The short stature homeobox-containing (SHOX) is the most frequently analysed gene in patients classified as short stature patients (ISS) or diagnosed with Leri-Weill dyschondrosteosis (LWD), Langer mesomelic dysplasia (LMD), or Madelung deformity (MD). However, clinical testing of this gene focuses primarily on single nucleotide variants (SNV) in its coding sequences and copy number variants (CNV) overlapping SHOX gene. This review summarizes the clinical impact of variants in noncoding regions of SHOX. RECENT FINDINGS: CNV extending exclusively into the regulatory elements (i.e., not interrupting the coding sequence) are found more frequently in downstream regulatory elements of SHOX. Further, duplications are more frequent than deletions. Interestingly, downstream duplications are more common than deletions in patients with ISS or LWD but no such differences exist for upstream CNV. Moreover, the presence of specific CNVs in the patient population suggests the involvement of additional unknown factors. Some of its intronic variants, notably NM_000451.3(SHOX):c.-9delG and c.-65C>A in the 5'UTR, have unclear clinical roles. However, these intronic SNV may increase the probability that other CNV will arise de novo in the SHOX gene based on homologous recombination or incorrect splicing of mRNA. SUMMARY: This review highlights the clinical impact of noncoding changes in the SHOX gene and the need to apply new technologies and genotype-phenotype correlation in their analysis.
- Klíčová slova
- CNV, ISS, LWD, Non-coding region, SHOX, SNV,
- MeSH
- fenotyp MeSH
- genetická variace * MeSH
- haploinsuficience genetika MeSH
- intergenová DNA genetika MeSH
- lidé MeSH
- protein SHOX genetika MeSH
- regulace genové exprese MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- intergenová DNA MeSH
- protein SHOX MeSH
The role of G-quadruplex (G4) RNA structures is multifaceted and controversial. Here, we have used as a model the EBV-encoded EBNA1 and the Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded LANA1 mRNAs. We have compared the G4s in these two messages in terms of nucleolin binding, nuclear mRNA retention, and mRNA translation inhibition and their effects on immune evasion. The G4s in the EBNA1 message are clustered in one repeat sequence and the G4 ligand PhenDH2 prevents all G4-associated activities. The RNA G4s in the LANA1 message take part in similar multiple mRNA functions but are spread throughout the message. The different G4 activities depend on flanking coding and non-coding sequences and, interestingly, can be separated individually. Together, the results illustrate the multifunctional, dynamic and context-dependent nature of G4 RNAs and highlight the possibility to develop ligands targeting specific RNA G4 functions. The data also suggest a common multifunctional repertoire of viral G4 RNA activities for immune evasion.
- MeSH
- G-kvadruplexy * MeSH
- intergenová DNA chemie genetika MeSH
- lidé MeSH
- regulace genové exprese MeSH
- RNA virová MeSH
- RNA chemie genetika MeSH
- transport RNA MeSH
- virus Epsteinův-Barrové - jaderné antigeny chemie genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- EBV-encoded nuclear antigen 1 MeSH Prohlížeč
- intergenová DNA MeSH
- RNA virová MeSH
- RNA MeSH
- virus Epsteinův-Barrové - jaderné antigeny MeSH
Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy.
