International Journal of Molecular Sciences

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23 pages, 1897 KiB

Open AccessArticle

Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia

by Anastasia V. Blokhina, Alexandra I. Ershova, Anna V. Kiseleva, Evgeniia A. Sotnikova, Anastasia A. Zharikova, Marija Zaicenoka, Yuri V. Vyatkin, Vasily E. Ramensky, Vladimir A. Kutsenko, Elizaveta V. Garbuzova, Mikhail G. Divashuk, Olga A. Litinskaya, Maria S. Pokrovskaya, Svetlana A. Shalnova, Alexey N. Meshkov and Oxana M. Drapkina

Int. J. Mol. Sci. 2024, 25(23), 12651; https://doi.org/10.3390/ijms252312651 - 25 Nov 2024

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Abstract

Familial dysbetalipoproteinemia (FD) is a highly atherogenic, prevalent genetically based lipid disorder. About 10% of FD patients have rare APOE variants associated with autosomal dominant FD. However, there are insufficient data on the relationship between rare APOE variants and FD. Genetic data from [...] Read more.

Familial dysbetalipoproteinemia (FD) is a highly atherogenic, prevalent genetically based lipid disorder. About 10% of FD patients have rare APOE variants associated with autosomal dominant FD. However, there are insufficient data on the relationship between rare APOE variants and FD. Genetic data from 4720 subjects were used to identify rare APOE variants and investigate their pathogenicity for autosomal dominant FD. We observed 24 variants in 86 unrelated probands. Most variants were unique (66.7%). Five identified APOE variants (p.Glu63ArgfsTer15, p.Gly145AlafsTer97, p.Lys164SerfsTer87, p.Arg154Cys, and p.Glu230Lys) are causal for autosomal dominant FD. One of them (p.Lys164SerfsTer87) was described for the first time. When we compared clinical data, it was found that carriers of pathogenic or likely pathogenic APOE variants had significantly higher triglyceride levels (median 5.01 mmol/L) than carriers of benign or likely benign variants (median 1.70 mmol/L, p = 0.034) and variants of uncertain significance (median 1.38 mmol/L, p = 0.036). For the first time, we estimated the expected prevalence of causal variants for autosomal dominant FD in the population sample: 0.27% (one in 619). Investigating the spectrum of APOE variants may advance our understanding of the genetic basis of FD and underscore the importance of APOE gene sequencing in patients with lipid metabolism disorders. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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19 pages, 3129 KiB

Open AccessArticle

Transcriptional Regulation of the Human MGP Promoter: Identification of Downstream Repressors

by Helena Caiado, M. Leonor Cancela and Natércia Conceição

Int. J. Mol. Sci. 2024, 25(23), 12597; https://doi.org/10.3390/ijms252312597 - 23 Nov 2024

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Abstract

Matrix Gla protein (MGP) is a vitamin K-dependent γ-carboxylated protein that was initially identified as a physiological inhibitor of ectopic calcification, primarily affecting cartilage and the vascular system. Mutations in the MGP gene were found to be responsible for the Keutel syndrome, a [...] Read more.

Matrix Gla protein (MGP) is a vitamin K-dependent γ-carboxylated protein that was initially identified as a physiological inhibitor of ectopic calcification, primarily affecting cartilage and the vascular system. Mutations in the MGP gene were found to be responsible for the Keutel syndrome, a condition characterized by abnormal calcifications in the cartilage, lungs, brain, and vascular system. MGP has been shown to be dysregulated in several tumors, including cervical, ovarian, urogenital, and breast cancers. Using bioinformatic approaches, transcription factor binding sites (TFBSs) containing CpG dinucleotides were identified in the MGP promoter, including those for YY1, GATA1, and C/EBPα. We carried out functional tests using transient transfections with a luciferase reporter assay, primarily for the transcription factors YY1, GATA1, C/EBPα, and RUNX2. By co-transfection analysis, we found that YY1, GATA1, and C/EBPα repressed the MGP promoter. Furthermore, the co-transfection with RUNX2 activated the MGP promoter. In addition, MGP expression is negatively or positively correlated with the studied TFs’ expression levels in several cancer types. This study provides novel insights into MGP regulation by demonstrating that YY1, GATA1, and C/EBPα are negative regulators of the MGP promoter, and DNA methylation may influence their activity. The dysregulation of these mechanisms in cancer should be further elucidated. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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13 pages, 2484 KiB

Open AccessArticle

Fahr’s Syndrome with Pseudohypoparathyroidism: Oral Features and Genetic Insights

by Xiangpu Wang, Taoyun Xu, Yulong Zhu and Xiaohong Duan

Int. J. Mol. Sci. 2024, 25(21), 11611; https://doi.org/10.3390/ijms252111611 - 29 Oct 2024

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Abstract

Fahr’s syndrome is a rare neurodegenerative disorder with limited research on its oral manifestations. This study investigates the dental features and genetic background of Fahr’s syndrome through a pedigree analysis and a retrospective literature study. A clinical examination and whole-exome sequencing (WES) were [...] Read more.

