehensive in silico saturation mutagenesis study has systematically evaluated the pathogenic potential and structural consequences of all possible missense mutations in adducins. This study aimed to identify high-risk variants and their potential impact on protein stability and function. Methods: We performed computational saturation mutagenesis for all possible single amino acid substitutions across the adducin proteins family. Pathogenicity predictions were conducted using four independent tools: AlphaMissense, Rhapsody, PolyPhen-2, and PMut. Predictions were validated against UniProt-annotated pathogenic variants. Predictive performance was assessed using Cohen’s Kappa, sensitivity, and precision. Mutations with a prediction probability ≥ 0.8 were further analyzed for structural stability using mCSM, DynaMut2, MutPred2, and Missense3D, with particular focus on functionally relevant domains such as phosphorylation and calmodulin-binding sites. Results: PMut identified the highest number of pathogenic mutations, while PolyPhen-2 yielded more conservative predictions. Several high-risk mutations clustered in known regulatory and binding regions. Substitutions involving glycine were consistently among the most destabilizing due to increased backbone flexibility. Validated variants showed strong agreement across multiple tools, supporting the robustness of the analysis. Conclusions: This study highlights the utility of multi-tool bioinformatic strategies for comprehensive mutation profiling. The results provide a prioritized list of high-impact adducin variants for future experimental validation and offer insights into potential therapeutic targets for disorders involving ADD1, ADD2, and ADD3 mutations. Full article

(This article belongs to the Section Bioinformatics)

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28 pages, 3082 KiB

Open AccessArticle

Genetic Insights and Diagnostic Challenges in Highly Attenuated Lysosomal Storage Disorders

by Elena Urizar, Eamon P. McCarron, Chaitanya Gadepalli, Andrew Bentley, Peter Woolfson, Siying Lin, Christos Iosifidis, Andrew C. Browning, John Bassett, Udara D. Senarathne, Neluwa-Liyanage R. Indika, Heather J. Church, James A. Cooper, Jorge Menendez Lorenzo, Maria Elena Farrugia, Simon A. Jones, Graeme C. Black and Karolina M. Stepien

Genes 2025, 16(8), 915; https://doi.org/10.3390/genes16080915 (registering DOI) - 30 Jul 2025

Abstract

Background: Lysosomal storage diseases (LSDs) are a genetically and clinically heterogeneous group of inborn errors of metabolism caused by variants in genes encoding lysosomal hydrolases, membrane proteins, activator proteins, or transporters. These disease-causing variants lead to enzymatic deficiencies and the progressive accumulation of [...] Read more.

Background: Lysosomal storage diseases (LSDs) are a genetically and clinically heterogeneous group of inborn errors of metabolism caused by variants in genes encoding lysosomal hydrolases, membrane proteins, activator proteins, or transporters. These disease-causing variants lead to enzymatic deficiencies and the progressive accumulation of undegraded substrates within lysosomes, disrupting cellular function across multiple organ systems. While classical phenotypes typically manifest in infancy or early childhood with severe multisystem involvement, a combination of advances in molecular diagnostics [particularly next-generation sequencing (NGS)] and improved understanding of disease heterogeneity have enabled the identification of attenuated forms characterised by residual enzyme activity and later-onset presentations. These milder phenotypes often evade early recognition due to nonspecific or isolated symptoms, resulting in significant diagnostic delays and missed therapeutic opportunities. Objectives/Methods: This study characterises the clinical, biochemical, and molecular profiles of 10 adult patients diagnosed with LSDs, all representing attenuated forms, and discusses them alongside a narrative review. Results: Enzyme activity, molecular data, and phenotypic assessments are described to explore genotype–phenotype correlations and identify diagnostic challenges. Conclusions: These findings highlight the variable expressivity and organ involvement of attenuated LSDs and reinforce the importance of maintaining clinical suspicion in adults presenting with unexplained cardiovascular, neurological, ophthalmological, or musculoskeletal findings. Enhanced recognition of atypical presentations is critical to facilitate earlier diagnosis, guide management, and enable cascade testing for at-risk family members. Full article