- MeSH
- adaptorové proteiny signální transdukční genetika imunologie MeSH
- B-lymfocyty imunologie patologie MeSH
- chromatin chemie imunologie MeSH
- chromozomální proteiny, nehistonové genetika imunologie MeSH
- genetická predispozice k nemoci * MeSH
- hodnocení rizik MeSH
- intergenová DNA genetika imunologie MeSH
- lidé MeSH
- lokus kvantitativního znaku MeSH
- mnohočetný myelom farmakoterapie genetika imunologie patologie MeSH
- nádorové proteiny genetika imunologie MeSH
- plazmatické buňky imunologie patologie MeSH
- polymorfismus genetický MeSH
- primární buněčná kultura MeSH
- proteiny buněčného cyklu genetika imunologie MeSH
- protokoly protinádorové kombinované chemoterapie MeSH
- regulace genové exprese u nádorů MeSH
- represorové proteiny genetika imunologie MeSH
- sekvence nukleotidů MeSH
- transkripční elongační faktory genetika imunologie MeSH
- typy dědičnosti MeSH
- výměnné faktory guaninnukleotidů genetika imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- adaptorové proteiny signální transdukční MeSH
- CDCA7L protein, human MeSH Prohlížeč
- CEP120 protein, human MeSH Prohlížeč
- chromatin MeSH
- chromozomální proteiny, nehistonové MeSH
- ELL2 protein, human MeSH Prohlížeč
- intergenová DNA MeSH
- nádorové proteiny MeSH
- PREX1 protein, human MeSH Prohlížeč
- proteiny buněčného cyklu MeSH
- represorové proteiny MeSH
- SMARCD3 protein, human MeSH Prohlížeč
- transkripční elongační faktory MeSH
- výměnné faktory guaninnukleotidů MeSH
- WAC protein, human MeSH Prohlížeč
In human cells, each rDNA unit consists of the ~13 kb long ribosomal part and ~30 kb long intergenic spacer (IGS). The ribosomal part, transcribed by RNA polymerase I (pol I), includes genes coding for 18S, 5.8S, and 28S RNAs of the ribosomal particles, as well as their four transcribed spacers. Being highly repetitive, intensively transcribed, and abundantly methylated, rDNA is a very fragile site of the genome, with high risk of instability leading to cancer. Multiple small mutations, considerable expansion or contraction of the rDNA locus, and abnormally enhanced pol I transcription are usual symptoms of transformation. Recently it was found that both IGS and the ribosomal part of the locus contain many functional/potentially functional regions producing non-coding RNAs, which participate in the pol I activity regulation, stress reactions, and development of the malignant phenotype. Thus, there are solid reasons to believe that rDNA locus plays crucial role in carcinogenesis. In this review we discuss the data concerning the human rDNA and its closely associated factors as both targets and drivers of the pathways essential for carcinogenesis. We also examine whether variability in the structure of the locus may be blamed for the malignant transformation. Additionally, we consider the prospects of therapy focused on the activity of rDNA.
- Klíčová slova
- IGS, cancer, copy number, human rDNA, non-coding RNA, ribosomal genes,
- MeSH
- genetická variace genetika MeSH
- intergenová DNA genetika MeSH
- lidé MeSH
- mutace genetika MeSH
- nádory genetika patologie MeSH
- nekódující RNA genetika MeSH
- ribozomální DNA genetika MeSH
- ribozomy genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- intergenová DNA MeSH
- nekódující RNA MeSH
- ribozomální DNA MeSH
Toenail onychomycosis caused by dermatophytes is a significant medical and financial worldwide burden. Relatively scant research has been undertaken as to the predominant species and strains causing this condition in Australia, which is a unique isolated continent with diverse geographical, climatic and population regions. Four regions were selected in Eastern Australia: Far North Queensland, Rural Victoria, Melbourne Metropolitan and Tasmania. From each of these areas, communal nail dust bags from podiatric physicians' work were collected and analysed. A total of 32 dust bags were collected: 10 from Far North Queensland, 8 from Melbourne Metropolitan, 8 from Rural Victoria and 6 from Tasmania. Dermatophyte test medium was used to isolate dermatophytes from the dust, and the colonies were subcultured to Potato Dextrose Agar. Of the bags collected, in total 69% were positive for dermatophytes: 40% from Far North Queensland, 75% from Melbourne Metropolitan, 88% from Rural Victoria and 83% from Tasmania. The internal transcribed spacer (ITS) region of ribosomal DNA was used to identify and compare isolates. A total of 148 dermatophyte strains were identified. The predominant species isolated was Trichophyton interdigitale (125 isolates), which was found in all four regions. This species was further subdivided into four ITS genotypes: the first two were present in all regions, but the third was found only in the Melbourne Metropolitan area and the fourth only in Tasmania. Only one strain of Trichophyton rubrum was found and only in Rural Victoria. Eighteen isolates of Arthroderma quadrifidum were cultured from Rural Victoria and Tasmania and were further classified into three ITS genotypes. Some isolates rarely reported in clinical material were identified as Paraphyton cookei, Arthroderma tuberculatum and Arthroderma crocatum. A potentially new species of Arthroderma was also found in Melbourne Metropolitan. These findings reveal a unique dermatophyte fingerprint in toenails for Eastern Australia.