Fahr’s syndrome is a rare neurodegenerative disorder with limited research on its oral manifestations. This study investigates the dental features and genetic background of Fahr’s syndrome through a pedigree analysis and a retrospective literature study. A clinical examination and whole-exome sequencing (WES) were conducted on a female patient with Fahr’s syndrome and pseudohypoparathyroidism, along with her family members. The patient presented with super-numerary teeth, tooth agenesis, enamel hypoplasia, and abnormal tooth eruption. The WES did not reveal any known pathogenic mutations related to pseudohypoparathyroidism or Fahr’s disease. However, genetic variations in KIF1A, FZD8, and PDGFA may underlie these dental abnormalities. Additionally, a retrospective analysis of 22 reported cases from PubMed and the Human Gene Mutation Database (1 January 1965–30 June 2024) was conducted with keywords such as “Fahr’s disease”, “Fahr’s syndrome”, “dental”, and “hypoparathyroidism”. The analysis showed that patients with Fahr’s syndrome, pseudohypoparathyroidism, and idiopathic hypoparathyroidism exhibited similar oral abnormalities, including tooth agenesis, root dysplasia, dental malformations, and abnormal tooth eruption. Variations in the incidence of tooth agenesis and dental malformation among these groups may be linked to differences in parathyroid hormone metabolism. These findings suggest oral abnormalities are the key local features of Fahr’s syndrome and related parathyroid disorders. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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14 pages, 5364 KiB

Open AccessArticle

Estimation of Chloride Channel Residual Function and Assessment of Targeted Drugs Efficiency in the Presence of a Complex Allele [L467F;F508del] in the CFTR Gene

by Anna Efremova, Yuliya Melyanovskaya, Maria Krasnova, Anna Voronkova, Diana Mokrousova, Elena Zhekaite, Nataliya Bulatenko, Oleg Makhnach, Tatiana Bukharova, Sergei Kutsev, Dmitry Goldshtein and Elena Kondratyeva

Int. J. Mol. Sci. 2024, 25(19), 10424; https://doi.org/10.3390/ijms251910424 - 27 Sep 2024

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Abstract

Complex alleles of the CFTR gene complicate the diagnosis of cystic fibrosis (CF), the classification of its pathogenic variants, affect the clinical picture of the disease and can affect the efficiency of targeted drugs. The total frequency of complex allele [L467F;F508del] in the [...] Read more.

Complex alleles of the CFTR gene complicate the diagnosis of cystic fibrosis (CF), the classification of its pathogenic variants, affect the clinical picture of the disease and can affect the efficiency of targeted drugs. The total frequency of complex allele [L467F;F508del] in the Russian population of patients with CF is 0.74%, and in patients with the F508del/F508del genotype, its frequency reaches 8%. This article presents multi-faceted study of the complex allele [L467F;F508del] in a cohort of patients with genotypes [L467F;F508del]/class I (c.3532_3535dup, c.1766+2T>C, W1310X, 712-1G>T), and data for a unique patient with the genotype [L467F;F508del]/[L467F;F508del]. Using the intestinal current measurement method, it was demonstrated the absence of CFTR function for [L467F;F508del]/class I and [L467F;F508del]/[L467F;F508del] genotypes. In intestinal organoids, it was shown that [L467F;F508del] in combination with class I variants and in the homozygotes abolishes the efficacy of both two-component (ivacaftor+lumacaftor; ivacaftor+tezacaftor) and three-component (ivacaftor+tezacaftor+elexacaftor) targeted drugs. When prescribing ivacaftor+tezacaftor+elexacaftor to three patients, they did not have a clinical effect after 6–12 months. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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11 pages, 1453 KiB

Open AccessArticle

The Study of the Inheritance Mechanisms of Myotonic Dystrophy Type 1 (DM1) in Families from the Republic of North Ossetia-Alania

by Sofya A. Ionova, Aysylu F. Murtazina, Andrey A. Marakhonov, Olga A. Shchagina, Nina V. Ryadninskaya, Inna S. Tebieva, Vitaly V. Kadyshev, Artem O. Borovikov, Evgeny K. Ginter, Sergey I. Kutsev and Rena A. Zinchenko

Int. J. Mol. Sci. 2024, 25(17), 9734; https://doi.org/10.3390/ijms25179734 - 9 Sep 2024

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Abstract

Myotonic dystrophy type 1 (DM1) is a multisystem disorder with progressive myopathy and myotonia. The clinical study was conducted in the Republic of North Ossetia-Alania (RNOA), and in it 39 individuals from 17 unrelated families were identified with DM1. Clinical presentations varied, including [...] Read more.

