Research

36 pages, 3980 KiB

Open AccessArticle

SNP and Structural Study of the Notch Superfamily Provides Insights and Novel Pharmacological Targets against the CADASIL Syndrome and Neurodegenerative Diseases

by Louis Papageorgiou, Lefteria Papa, Eleni Papakonstantinou, Antonia Mataragka, Konstantina Dragoumani, Dimitrios Chaniotis, Apostolos Beloukas, Costas Iliopoulos, Erik Bongcam-Rudloff, George P. Chrousos, Sofia Kossida, Elias Eliopoulos and Dimitrios Vlachakis

Genes 2024, 15(5), 529; https://doi.org/10.3390/genes15050529 - 23 Apr 2024

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Abstract

The evolutionary conserved Notch signaling pathway functions as a mediator of direct cell–cell communication between neighboring cells during development. Notch plays a crucial role in various fundamental biological processes in a wide range of tissues. Accordingly, the aberrant signaling of this pathway underlies [...] Read more.

The evolutionary conserved Notch signaling pathway functions as a mediator of direct cell–cell communication between neighboring cells during development. Notch plays a crucial role in various fundamental biological processes in a wide range of tissues. Accordingly, the aberrant signaling of this pathway underlies multiple genetic pathologies such as developmental syndromes, congenital disorders, neurodegenerative diseases, and cancer. Over the last two decades, significant data have shown that the Notch signaling pathway displays a significant function in the mature brains of vertebrates and invertebrates beyond neuronal development and specification during embryonic development. Neuronal connection, synaptic plasticity, learning, and memory appear to be regulated by this pathway. Specific mutations in human Notch family proteins have been linked to several neurodegenerative diseases including Alzheimer’s disease, CADASIL, and ischemic injury. Neurodegenerative diseases are incurable disorders of the central nervous system that cause the progressive degeneration and/or death of brain nerve cells, affecting both mental function and movement (ataxia). There is currently a lot of study being conducted to better understand the molecular mechanisms by which Notch plays an essential role in the mature brain. In this study, an in silico analysis of polymorphisms and mutations in human Notch family members that lead to neurodegenerative diseases was performed in order to investigate the correlations among Notch family proteins and neurodegenerative diseases. Particular emphasis was placed on the study of mutations in the Notch3 protein and the structure analysis of the mutant Notch3 protein that leads to the manifestation of the CADASIL syndrome in order to spot possible conserved mutations and interpret the effect of these mutations in the Notch3 protein structure. Conserved mutations of cysteine residues may be candidate pharmacological targets for the potential therapy of CADASIL syndrome. Full article

(This article belongs to the Special Issue Head and Neck Genetics)

12 pages, 796 KiB

Open AccessArticle

by Ieva Golubickaite, Rasa Ugenskiene, Agne Bartnykaite, Lina Poskiene, Aurelija Vegiene, Evaldas Padervinskis, Viktoras Rudzianskas and Elona Juozaityte

Genes 2023, 14(2), 434; https://doi.org/10.3390/genes14020434 - 08 Feb 2023

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Abstract

In 2020, 878,348 newly reported cases and 444,347 deaths related to head and neck cancer were reported. These numbers suggest that there is still a need for molecular biomarkers for the diagnosis and prognosis of the disease. In this study, we aimed to [...] Read more.

In 2020, 878,348 newly reported cases and 444,347 deaths related to head and neck cancer were reported. These numbers suggest that there is still a need for molecular biomarkers for the diagnosis and prognosis of the disease. In this study, we aimed to analyze mitochondria-related mitochondrial transcription factor A (TFAM) and DNA polymerase γ (POLG) single-nucleotide polymorphisms (SNPs) in the head and neck cancer patient group and evaluate associations between SNPs, disease characteristics, and patient outcomes. Genotyping was performed using TaqMan probes with Real-Time polymerase chain reaction. We found associations between TFAM gene SNPs rs11006129 and rs3900887 and patient survival status. We found that patients with the TFAM rs11006129 CC genotype and non-carriers of the T allele had longer survival times than those with the CT genotype or T-allele carriers. Additionally, patients with the TFAM rs3900887 A allele tended to have shorter survival times than non-carriers of the A allele. Our findings suggest that variants in the TFAM gene may play an important role in head and neck cancer patient survival and could be considered and further evaluated as prognostic biomarkers. However, due to the limited sample size (n = 115), further studies in larger and more diverse cohorts are needed to confirm these findings. Full article

