Albinism is a widespread departure from a typical body colouration due to altered melanin production. The Wels catfish (Silurus glanis) is among the largest freshwater fish species in the world, and albino individuals occur both in the wild and in aquaculture. Here, we performed transcriptome-wide analysis of albino and normally pigmented S. glanis using four tissues (skin, dorsal fin, whole eye and liver) to identify genes associated with albinism by exploring patterns of differential expression (DE) and differential alternative splicing (DAS). Multi-tissue analyses revealed a large number of genes in skin (n = 1355) and fin (n = 614) tissue associated with the albino phenotype in S. glanis, while the number of DE genes in eye and liver tissues was lower (n = 188, n = 189, respectively). Several DE genes across multiple tissues were detected as the most promising candidates (e.g., hsp4, hsp90b1, raph1, uqcrfs1, adcy-family and wnt-family) potentially causally linked to the albino phenotype in Wels catfish. Moreover, our findings supported earlier observations of physiological differences between albino and normally pigmented individuals, particularly in energy metabolism and immune response. In contrast, there were only a few pigmentation-related genes observed among DAS genes (4 in skin, 2 in fin), the overlap between DAS and DE genes was low (n = 25) and did not include known pigmentation-related genes. This suggests that DAS and DE in Wels catfish are, to a large extent, independent processes, and the observed alternative splicing cases are probably not causally linked with albinism in S. glanis. This work provides the first transcriptome-wide multi-tissue insights into the albinism of Wels catfish and serves as a valuable resource for further understanding the genetic mechanisms of pigmentation in fish.
- Klíčová slova
- ADCY, Catfish, Fish, Genomics, HPS4, Omics, Pigmentation-related genes, Transcriptome, WNT,
- MeSH
- albinismus * genetika MeSH
- alternativní sestřih MeSH
- stanovení celkové genové exprese MeSH
- sumci * genetika metabolismus MeSH
- transkriptom MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
UV irradiation induces "bulky" DNA photodimers such as (6-4)-photoproducts and cyclobutane pyrimidine dimers that are removed by nucleotide excision repair, a complex process defective in the sunlight-sensitive and cancer-prone disease xeroderma pigmentosum. Some bacteria and lower eukaryotes can also repair photodimers by enzymatically simpler mechanisms, but such pathways have not been reported in normal human cells. Here, we have identified such a mechanism. We show that normal human cells can employ a DNA base excision repair process involving NTH1, APE1, PARP1, XRCC1, and FEN1 to rapidly remove a subset of photodimers at early times following UVC irradiation. Loss of these proteins slows the early rate of repair of photodimers in normal cells, ablates their residual repair in xeroderma pigmentosum cells, and increases UVC sensitivity ∼2-fold. These data reveal that human cells can excise photodimers using a long-patch base excision repair process that functions additively but independently of nucleotide excision repair.
- Klíčová slova
- PARP1, base excision repair, nucleotide excision repair, photoproducts, single-strand break repair,
- MeSH
- DNA genetika MeSH
- lidé MeSH
- oprava DNA genetika MeSH
- poškození DNA genetika MeSH
- protein XRCC1 metabolismus MeSH
- pyrimidinové dimery genetika metabolismus MeSH
- ultrafialové záření MeSH
- xeroderma pigmentosum * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- DNA MeSH
- protein XRCC1 MeSH
- pyrimidinové dimery MeSH
- XRCC1 protein, human MeSH Prohlížeč
BACKGROUND: Ionizing radiation DNA damage is the main mechanism of radiotherapy (RT) action and the outcome of treatment and healthy tissue toxicity is influenced by a number of external and internal factors, including mutations in DNA damage recognition and repair. Disorders of DNA repair may result in increased sensitivity to cancer treatment. PURPOSE: The mechanism of DNA repair and an overview of genetic syndromes with mutations in genes involved in DNA repair clarify the accelerated carcinogenesis and increased radiosensitivity in RT cancers. Most radiosensitivity syndromes are autosomal recessively inherited; examples are ataxia teleangiectasia, Nijmegen breakage syndrome, xeroderma pigmentosum, Cockayne syndrome, Bloom syndrome and Werner syndrome. CONCLUSION: Radiotherapy is contraindicated in most homozygous patients with recessive radiosensitivity syndromes. Asymptomatic heterozygotes may have an increased risk of tumor incidence and a small part of them slightly increased risk of RT intolerance; however, this does not limit RT treatment. The high risk of secondary malignancies after radiotherapy is a contraindication to adjuvant RT in Li-Fraumeni syndrome.