Myotonic dystrophy type 1 (DM1) is a multisystem disorder with progressive myopathy and myotonia. The clinical study was conducted in the Republic of North Ossetia-Alania (RNOA), and in it 39 individuals from 17 unrelated families were identified with DM1. Clinical presentations varied, including muscle weakness, fatigue, intellectual disability, hypersomnia, ophthalmological abnormalities, and alopecia. Using clinical and genotyping data, we confirmed the diagnosis and enabled the study of CTG-repeat anticipation and DM1 prevalence in the Ossetian and Ingush populations. CTG expansion correlated with age of onset, with clinical severity, and with offspring showing more severe symptoms than parents. In many families, the youngest child had a more severe DM1 phenotype than older siblings. The prevalence was 14.17 per 100,000 in Ossetians and 18.74 per 100,000 in Ingush people, aligning with global data. Segregation analysis showed a higher frequency of maternal transmission. The study highlights the clinical and genetic heterogeneity of DM1 and its dependence on repeat expansion and paternal and maternal age. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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14 pages, 469 KiB

Open AccessArticle

Association Study of CACNA1D, KCNJ11, KCNQ1, and CACNA1E Single-Nucleotide Polymorphisms with Type 2 Diabetes Mellitus

by Juan Daniel Díaz-García, Margarita Leyva-Leyva, Fabiola Sánchez-Aguillón, Mercedes Piedad de León-Bautista, Abel Fuentes-Venegas, Alfredo Torres-Viloria, Erika Karina Tenorio-Aguirre, Sara Luz Morales-Lázaro, Angélica Olivo-Díaz and Ricardo González-Ramírez

Int. J. Mol. Sci. 2024, 25(17), 9196; https://doi.org/10.3390/ijms25179196 - 24 Aug 2024

Viewed by 909

Abstract

Type 2 diabetes mellitus (T2DM) is a complex chronic disease characterized by decreased insulin secretion and the development of insulin resistance. Previous genome-wide association studies demonstrated that single-nucleotide polymorphisms (SNPs) present in genes coding for ion channels involved in insulin secretion increase the [...] Read more.

Type 2 diabetes mellitus (T2DM) is a complex chronic disease characterized by decreased insulin secretion and the development of insulin resistance. Previous genome-wide association studies demonstrated that single-nucleotide polymorphisms (SNPs) present in genes coding for ion channels involved in insulin secretion increase the risk of developing this disease. We determined the association of 16 SNPs found in CACNA1D, KCNQ1, KCNJ11, and CACNA1E genes and the increased probability of developing T2DM. In this work, we performed a case-control study in 301 Mexican adults, including 201 cases with diabetes and 100 controls without diabetes. Our findings indicate a moderate association between T2DM and the C allele, and the C/C genotype of rs312480 within CACNA1D. The CAG haplotype surprisingly showed a protective effect, whereas the CAC and CGG haplotypes have a strong association with T2DM. The C allele and C/C genotype of rs5219 were significantly associated with diabetes. Also, an association was observed between diabetes and the A allele and the A/A genotype of rs3753737 and rs175338 in CACNA1E. The TGG and CGA haplotypes were also found to be significantly associated. The findings of this study indicate that the SNPs examined could serve as a potential diagnostic tool and contribute to the susceptibility of the Mexican population to this disease. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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13 pages, 1831 KiB

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Clinical and Molecular Characterization of SMAD4 Splicing Variants in Patients with Juvenile Polyposis Syndrome

by Giovanna Forte, Antonia Lucia Buonadonna, Candida Fasano, Paola Sanese, Filomena Cariola, Andrea Manghisi, Anna Filomena Guglielmi, Martina Lepore Signorile, Katia De Marco, Valentina Grossi, Vittoria Disciglio and Cristiano Simone

Int. J. Mol. Sci. 2024, 25(14), 7939; https://doi.org/10.3390/ijms25147939 - 20 Jul 2024

Cited by 1 | Viewed by 1205

Abstract

Juvenile polyposis syndrome (JPS) is an inherited autosomal dominant condition that predisposes to the development of juvenile polyps throughout the gastrointestinal (GI) tract, and it poses an increased risk of GI malignancy. Germline causative variants were identified in the SMAD4 gene in a [...] Read more.

Juvenile polyposis syndrome (JPS) is an inherited autosomal dominant condition that predisposes to the development of juvenile polyps throughout the gastrointestinal (GI) tract, and it poses an increased risk of GI malignancy. Germline causative variants were identified in the SMAD4 gene in a subset (20%) of JPS cases. Most SMAD4 germline genetic variants published to date are missense, nonsense, and frameshift mutations. SMAD4 germline alterations predicted to result in aberrant splicing have rarely been reported. Here, we report two unrelated Italian families harboring two different SMAD4 intronic variants, c.424+5G>A and c.425-9A>G, which are clinically associated with colorectal cancer and/or juvenile GI polyps. In silico prediction analysis, in vitro minigene assays, and RT-PCR showed that the identified variants lead to aberrant SMAD4 splicing via the exonization of intronic nucleotides, resulting in a premature stop codon. This is expected to cause the production of a truncated protein. This study expands the landscape of SMAD4 germline genetic variants associated with GI polyposis and/or cancer. Moreover, it emphasizes the importance of the functional characterization of SMAD4 splicing variants through RNA analysis, which can provide new insights into genetic disease variant interpretation, enabling tailored genetic counseling, management, and surveillance of patients with GI polyposis and/or cancer. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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10 pages, 2927 KiB

Open AccessArticle

O-Sialoglycoprotein Endopeptidase Deficiency Impairs Proteostasis and Induces Autophagy in Human Embryonic Stem Cells

by Hua Teng, Siyi Chen, Fang Liu, Yanling Teng, Yunlong Li, Desheng Liang, Lingqian Wu and Zhuo Li

Int. J. Mol. Sci. 2024, 25(14), 7889; https://doi.org/10.3390/ijms25147889 - 18 Jul 2024

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Abstract

The OSGEP gene encodes O-sialoglycoprotein endopeptidase, a catalytic unit of the highly conserved KEOPS complex (Kinase, Endopeptidase, and Other Proteins of small Size) that regulates the second biosynthetic step in the formation of N-6-threonylcarbamoyladenosine (t6A). Mutations in KEOPS cause Galloway–Mowat syndrome (GAMOS), whose [...] Read more.