(This article belongs to the Special Issue Head and Neck Genetics)

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9 pages, 267 KiB

Open AccessCommunication

Selected SNPs of FCN2 Associated with Chronic Tonsillitis in the Polish Adult Population

by Jadwiga Gaździcka, Karolina Gołąbek, Dorota Hudy, Katarzyna Miśkiewicz-Orczyk, Natalia Zięba, Wojciech Tynior, Marek Asman, Maciej Misiołek and Joanna Katarzyna Strzelczyk

Genes 2023, 14(2), 242; https://doi.org/10.3390/genes14020242 - 17 Jan 2023

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Abstract

Chronic tonsillitis is a problem related to bacterial and viral infections. Ficolins play a key role in the defence against various pathogens. In the present study, we investigated the associations between the selected single nucleotide polymorphisms (SNPs) of the FCN2 gene and chronic [...] Read more.

Chronic tonsillitis is a problem related to bacterial and viral infections. Ficolins play a key role in the defence against various pathogens. In the present study, we investigated the associations between the selected single nucleotide polymorphisms (SNPs) of the FCN2 gene and chronic tonsillitis in the Polish population. The study included 101 patients with chronic tonsillitis and 101 healthy individuals. The selected SNPs of FCN2 (rs3124953, rs17514136 and rs3124954) were genotyped using TaqMan SNP Genotyping Assays (Applied Biosystem, Foster City, CA, USA). The analysis of rs17514136 and rs3124953 showed no significant differences in genotype frequencies between the chronic tonsillitis patients and controls (p > 0.01). The CT genotype of rs3124954 was significantly more frequent, while the CC genotype was less frequent in chronic tonsillitis patients (p = 0.003 and p = 0.001, respectively). The frequency of the A/G/T haplotype (rs17514136/rs3124953/rs3124954) was significantly more common in chronic tonsillitis patients (p = 0.0011). Moreover, the FCN2 CT genotype of rs3124954 was associated with a higher risk of chronic tonsillitis, while the CC genotype of rs3124954 decreased this risk. Our findings demonstrate that FCN2 rs3124954 may be associated with chronic tonsillitis in the Polish adult population. Full article

(This article belongs to the Special Issue Head and Neck Genetics)

18 pages, 1522 KiB

Open AccessArticle

Rare CNVs and Known Genes Linked to Macrocephaly: Review of Genomic Loci and Promising Candidate Genes

by Giovanna Civitate Bastos, Giovanna Cantini Tolezano and Ana Cristina Victorino Krepischi

Genes 2022, 13(12), 2285; https://doi.org/10.3390/genes13122285 - 04 Dec 2022

Cited by 2 | Viewed by 1835

Abstract

Macrocephaly frequently occurs in single-gene disorders affecting the PI3K-AKT-MTOR pathway; however, epigenetic mutations, mosaicism, and copy number variations (CNVs) are emerging relevant causative factors, revealing a higher genetic heterogeneity than previously expected. The aim of this study was to investigate the role of [...] Read more.

Macrocephaly frequently occurs in single-gene disorders affecting the PI3K-AKT-MTOR pathway; however, epigenetic mutations, mosaicism, and copy number variations (CNVs) are emerging relevant causative factors, revealing a higher genetic heterogeneity than previously expected. The aim of this study was to investigate the role of rare CNVs in patients with macrocephaly and review genomic loci and known genes. We retrieved from the DECIPHER database de novo <500 kb CNVs reported on patients with macrocephaly; in four cases, a candidate gene for macrocephaly could be pinpointed: a known microcephaly gene–TRAPPC9, and three genes based on their functional roles–RALGAPB, RBMS3, and ZDHHC14. From the literature review, 28 pathogenic CNV genomic loci and over 300 known genes linked to macrocephaly were gathered. Among the genomic regions, 17 CNV loci (~61%) exhibited mirror phenotypes, that is, deletions and duplications having opposite effects on head size. Identifying structural variants affecting head size can be a preeminent source of information about pathways underlying brain development. In this study, we reviewed these genes and recurrent CNV loci associated with macrocephaly, as well as suggested novel potential candidate genes deserving further studies to endorse their involvement with this phenotype. Full article