(This article belongs to the Special Issue Molecular Basis and Genetics of Intellectual Disability)

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14 pages, 8505 KiB

Open AccessArticle

Overexpression of Ent-Kaurene Synthase Genes Enhances Gibberellic Acid Biosynthesis and Improves Salt Tolerance in Anoectochilus roxburghii (Wall.) Lindl.

by Lin Yang, Fuai Sun, Shanyan Zhao, Hangying Zhang, Haoqiang Yu, Juncheng Zhang and Chunyan Yang

Genes 2025, 16(8), 914; https://doi.org/10.3390/genes16080914 - 30 Jul 2025

Abstract

Background: Anoectochilus roxburghii (Wall.) Lindl. (A. roxburghii) was widely used in traditional Chinese medicine and also as a health food in China. Gibberellins (GAs) are plant hormones that regulate various aspects of growth and development in A. roxburghii. Ent-kaurene [...] Read more.

Background: Anoectochilus roxburghii (Wall.) Lindl. (A. roxburghii) was widely used in traditional Chinese medicine and also as a health food in China. Gibberellins (GAs) are plant hormones that regulate various aspects of growth and development in A. roxburghii. Ent-kaurene synthase (KS) plays a crucial role in the biosynthesis of GAs in plants. However, there is limited functional analysis of KS in GA biosynthesis and its effect on salt tolerance, especially in A. roxburghii. Methods: The ArKS genes were cloned from A. roxburghii, and its salt tolerance characteristics were verified by prokaryotic expression. Under salt stress, analyze the regulation of KS gene on GA and active ingredient content by qRT-PCR and HPLC-MS/MS, and explore the mechanism of exogenous GAs promoting active ingredient enrichment by regulating the expression level of the KS under salt stress. Results: The ArKS protein was highly homologous to KSs with other plant species; subcellular localization of KS protein was lacking kytic vacuole. The transformants displayed a significant increase in salt tolerance under the stress conditions of 300 mM NaCl. And the expression of ArKS genes and the GAs accumulation was downregulated under the salt stress; among them, the contents of GA3, GA7, GA8, GA24, and GA34 showed a significant decrease. It was further found that there was an increase (1.36 times) in MDA content and a decrease (0.84 times) in relative chlorophyll content under the salt conditions from A. roxburghii. However, the content of active constituents was elevated from A. roxburghii under the NaCl stress, including polysaccharides, total flavonoids, and free amino acids, which increased by 1.14, 1.23, and 1.44 times, respectively. Interestingly, the ArKS gene expression and the chlorophyll content was increased, MDA content showed a decrease from 2.02 μmoL·g⁻¹ to 1.74 μmoL·g⁻¹ after exogenous addition of GAs, and the elevation of active constituents of polysaccharides, total flavonoids, and free amino acids were increased by 1.02, 1.09, and 1.05 times, implying that GAs depletion mitigated the damage caused by adversity to A. roxburghii. Conclusions: The ArKS gene cloned from A. roxburghii improved the salt tolerance of plants under salt stress by regulating GA content. Also, GAs not only alleviate salt tolerance but also play a key role in the synthesis of active components in A. roxburghii. The functions of KS genes and GAs were identified to provide ideas for improving the salt tolerance and quality of ingredients in artificial cultivation from A. roxburghii. Full article

(This article belongs to the Section Plant Genetics and Genomics)

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26 pages, 11108 KiB

Open AccessArticle

Warming in the Maternal Environment Alters Seed Performance and Genetic Diversity of Stylosanthes capitata, a Tropical Legume Forage

by Priscila Marlys Sá Rivas, Fernando Bonifácio-Anacleto, Ivan Schuster, Carlos Alberto Martinez and Ana Lilia Alzate-Marin

Genes 2025, 16(8), 913; https://doi.org/10.3390/genes16080913 (registering DOI) - 30 Jul 2025

Abstract

Background/Objectives: Global warming and rising CO₂ concentrations pose significant challenges to plant systems. Amid these pressures, this study contributes to understanding how tropical species respond by simultaneously evaluating reproductive and genetic traits. It specifically investigates the effects of maternal exposure to [...] Read more.