The OSGEP gene encodes O-sialoglycoprotein endopeptidase, a catalytic unit of the highly conserved KEOPS complex (Kinase, Endopeptidase, and Other Proteins of small Size) that regulates the second biosynthetic step in the formation of N-6-threonylcarbamoyladenosine (t6A). Mutations in KEOPS cause Galloway–Mowat syndrome (GAMOS), whose cellular function in mammals and underlying molecular mechanisms are not well understood. In this study, we utilized lentivirus-mediated OSGEP knockdown to generate OSGEP-deficient human embryonic stem cells (hESCs). OSGEP-knockdown hESCs exhibited reduced stemness factor expression and G2/M phase arrest, indicating a potential role of OSGEP in the regulation of hESC fate. Additionally, OSGEP silencing led to enhanced protein synthesis and increased aggregation of proteins, which further induced inappropriate autophagy, as evidenced by the altered expression of P62 and the conversion of LC3-I to LC3-II. The above findings shed light on the potential involvement of OSGEP in regulating pluripotency and differentiation in hESCs while simultaneously highlighting its crucial role in maintaining proteostasis and autophagy, which may have implications for human disease. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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13 pages, 2805 KiB

Open AccessArticle

A Rare Coincidence of Three Inherited Diseases in a Family with Cardiomyopathy and Multiple Extracardiac Abnormalities

by Anna Bukaeva, Roman Myasnikov, Olga Kulikova, Alexey Meshkov, Anna Kiseleva, Anna Petukhova, Evgenia Zotova, Peter Sparber, Alexandra Ershova, Evgeniia Sotnikova, Maria Kudryavtseva, Anastasia Zharikova, Sergey Koretskiy, Elena Mershina, Vasily Ramensky, Marija Zaicenoka, Yuri Vyatkin, Alisa Muraveva, Alexandra Abisheva, Tatiana Nikityuk, Valentin Sinitsyn, Mikhail Divashuk, Elena Dadali, Maria Pokrovskaya and Oxana Drapkina Show full author list Hide full author list

Int. J. Mol. Sci. 2024, 25(14), 7556; https://doi.org/10.3390/ijms25147556 - 10 Jul 2024

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Abstract

A genetic diagnosis of primary cardiomyopathies can be a long-unmet need in patients with complex phenotypes. We investigated a three-generation family with cardiomyopathy and various extracardiac abnormalities that had long sought a precise diagnosis. The 41-year-old proband had hypertrophic cardiomyopathy (HCM), left ventricular [...] Read more.

A genetic diagnosis of primary cardiomyopathies can be a long-unmet need in patients with complex phenotypes. We investigated a three-generation family with cardiomyopathy and various extracardiac abnormalities that had long sought a precise diagnosis. The 41-year-old proband had hypertrophic cardiomyopathy (HCM), left ventricular noncompaction, myocardial fibrosis, arrhythmias, and a short stature. His sister showed HCM, myocardial hypertrabeculation and fibrosis, sensorineural deafness, and congenital genitourinary malformations. Their father had left ventricular hypertrophy (LVH). The proband’s eldest daughter demonstrated developmental delay and seizures. We performed a clinical examination and whole-exome sequencing for all available family members. All patients with HCM/LVH shared a c.4411-2A>C variant in ALPK3, a recently known HCM-causative gene. Functional studies confirmed that this variant alters ALPK3 canonical splicing. Due to extracardiac symptoms in the female patients, we continued the search and found two additional single-gene disorders. The proband’s sister had a p.Trp329Gly missense in GATA3, linked to hypoparathyroidism, sensorineural deafness, and renal dysplasia; his daughter had a p.Ser251del in WDR45, associated with beta-propeller protein-associated neurodegeneration. This unique case of three monogenic disorders in one family shows how a comprehensive approach with thorough phenotyping and extensive genetic testing of all symptomatic individuals provides precise diagnoses and appropriate follow-up, embodying the concept of personalized medicine. We also present the first example of a splicing functional study for ALPK3 and describe the genotype–phenotype correlations in cardiomyopathy. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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17 pages, 1154 KiB

Open AccessArticle

Integrative Bioinformatics Analysis Reveals a Transcription Factor EB-Driven MicroRNA Regulatory Network in Endothelial Cells

by Teresa Gravina, Francesco Favero, Stefania Rosano, Sushant Parab, Alejandra Diaz Alcalde, Federico Bussolino, Gabriella Doronzo and Davide Corà

Int. J. Mol. Sci. 2024, 25(13), 7123; https://doi.org/10.3390/ijms25137123 - 28 Jun 2024

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Abstract

Various human diseases are triggered by molecular alterations influencing the fine-tuned expression and activity of transcription factors, usually due to imbalances in targets including protein-coding genes and non-coding RNAs, such as microRNAs (miRNAs). The transcription factor EB (TFEB) modulates human cellular networks, overseeing [...] Read more.