(This article belongs to the Special Issue Head and Neck Genetics)

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10 pages, 249 KiB

Open AccessArticle

Single Nucleotide Polymorphism and mRNA Expression of LTF in Oral Squamous Cell Carcinoma

by Karolina Gołąbek, Grzegorz Rączka, Jadwiga Gaździcka, Katarzyna Miśkiewicz-Orczyk, Natalia Zięba, Łukasz Krakowczyk, Dorota Hudy, Marek Asman, Maciej Misiołek and Joanna Katarzyna Strzelczyk

Genes 2022, 13(11), 2085; https://doi.org/10.3390/genes13112085 - 10 Nov 2022

Cited by 2 | Viewed by 1226

Abstract

Oral squamous cell carcinoma (OSCC) is one of the most prevalent types of cancers worldwide. LTF arrests the G1 to S phase transition of the cell cycle. This study is the first that has aimed to determine the possible association between the LTF [...] Read more.

Oral squamous cell carcinoma (OSCC) is one of the most prevalent types of cancers worldwide. LTF arrests the G1 to S phase transition of the cell cycle. This study is the first that has aimed to determine the possible association between the LTF polymorphisms (rs2073495, rs1126478, rs34827868, rs1042073, rs4637321, rs2239692 and rs10865941), the mRNA LTF expression, the risk of OSCC and the influence on the TNM staging and histological grading. This study was composed of 176 Polish patients, including 88 subjects diagnosed with OSCC and 88 healthy individuals. QuantStudio Design and Analysis Software v1.5.1 was used for the single nucleotide polymorphism (SNP) analysis and mRNA LTF expression. The G/G genotype of rs2073495 and the G/G genotype of rs4637321 were linked, with an increased risk of OSCC. There were no significant influences between the TNM staging and the histological grading and the LTF genotype. We found no statistically significant dissimilarities in the expression level of LTF genes in the tumour and margin specimens. No association was found between the gene expression levels, the other parameters or LTF polymorphisms in the tumour and margin samples. In conclusion, rs2073495 and rs4637321 polymorphisms may affect the risk of OSCC. These results should be validated on larger and different cohorts to better comprehend the role of the LTF gene in OSCC. Full article

(This article belongs to the Special Issue Head and Neck Genetics)

Review

Jump to: Research, Other

32 pages, 16184 KiB

Open AccessReview

Review of Disease-Specific microRNAs by Strategically Bridging Genetics and Epigenetics in Oral Squamous Cell Carcinoma

by Iphigenia Gintoni, Stavros Vassiliou, George P. Chrousos and Christos Yapijakis

Genes 2023, 14(8), 1578; https://doi.org/10.3390/genes14081578 - 02 Aug 2023

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Abstract

Oral squamous cell carcinoma (OSCC) is one of the most prevalent human malignancies and a global health concern with a poor prognosis despite some therapeutic advances, highlighting the need for a better understanding of its molecular etiology. The genomic landscape of OSCC is [...] Read more.

Oral squamous cell carcinoma (OSCC) is one of the most prevalent human malignancies and a global health concern with a poor prognosis despite some therapeutic advances, highlighting the need for a better understanding of its molecular etiology. The genomic landscape of OSCC is well-established and recent research has focused on miRNAs, which regulate gene expression and may be useful non-invasive biomarkers or therapeutic targets. A plethora of findings regarding miRNA expression have been generated, posing challenges for the interpretation and identification of disease-specific molecules. Hence, we opted to identify the most important regulatory miRNAs by bridging genetics and epigenetics, focusing on the key genes implicated in OSCC development. Based on published reports, we have developed custom panels of fifteen major oncogenes and five major tumor suppressor genes. Following a miRNA/target gene interaction analysis and a comprehensive study of the literature, we selected the miRNA molecules which target the majority of these panels that have been reported to be downregulated or upregulated in OSCC, respectively. As a result, miR-34a-5p, miR-155-5p, miR-124-3p, miR-1-3p, and miR-16-5p appeared to be the most OSCC-specific. Their expression patterns, verified targets, and the signaling pathways affected by their dysregulation in OSCC are thoroughly discussed. Full article