- Klíčová slova
- Arthroderma, Dermatophyte, Geophilic dermatophytes, Nail dust, Onychomycosis, Trichophyton,
- MeSH
- genotyp MeSH
- intergenová DNA genetika MeSH
- lidé MeSH
- nehty mikrobiologie MeSH
- onychomykóza mikrobiologie MeSH
- Trichophyton genetika patogenita MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Austrálie MeSH
- Názvy látek
- intergenová DNA MeSH
Rapid diagnostics of fungal pneumonia and initiation of appropriate therapy are still challenging. In this study, we used two panfungal assays to test bronchoalveolar lavage fluid (BALF) samples to prove their ability to confirm invasive fungal disease diagnosis and identify causative agents. Two methods targeting different fungal rDNA regions were used, and the obtained PCR products were sequenced directly or after cloning. In total, 106 BALF samples from 104 patients were tested. After sequencing, we obtained 578 sequences. Four hundred thirty-seven sequences were excluded from further analysis due to duplication (n = 335) or similarity with sequences detected in the extraction control sample (n = 102); 141 unique sequences were analyzed. Altogether, 23/141 (16%) of the fungi detected belonged to pathogenic species, and 63/141 (45%) were identified as various yeasts; a variety of environmental or very rare fungal human pathogens represented 29/141 (21%) of the total and 26/141 (18%) were described as uncultured fungus. Panfungal PCR detected fungal species that would be missed by specific methods in only one case (probable cryptococcosis). Panfungal PCR followed by sequencing has limited use for testing BALF samples due to frequent commensal or environmental fungal species pickup.
- MeSH
- bronchoalveolární lavážní tekutina mikrobiologie MeSH
- diagnostické techniky molekulární MeSH
- DNA fungální genetika MeSH
- DNA primery genetika MeSH
- houby genetika izolace a purifikace patogenita MeSH
- imunokompromitovaný pacient * MeSH
- intergenová DNA genetika MeSH
- invazivní mykotické infekce diagnóza MeSH
- lidé MeSH
- polymerázová řetězová reakce MeSH
- sekvenční analýza DNA MeSH
- senzitivita a specificita MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- DNA fungální MeSH
- DNA primery MeSH
- intergenová DNA MeSH
- Klíčová slova
- Candida, Candida parapsilosis complex, MALDI-TOF, fluorescent capillary electrophoresis, fungi,
- MeSH
- Candida parapsilosis klasifikace izolace a purifikace MeSH
- DNA fungální genetika MeSH
- elektroforéza kapilární metody normy MeSH
- fluorescence MeSH
- intergenová DNA genetika MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
- práce podpořená grantem MeSH
- Názvy látek
- DNA fungální MeSH
- intergenová DNA MeSH
Seven new species and two varieties of Klebsormidium were described using an integrative approach on the base of 28 strains from the poorly studied phylogenetic superclade G. These strains originated from the unusual and exotic habitats (semi-deserts, semi-arid shrublands, Mediterranean shrub and deciduous vegetation, temperate Araucaria forests, peat bogs, dumps after coal mining, maritime sand dunes etc.) of four continents (Africa, South and North America, and Europe). Molecular phylogenies based on ITS-1,2, rbcL gene and concatenated dataset of ITS-1,2-rbcL, secondary structure of ITS-2, morphology, ecology and biogeography, micrographs and drawings of the investigated strains were assessed. Additionally, phylogeny and morphology of 18 Klebsormidium strains from other lineages isolated from the same localities (different vegetation types of Chile and maritime sand dunes of Germany) were investigated for the comparison with representatives of clade G. Clade G Klebsormidium is characterized by distant phylogenetic position from the other Klebsormidium lineages and prominent morphology: four-lobed chloroplasts and mostly short swollen cells in young culture, compact small pyrenoids, curved or disintegrated filaments, unusual elongation of cells in old culture, formation of specific cluster- and knot-like colonies on agar surface, especially prominent in strains isolated from desert regions, from which the group probably originated. Comparison of Klebsormidium diversity from different biogeographic regions showed that the representatives of clade G are common algae in regions of the southern hemisphere (South Africa and Chile) and rare representatives in terrestrial ecosystems of the northern hemisphere. Further investigation of mostly unstudied territories of the southern hemisphere could bring many surprises and discoveries, leading to a change of the present concept that Klebsormidium is cosmopolitan in distribution.