Various human diseases are triggered by molecular alterations influencing the fine-tuned expression and activity of transcription factors, usually due to imbalances in targets including protein-coding genes and non-coding RNAs, such as microRNAs (miRNAs). The transcription factor EB (TFEB) modulates human cellular networks, overseeing lysosomal biogenesis and function, plasma–membrane trafficking, autophagic flux, and cell cycle progression. In endothelial cells (ECs), TFEB is essential for the maintenance of endothelial integrity and function, ensuring vascular health. However, the comprehensive regulatory network orchestrated by TFEB remains poorly understood. Here, we provide novel mechanistic insights into how TFEB regulates the transcriptional landscape in primary human umbilical vein ECs (HUVECs), using an integrated approach combining high-throughput experimental data with dedicated bioinformatics analysis. By analyzing HUVECs ectopically expressing TFEB using ChIP-seq and examining both polyadenylated mRNA and small RNA sequencing data from TFEB-silenced HUVECs, we have developed a bioinformatics pipeline mapping the different gene regulatory interactions driven by TFEB. We show that TFEB directly regulates multiple miRNAs, which in turn post-transcriptionally modulate a broad network of target genes, significantly expanding the repertoire of gene programs influenced by this transcription factor. These insights may have significant implications for vascular biology and the development of novel therapeutics for vascular disease. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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13 pages, 3914 KiB

Open AccessArticle

A Case of CDKL5 Deficiency Due to an X Chromosome Pericentric Inversion: Delineation of Structural Rearrangements as an Overlooked Recurrent Pathological Mechanism

by Antonietta Lombardo, Lorenzo Sinibaldi, Silvia Genovese, Giorgia Catino, Valerio Mei, Daniele Pompili, Ester Sallicandro, Roberto Falasca, Maria Teresa Liambo, Maria Vittoria Faggiano, Maria Cristina Roberti, Maddalena Di Donato, Anna Vitelli, Serena Russo, Rosalinda Giannini, Alessia Micalizzi, Nicola Pietrafusa, Maria Cristina Digilio, Antonio Novelli, Lucia Fusco and Viola Alesi Show full author list Hide full author list

Int. J. Mol. Sci. 2024, 25(13), 6912; https://doi.org/10.3390/ijms25136912 - 24 Jun 2024

Viewed by 949

Abstract

CDKL5 deficiency disorder (CDD) is an X-linked dominant epileptic encephalopathy, characterized by early-onset and drug-resistant seizures, psychomotor delay, and slight facial features. Genomic variants inactivating CDKL5 or impairing its protein product kinase activity have been reported, making next-generation sequencing (NGS) and chromosomal microarray [...] Read more.

CDKL5 deficiency disorder (CDD) is an X-linked dominant epileptic encephalopathy, characterized by early-onset and drug-resistant seizures, psychomotor delay, and slight facial features. Genomic variants inactivating CDKL5 or impairing its protein product kinase activity have been reported, making next-generation sequencing (NGS) and chromosomal microarray analysis (CMA) the standard diagnostic tests. We report a suspicious case of CDD in a female child who tested negative upon NGS and CMA and harbored an X chromosome de novo pericentric inversion. The use of recently developed genomic techniques (optical genome mapping and whole-genome sequencing) allowed us to finely characterize the breakpoints, with one of them interrupting CDKL5 at intron 1. This is the fifth case of CDD reported in the scientific literature harboring a structural rearrangement on the X chromosome, providing evidence for the hypothesis that this type of anomaly can represent a recurrent pathogenic mechanism, whose frequency is likely underestimated, with it being overlooked by standard techniques. The identification of the molecular etiology of the disorder is extremely important in evaluating the pathological outcome and to better investigate the mechanisms associated with drug resistance, paving the way for the development of specific therapies. Karyotype and genomic techniques should be considered in all cases presenting with CDD without molecular confirmation. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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18 pages, 3488 KiB

Open AccessArticle

The Role of TPM3 in Protecting Cardiomyocyte from Hypoxia-Induced Injury via Cytoskeleton Stabilization

by Ke Huang, Weijia Yang, Mingxuan Shi, Shiqi Wang, Yi Li and Zhaoqing Xu

Int. J. Mol. Sci. 2024, 25(12), 6797; https://doi.org/10.3390/ijms25126797 - 20 Jun 2024

Cited by 2 | Viewed by 1044

Abstract

Ischemic heart disease (IHD) remains a major global health concern, with ischemia-reperfusion injury exacerbating myocardial damage despite therapeutic interventions. In this study, we investigated the role of tropomyosin 3 (TPM3) in protecting cardiomyocytes against hypoxia-induced injury and oxidative stress. Using the AC16 and [...] Read more.