(This article belongs to the Special Issue Head and Neck Genetics)

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Jump to: Research, Review

8 pages, 1764 KiB

Open AccessCase Report

A TMEM63A Nonsense Heterozygous Variant Linked to Infantile Transient Hypomyelinating Leukodystrophy Type 19?

by Dimitra Siori, Dimitrios Vlachakis, Periklis Makrythanasis, Joanne Traeger-Synodinos, Danai Veltra, Afrodite Kampouraki and George P. Chrousos

Genes 2024, 15(5), 525; https://doi.org/10.3390/genes15050525 - 23 Apr 2024

Viewed by 260

Abstract

Infantile onset transient hypomyelination (IOTH) is a rare form of leukodystrophy that is associated with transient motor impairment and delayed central nervous system myelination. Here, we report a case of a new mutation in the transmembrane protein 63A (TMEM63A) gene identified [...] Read more.

Infantile onset transient hypomyelination (IOTH) is a rare form of leukodystrophy that is associated with transient motor impairment and delayed central nervous system myelination. Here, we report a case of a new mutation in the transmembrane protein 63A (TMEM63A) gene identified using Whole-Exome Sequencing (WES) in an 8.5-year-old boy with clinical symptoms similar to IOTH. The patient exhibited a mild developmental delay, including hypotonia and delayed motor milestones, as well as some notable phenotypic characteristics, such as macrocephaly and macrosomia. Despite the absence of early neuroimaging, genetic testing revealed a paternally inherited variant in TMEM63A (NM_14698.3:c.220A>T;p:(Arg74*)), potentially linked to infantile transient hypomyelinating leukodystrophy type 19. Our findings in this study and the patient’s favorable clinical course underscore the potential for successful myelination even with delayed initiation and may contribute to a better understanding of the genotype–phenotype correlation in IOTH, emphasizing the importance of genetic analysis in unresolved developmental delay cases and providing critical insights for accurate diagnosis, prognosis and potential therapeutic strategies in rare leukodystrophies. Full article

(This article belongs to the Special Issue Head and Neck Genetics)

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14 pages, 2987 KiB

Open AccessCase Report

Molecular Modeling Analysis Provides Genotype–Phenotype Correlation Insights in a Patient with Ankyloblepharon-Ectodermal Dysplasia-Clefting Syndrome

by Anna Douka, Lambros Goutzanis, Dimitrios Vlachakis, George P. Chrousos and Christos Yapijakis

Genes 2023, 14(6), 1246; https://doi.org/10.3390/genes14061246 - 10 Jun 2023

Viewed by 1943

Abstract

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is a rare autosomal dominant disorder. AEC is caused by mutations in the TP63 gene that encodes the tumor suppressor p63 protein, itself involved in the regulation of epidermal proliferation, development, and differentiation. We present here a typical [...] Read more.

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is a rare autosomal dominant disorder. AEC is caused by mutations in the TP63 gene that encodes the tumor suppressor p63 protein, itself involved in the regulation of epidermal proliferation, development, and differentiation. We present here a typical AEC case of a four-year-old girl with extensive skin erosions and erythroderma of the scalp and the trunk, and to a lesser extent of the limbs, nail dystrophy on the fingers and toes, xerophthalmia, a high-arched palate, oligodontia, and hypohidrosis. Mutation analysis of the TP63 gene detected a de novo missense mutation in exon 14 (c.1799G>T; p.Gly600Val). We discuss the phenotype–genotype correlation by presenting the clinical features of AEC in the patient, and the effect of the detected mutation in p63 structure and function using protein structural modeling, in view of similar cases in the literature. We performed a molecular modeling study in order to link the effect on the protein structure level of the missense mutation G600V. We noted that the introduction of the bulkier Valine residue in place of the slim Glycine residue caused a significantly altered 3D conformational arrangement of that protein region, pushing away the adjacent antiparallel α helix. We propose that the introduced locally altered structure of the G600V mutant p63 has a significant functional effect on specific protein–protein interactions, thus affecting the clinical phenotype. Full article

(This article belongs to the Special Issue Head and Neck Genetics)

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