Background/Objectives: Global warming and rising CO₂ concentrations pose significant challenges to plant systems. Amid these pressures, this study contributes to understanding how tropical species respond by simultaneously evaluating reproductive and genetic traits. It specifically investigates the effects of maternal exposure to warming and elevated CO₂ on progeny physiology, genetic diversity, and population structure in Stylosanthes capitata, a resilient forage legume native to Brazil. Methods: Maternal plants were cultivated under controlled treatments, including ambient conditions (control), elevated CO₂ at 600 ppm (eCO₂), elevated temperature at +2 °C (eTE), and their combined exposure (eTEeCO₂), within a Trop-T-FACE field facility (Temperature Free-Air Controlled Enhancement and Free-Air Carbon Dioxide Enrichment). Seed traits (seeds per inflorescence, hundred-seed mass, abortion, non-viable seeds, coat color, germination at 32, 40, 71 weeks) and abnormal seedling rates were quantified. Genetic diversity metrics included the average (A) and effective (Ae) number of alleles, observed (Ho) and expected (He) heterozygosity, and inbreeding coefficient (Fis). Population structure was assessed using Principal Coordinates Analysis (PCoA), Analysis of Molecular Variance (AMOVA), number of migrants per generation (Nm), and genetic differentiation index (Fst). Two- and three-way Analysis of Variance (ANOVA) were used to evaluate factor effects. Results: Compared to control conditions, warming increased seeds per inflorescence (+46%), reduced abortion (−42.9%), non-viable seeds (−57%), and altered coat color. The germination speed index (GSI +23.5%) and germination rate (Gr +11%) improved with warming; combined treatments decreased germination time (GT −9.6%). Storage preserved germination traits, with warming enhancing performance over time and reducing abnormal seedlings (−54.5%). Conversely, elevated CO₂ shortened GSI in late stages, impairing germination efficiency. Warming reduced Ae (−35%), He (−20%), and raised Fis (maternal 0.50, progeny 0.58), consistent with the species’ mixed mating system; A and Ho were unaffected. Allele frequency shifts suggested selective pressure under eTE. Warming induced slight structure in PCoA, and AMOVA detected 1% (maternal) and 9% (progeny) variation. Fst = 0.06 and Nm = 3.8 imply environmental influence without isolation. Conclusions: Warming significantly shapes seed quality, reproductive success, and genetic diversity in S. capitata. Improved reproduction and germination suggest adaptive advantages, but higher inbreeding and reduced diversity may constrain long-term resilience. The findings underscore the need for genetic monitoring and broader genetic bases in cultivars confronting environmental stressors. Full article

(This article belongs to the Special Issue Genetics and Breeding of Forage)

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14 pages, 2074 KiB

Open AccessArticle

Special Regulation of GhANT in Ovules Increases the Size of Cotton Seeds

by Ning Liu, Yuping Chen, Yangbing Guan, Geyi Guan, Jian Yang, Feng Nie, Kui Ming, Wenqin Bai, Ming Luo and Xingying Yan

Genes 2025, 16(8), 912; https://doi.org/10.3390/genes16080912 - 30 Jul 2025

Abstract

Background: Gossypium hirsutum L. is one of the main economic crops worldwide, and increasing the size/weight of its seeds is a potential strategy to improve its seed-related yield. AINTEGUMENTA (ANT) is an organogenesis transcription factor mediating cell proliferation and expansion in Arabidopsis, [...] Read more.