Ischemic heart disease (IHD) remains a major global health concern, with ischemia-reperfusion injury exacerbating myocardial damage despite therapeutic interventions. In this study, we investigated the role of tropomyosin 3 (TPM3) in protecting cardiomyocytes against hypoxia-induced injury and oxidative stress. Using the AC16 and H9c2 cell lines, we established a chemical hypoxia model by treating cells with cobalt chloride (CoCl₂) to simulate low-oxygen conditions. We found that CoCl₂ treatment significantly upregulated the expression of hypoxia-inducible factor 1 alpha (HIF-1α) in cardiomyocytes, indicating the successful induction of hypoxia. Subsequent morphological and biochemical analyses revealed that hypoxia altered cardiomyocyte morphology disrupted the cytoskeleton, and caused cellular damage, accompanied by increased lactate dehydrogenase (LDH) release and malondialdehyde (MDA) levels, and decreased superoxide dismutase (SOD) activity, indicative of oxidative stress. Lentivirus-mediated TPM3 overexpression attenuated hypoxia-induced morphological changes, cellular damage, and oxidative stress imbalance, while TPM3 knockdown exacerbated these effects. Furthermore, treatment with the HDAC1 inhibitor MGCD0103 partially reversed the exacerbation of hypoxia-induced injury caused by TPM3 knockdown. Protein–protein interaction (PPI) network and functional enrichment analysis suggested that TPM3 may modulate cardiac muscle development, contraction, and adrenergic signaling pathways. In conclusion, our findings highlight the therapeutic potential of TPM3 modulation in mitigating hypoxia-associated cardiac injury, suggesting a promising avenue for the treatment of ischemic heart disease and other hypoxia-related cardiac pathologies. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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13 pages, 902 KiB

Open AccessArticle

Analysis of VEGF, IGF1/2 and the Long Noncoding RNA (lncRNA) H19 Expression in Polish Women with Endometriosis

by Beata Smolarz, Tomasz Szaflik, Hanna Romanowicz, Magdalena Bryś, Ewa Forma and Krzysztof Szyłło

Int. J. Mol. Sci. 2024, 25(10), 5271; https://doi.org/10.3390/ijms25105271 - 12 May 2024

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Abstract

The coordinated action of VEGF, IGF1/2 and H19 factors influences the development of endometriosis. The aim of this study was to analyze the expression level of these genes in patients with endometriosis. The study group consisted of 100 patients who were diagnosed with [...] Read more.

The coordinated action of VEGF, IGF1/2 and H19 factors influences the development of endometriosis. The aim of this study was to analyze the expression level of these genes in patients with endometriosis. The study group consisted of 100 patients who were diagnosed with endometriosis on laparoscopic and pathological examination. The control group consisted of 100 patients who were found to be free of endometriosis during the surgical procedure and whose eutopic endometrium wasnormal on histopathological examination. These patients were operated on for uterine fibroids. Gene expression was determined by RT-PCR. The expression of the VEGF gene was significantly higher in the samples classified as clinical stage 1–2 compared to the control material (p < 0.05). There was also a statistically significant difference between the samples studied at clinical stages 1–2 and 3–4 (p < 0.01). The expression of the VEGF gene in the group classified as 1–2 was significantly higher. IGF1 gene expression was significantly lower both in the group of samples classified as clinical stages 1–2 and 3–4 compared to the control group (p < 0.05 in both cases). The expression of the H19 gene was significantly lower in the group of samples classified as clinical stage 3–4 compared to the control group (p < 0.01). The reported studies suggest significant roles of VEGF, IGF and H19 expression in the pathogenesis of endometriosis. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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32 pages, 5088 KiB

Open AccessArticle

Sex-Hormone-Binding Globulin Gene Polymorphisms and Breast Cancer Risk in Caucasian Women of Russia

by Irina Ponomarenko, Konstantin Pasenov, Maria Churnosova, Inna Sorokina, Inna Aristova, Vladimir Churnosov, Marina Ponomarenko, Evgeny Reshetnikov and Mikhail Churnosov

Int. J. Mol. Sci. 2024, 25(4), 2182; https://doi.org/10.3390/ijms25042182 - 11 Feb 2024

Cited by 3 | Viewed by 1777

Abstract

In our work, the associations of GWAS (genome-wide associative studies) impact for sex-hormone-binding globulin (SHBG)-level SNPs with the risk of breast cancer (BC) in the cohort of Caucasian women of Russia were assessed. The work was performed on a sample of 1498 women [...] Read more.