- Klíčová slova
- Integrative approach, Klebsormidium, New species, New varieties, Phylogenetic superclade G, Southern hemisphere, Streptophyta, Unusual habitats,
- MeSH
- biodiverzita * MeSH
- chloroplasty MeSH
- fylogeneze * MeSH
- intergenová DNA genetika MeSH
- konformace nukleové kyseliny MeSH
- lesy MeSH
- půda * MeSH
- Streptophyta klasifikace MeSH
- zeměpis MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- intergenová DNA MeSH
- půda * MeSH
In a large family of Czech origin, we mapped a locus for an autosomal-dominant corneal endothelial dystrophy, posterior polymorphous corneal dystrophy 4 (PPCD4), to 8q22.3-q24.12. Whole-genome sequencing identified a unique variant (c.20+544G>T) in this locus, within an intronic regulatory region of GRHL2. Targeted sequencing identified the same variant in three additional previously unsolved PPCD-affected families, including a de novo occurrence that suggests this is a recurrent mutation. Two further unique variants were identified in intron 1 of GRHL2 (c.20+257delT and c.20+133delA) in unrelated PPCD-affected families. GRHL2 is a transcription factor that suppresses epithelial-to-mesenchymal transition (EMT) and is a direct transcriptional repressor of ZEB1. ZEB1 mutations leading to haploinsufficiency cause PPCD3. We previously identified promoter mutations in OVOL2, a gene not normally expressed in the corneal endothelium, as the cause of PPCD1. OVOL2 drives mesenchymal-to-epithelial transition (MET) by directly inhibiting EMT-inducing transcription factors, such as ZEB1. Here, we demonstrate that the GRHL2 regulatory variants identified in PPCD4-affected individuals induce increased transcriptional activity in vitro. Furthermore, although GRHL2 is not expressed in corneal endothelial cells in control tissue, we detected GRHL2 in the corneal "endothelium" in PPCD4 tissue. These cells were also positive for epithelial markers E-Cadherin and Cytokeratin 7, indicating they have transitioned to an epithelial-like cell type. We suggest that mutations inducing MET within the corneal endothelium are a convergent pathogenic mechanism leading to dysfunction of the endothelial barrier and disease.
- Klíčová slova
- GRHL2, PPCD, corneal dystrophy, corneal edema, corneal endothelium, ectopic expression, epithelial-to-mesenchymal transition, mesenchymal-to-epithelial transition, non-coding mutation, regulatory region,
- MeSH
- dědičné dystrofie rohovky genetika MeSH
- DNA vazebné proteiny genetika MeSH
- genetická transkripce MeSH
- genetické lokusy MeSH
- HEK293 buňky MeSH
- intergenová DNA genetika MeSH
- introny genetika MeSH
- lidé MeSH
- modely genetické MeSH
- mutace genetika MeSH
- promotorové oblasti (genetika) genetika MeSH
- rodina MeSH
- rodokmen MeSH
- rohovkový endotel patologie MeSH
- sekvence nukleotidů MeSH
- sekvenování celého genomu MeSH
- transkripční faktory genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- DNA vazebné proteiny MeSH
- GRHL2 protein, human MeSH Prohlížeč
- intergenová DNA MeSH
- transkripční faktory MeSH
During a survey of the biodiversity of entomopathogenic nematodes in Ukraine, a population of Steinernema arenarium, strain Ch, was recovered in the sensitive Chornobyl Exclusion Zone. In the present work, this strain was morphologically and molecularly characterised using light microscopy and the sequences of the ITS and D2-D3 region of the 28S rDNA. In addition, we sequenced the ITS and D2-D3 regions of four populations of S. arenarium from a laboratory collection. Phylogenetic analyses were performed and the phylogenetic structure and geographic distribution of S. arenarium are discussed.
- Klíčová slova
- Steinernema arenarium, Ukraine, distribution, entomopathogenic nematodes, morphology, phylogeny,
- MeSH
- DNA helmintů genetika MeSH
- fylogeneze MeSH
- intergenová DNA genetika MeSH
- půda parazitologie MeSH
- Rhabditida genetika izolace a purifikace MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Ukrajina MeSH
- Názvy látek
- DNA helmintů MeSH
- intergenová DNA MeSH
- půda MeSH