Background: Gossypium hirsutum L. is one of the main economic crops worldwide, and increasing the size/weight of its seeds is a potential strategy to improve its seed-related yield. AINTEGUMENTA (ANT) is an organogenesis transcription factor mediating cell proliferation and expansion in Arabidopsis, but little is known about its candidate function in upland cotton seed. Results: In this study, functional characterization of GhANT in the cotton seed development stage was performed. The expression pattern analysis showed that GhANT was predominantly expressed in the ovules, and its expression was consistent with the ovules’ development stage. Heterologous expression of GhANT in Arabidopsis promoted plant organ growth and led to larger seeds. Importantly, specific expression of GhANT by the TFM7 promoter in the cotton ovules enlarged the seeds and increased the cotton seed yield, as compared with the wild-type in a three-year field trial. Furthermore, transcription level analysis showed that numerous genes involved in cell division were up-regulated in the ovules of TFM7::GhANT lines in comparison to the wild-type. These results indicate that GhANT is a potential genetic resource for improving cotton seed yield through its molecular links with cell cycle controllers. Full article

(This article belongs to the Special Issue 5Gs in Crop Genetic and Genomic Improvement: 2nd Edition)

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11 pages, 1043 KiB

Open AccessReview

GPR143-Associated Ocular Albinism in a Hispanic Family and Review of the Literature

by Anushree Aneja, Brenda L. Bohnsack, Valerie Allegretti, Allison Goetsch Weisman, Andy Drackley, Alexander Ing, Patrick McMullen, Andrew Skol, Hantamalala Ralay Ranaivo, Kai Lee Yap, Pamela Rathbun, Adam Gordon and Jennifer L. Rossen

Genes 2025, 16(8), 911; https://doi.org/10.3390/genes16080911 - 30 Jul 2025

Abstract

Background/Objectives: While ocular albinism (OA) is usually associated with reduced vision, nystagmus, and foveal hypoplasia, there is phenotypic variability in iris and fundus hypopigmentation. Hemizygous pathogenic/likely pathogenic (P/LP) variants in GPR143 at X: 151.56–151.59 have been shown in the literature to be associated [...] Read more.

Background/Objectives: While ocular albinism (OA) is usually associated with reduced vision, nystagmus, and foveal hypoplasia, there is phenotypic variability in iris and fundus hypopigmentation. Hemizygous pathogenic/likely pathogenic (P/LP) variants in GPR143 at X: 151.56–151.59 have been shown in the literature to be associated with OA. The purpose of this study was to report the case of a Hispanic male with X-linked inherited OA associated with a hemizygous GPR143 variant and to review the literature relating to genotype–phenotype associations with GPR143 and OA. Methods: After consent to an IRB-approved protocol, a 14-year-old Hispanic male patient with OA and his parents underwent whole genome sequencing (WGS) in 2023. Two maternal uncles with nystagmus underwent targeted variant testing in 2024. A literature review of reported GPR143 variants was completed. Results: A male with reduced visual acuity, infantile-onset nystagmus, foveal hypoplasia, and iris hypopigmentation was identified to have the variant GPR143, c.455+3A>G, which was also present in his mother and two affected maternal uncles. This variant has been previously identified in other Hispanic patients of Mexican descent. Additionally, 127 variants were identified in the literature and reported to be associated with OA. All patients had reduced visual acuity (average 0.71 ± 0.23 logMAR), 99% had nystagmus, 97% foveal hypoplasia, 79% fundus hypopigmentation, and 71% iris hypopigmentation. Of those patients with reported optotype best corrected visual acuity (BCVA), eight (9%) had VA from 20/25 to 20/40, 24 (24%) had VA from 20/50 to 20/80, and 63 (67%) had VA from 20/100 to 20/200. The most frequent type of variant was missense (31%, n = 39). Frameshift and nonsense variants were associated with the lowest rates of iris hypopigmentation (50% [n = 11] and 44% [n = 8], respectively; p = 0.0068). Conclusions: This case represents phenotypic variability of GPR143-associated OA and highlights the importance of repeat genetic testing and independent analyses of test results for accurate variant classification, particularly in non-White and Hispanic patients. Further studies in more diverse populations are needed to better develop genotype–phenotype associations for GPR143-associated OA. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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