In our work, the associations of GWAS (genome-wide associative studies) impact for sex-hormone-binding globulin (SHBG)-level SNPs with the risk of breast cancer (BC) in the cohort of Caucasian women of Russia were assessed. The work was performed on a sample of 1498 women (358 BC patients and 1140 control (non BC) subjects). SHBG correlated in previously GWAS nine polymorphisms such as rs780093 GCKR, rs17496332 PRMT6, rs3779195 BAIAP2L1, rs10454142 PPP1R21, rs7910927 JMJD1C, rs4149056 SLCO1B1, rs440837 ZBTB10, rs12150660 SHBG, and rs8023580 NR2F2 have been genotyped. BC risk effects of allelic and non-allelic SHBG-linked gene SNPs interactions were detected by regression analysis. The risk genetic factor for BC developing is an SHBG-lowering allele variant C rs10454142 PPP1R21 ([additive genetic model] OR = 1.31; 95%CI = 1.08–1.65; p_perm = 0.024; power = 85.26%), which determines 0.32% of the cancer variance. Eight of the nine studied SHBG-related SNPs have been involved in cancer susceptibility as part of nine different non-allelic gene interaction models, the greatest contribution to which is made by rs10454142 PPP1R21 (included in all nine models, 100%) and four more SNPs—rs7910927 JMJD1C (five models, 55.56%), rs17496332 PRMT6 (four models, 44.44%), rs780093 GCKR (four models, 44.44%), and rs440837 ZBTB10 (four models, 44.44%). For SHBG-related loci, pronounced functionality in the organism (including breast, liver, fibroblasts, etc.) was predicted in silico, having a direct relationship through many pathways with cancer pathophysiology. In conclusion, our results demonstrated the involvement of SHBG-correlated genes polymorphisms in BC risk in Caucasian women in Russia. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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16 pages, 2538 KiB

Open AccessArticle

Sequence Variant Analysis of the APOCII Locus among an Arab Cohort

by Suzanne A. Al-Bustan, Maryam H. Alrashid, Ahmad E. Al-Serri, Babitha G. Annice and Hussain M. Bahbahani

Int. J. Mol. Sci. 2023, 24(22), 16293; https://doi.org/10.3390/ijms242216293 - 14 Nov 2023

Viewed by 1126

Abstract

Apolipoprotein CII (ApocII) plays a key role in regulating lipoprotein lipase (LPL) in lipid metabolism and transport. Numerous polymorphisms within APOCII are reportedly associated with type 2 diabetes mellitus (T2DM), dyslipidemia, and aberrant plasma lipid levels. Few studies have investigated sequence variants at [...] Read more.

Apolipoprotein CII (ApocII) plays a key role in regulating lipoprotein lipase (LPL) in lipid metabolism and transport. Numerous polymorphisms within APOCII are reportedly associated with type 2 diabetes mellitus (T2DM), dyslipidemia, and aberrant plasma lipid levels. Few studies have investigated sequence variants at APOCII loci and their association with metabolic disorders. This study aimed to identify and characterize genetic variants by sequencing the full APOCII locus and its flanking sequences in a sample of the Kuwaiti Arab population, including patients with T2DM, hypertriglyceridemia, non-Arab patients with T2DM, and healthy Arab controls. A total of 52 variants were identified in the noncoding sequences: 45 single nucleotide polymorphisms, wherein five were novel, and seven insertion deletions. The minor allele frequency (MAF) of the 47 previously reported variants was similar to the global MAF and to that reported in major populations. Sequence variant analysis predicted a conserved role for APOCII with a potential role for rs5120 in T2DM and rs7133873 as an informative ethnicity marker. This study adds to the ongoing research that attempts to identify ethnicity-specific variants in the apolipoprotein gene loci and associated LPL genes to elucidate the molecular mechanisms of metabolic disorders. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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15 pages, 3138 KiB

Open AccessArticle

Cervical and Vaginal Microbiomes in Early Miscarriages and Ongoing Pregnancy with and without Dydrogesterone Usage

by Mariya Gryaznova, Olesya Kozarenko, Yuliya Smirnova, Inna Burakova, Mikhail Syromyatnikov, Alexander Maslov and Olga Lebedeva

Int. J. Mol. Sci. 2023, 24(18), 13836; https://doi.org/10.3390/ijms241813836 - 8 Sep 2023

Cited by 5 | Viewed by 1833

Abstract

Emerging evidence suggests that the reproductive tract microbiota is a key modulator of local inflammatory and immune pathways throughout pregnancy and may subsequently impact pregnancy outcomes. In this study, our objective was to analyze the cervical and vaginal microbiomes during early pregnancy among [...] Read more.

Emerging evidence suggests that the reproductive tract microbiota is a key modulator of local inflammatory and immune pathways throughout pregnancy and may subsequently impact pregnancy outcomes. In this study, our objective was to analyze the cervical and vaginal microbiomes during early pregnancy among three groups: women with healthy ongoing pregnancies, women undergoing dydrogesterone treatment, and those who experienced miscarriages. The experiment involved 51 women at 8–11 weeks of gestation. The microbiome was examined using 16S rRNA sequencing on the Ion Torrent PGM platform. Across all groups, Lactobacillus iners was predominant, suggesting that the vaginal community type CST III is common among the majority of participants. Notably, our data highlighted the significant roles of Gardnerella vaginalis and Mycoplasma girerdii in the pathogenesis of early miscarriage. Conversely, L. iners and Bifidobacterium longum have a protective effect in early pregnancy. Moreover, dydrogesterone intake appeared to influence notable differences between the cervical and vaginal microbiomes. Overall, our study enhanced our understanding of the cervical and vaginal microbiome composition in the eastern European population during early pregnancy. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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Review

Jump to: Research, Other

17 pages, 1380 KiB

Open AccessReview

Chromosomal Instability in Gastric Cancer: Role in Tumor Development, Progression, and Therapy

by Marina V. Nemtsova, Ekaterina B. Kuznetsova and Irina V. Bure

Int. J. Mol. Sci. 2023, 24(23), 16961; https://doi.org/10.3390/ijms242316961 - 30 Nov 2023

Cited by 3 | Viewed by 2194

Abstract

According to the Cancer Genome Atlas (TCGA), gastric cancers are classified into four molecular subtypes: Epstein–Barr virus-positive (EBV+), tumors with microsatellite instability (MSI), tumors with chromosomal instability (CIN), and genomically stable (GS) tumors. However, the gastric cancer (GC) with chromosomal instability remains insufficiently [...] Read more.

According to the Cancer Genome Atlas (TCGA), gastric cancers are classified into four molecular subtypes: Epstein–Barr virus-positive (EBV+), tumors with microsatellite instability (MSI), tumors with chromosomal instability (CIN), and genomically stable (GS) tumors. However, the gastric cancer (GC) with chromosomal instability remains insufficiently described and does not have effective markers for molecular and histological verification and diagnosis. The CIN subtype of GC is characterized by chromosomal instability, which is manifested by an increased frequency of aneuploidies and/or structural chromosomal rearrangements in tumor cells. Structural rearrangements in the CIN subtype of GC are not accidental and are commonly detected in chromosomal loci, being abnormal because of specific structural organization. The causes of CIN are still being discussed; however, according to recent data, aberrations in the TP53 gene may cause CIN development or worsen its phenotype. Clinically, patients with the CIN subtype of GC demonstrate poor survival, but receive the maximum benefit from adjuvant chemotherapy. In the review, we consider the molecular mechanisms and possible causes of chromosomal instability in GC, the common rearrangements of chromosomal loci and their impact on the development and clinical course of the disease, as well as the driver genes, their functions, and perspectives on their targeting in the CIN subtype of GC. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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Other

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11 pages, 1175 KiB

Open AccessBrief Report

Gene Therapy Approach for Treatment of Obese Agouti Mice

by Maxim A. Yunin, Stanislav S. Boychenko, Petr Lebedev, Alexey V. Deykin, Mikhail V. Pokrovskii and Alexander D. Egorov

Int. J. Mol. Sci. 2024, 25(22), 12144; https://doi.org/10.3390/ijms252212144 - 12 Nov 2024

Viewed by 276

Abstract

Obesity is a significant metabolic disorder associated with excessive fat accumulation and insulin resistance. In this study, we explored a gene therapy approach to treat obesity in agouti mice using adeno-associated viruses (AAVs) carrying PRDM16, FoxP4, or Follistatin (FST) genes, which are known [...] Read more.

Obesity is a significant metabolic disorder associated with excessive fat accumulation and insulin resistance. In this study, we explored a gene therapy approach to treat obesity in agouti mice using adeno-associated viruses (AAVs) carrying PRDM16, FoxP4, or Follistatin (FST) genes, which are known to promote the browning of white adipose tissue. Mice treated with AAVs encoding PRDM16, FoxP4, or FST genes showed a reduction in body weight (10–14%) within the first three weeks after administration, compared to the control groups. A lipidomic analysis of the adipose tissue revealed a dramatic reduction in triacylglycerol (TAG) species with low carbon numbers (40–54 acyl carbons) in treated mice. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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6 pages, 2308 KiB

Open AccessCase Report

The First Patient with Tibial Hemimelia-Polysyndactyly-Triphalangeal Thumb Syndrome Caused by De Novo c.423+4916 T>C ZRS Variant: A Case Report

by Paola Montserrat Zepeda-Olmos, Kiabeth Robles-Espinoza, Eduardo Esparza-García and María Teresa Magaña-Torres

Int. J. Mol. Sci. 2024, 25(17), 9348; https://doi.org/10.3390/ijms25179348 - 29 Aug 2024

Viewed by 821

Abstract

Genetic variants in the zone of polarizing activity regulatory sequence (ZRS) that induce ectopic expression of the SHH gene have been associated with different ZRS-related phenotypes. We report the first patient with a de novo variant, c.423+4916 T>C, in ZRS (previously classified as [...] Read more.

Genetic variants in the zone of polarizing activity regulatory sequence (ZRS) that induce ectopic expression of the SHH gene have been associated with different ZRS-related phenotypes. We report the first patient with a de novo variant, c.423+4916 T>C, in ZRS (previously classified as a variant of uncertain significance) that causes tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS). A two-month-old male patient presented with bilateral preaxial polydactyly, triphalangeal thumb, and tibial agenesis and was heterozygous for the variant c.423+4916T>C (neither of his parents was a carrier). The findings obtained from the family study were sufficient to reclassify the variant from “uncertain significance” to “likely pathogenic” according to three criteria from the American College of Medical Genetics and Genomics guidelines, as follows: (1) absence of gnomAD, (2) confirmation of paternity and maternity, and (3) strong phenotype–genotype association. In ZRS-associated syndromes, a wide clinical spectrum has been observed, ranging from polydactyly to THPTTS; our patient has the most severe and rare phenotype. We did not perform functional assays. However, the c.423+4916T>C variant is flanked by three variants, which have been proven not only to cause the phenotype but also to increase the expression of SHH. Through all this data gathering, we consider the c.423+4916T>C variant to be causative of THPTTS. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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