- Klíčová slova
- DNA repair, radiosensitivity, radiotherapy,
- MeSH
- Cockayneův syndrom * genetika MeSH
- lidé MeSH
- mutace MeSH
- oprava DNA genetika MeSH
- tolerance záření genetika MeSH
- xeroderma pigmentosum * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Oculocutaneous albinism is the result of a combination of homozygous recessive mutations that block the synthesis of the tyrosine and melatonin hormones. This disability is associated with physiological limitations, e.g., visual impairment expressed by lower visual acuity and movement perception, and eventually leads to acrophobia and/or photophobia, suggesting a potentially higher stress level associated with the behavioral responses of individuals with albinism to external stimuli compared to their pigmented conspecifics. However, in fish, differences in behavioral and/or physiological responses and stress levels between these phenotypes have been poorly documented. While acoustic perception of albino individuals is well known, the use of olfactory sensors for social communication, e.g., for the preference for familiar conspecifics, remains poorly understood. We performed two laboratory experiments with albino and pigmented European catfish Silurus glanis to observe: i) their behavioral and physiological responses to short-term stress induced by a combination of air exposure and novel environmental stressors and ii) their ability to use odor keys to recognize of familiar conspecifics and the influence of lateralization on this preference. In response to stress stimuli, albino fish showed higher movement activities and ventilatory frequencies and more often changed their swimming directions compared to their pigmented conspecifics. Blood plasma analysis showed significantly higher values of stress-, deprivation-, and emotional arousal-associated substances, e.g., glucose and lactate, as well as of substances released during intensive muscle activity of hyperventilation and tissue hypoxia, e.g., hemoglobin, mean corpuscular hemoglobin, erythrocytes, and neutrophil granulocytes. A preference test between environments with and without scented water showed the preference by both albino and pigmented catfish for environments with scent of familiar conspecifics, and both groups of fish displayed left-side lateralization associated with the observation of conspecifics and group coordination. The results tended to show higher physiological and behavioral responses of albinos to stress stimuli compared to the responses of their pigmented conspecifics, but the uses of olfactory sensors and lateralization were not differentiated between the two groups.
- Klíčová slova
- albinism, blood plasma, fish, frequency, movement activity, preference test, ventilatory,
- MeSH
- albinismus * MeSH
- fobie MeSH
- plavání MeSH
- rozpoznávání (psychologie) MeSH
- sumci * MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Lichen aureus is a variant of pigmented purpuric dermatoses. The usual histopathology of lichen aureus is characterized by a subepidermal dense, band-like lymphocytic infiltrate, extravasated erythrocytes, and hemosiderin deposits. We report three patients with lichen aureus on the extremities with similar clinical, dermoscopic, and histopathological findings characterized by a dense band-like relatively deep dermal infiltrate accompanied by extravasation of erythrocytes and hemosiderin deposits occasioning a resemblance to a lymphoproliferative disorder.
- Klíčová slova
- lichen aureus, mycosis fungoides, pigmented purpuric dermatosis, pseudolymphoma,
- MeSH
- dermatoskopie metody MeSH
- diferenciální diagnóza MeSH
- dospělí MeSH
- erytrocyty patologie MeSH
- hemosiderin analýza MeSH
- imunohistochemie metody MeSH
- kožní nemoci patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfocyty patologie MeSH
- lymfoproliferativní nemoci metabolismus patologie MeSH
- plazmatické buňky patologie MeSH
- poruchy pigmentace patologie MeSH
- pseudolymfom komplikace patologie MeSH
- purpura diagnóza patologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- Názvy látek
- hemosiderin MeSH
PURPOSE OF REVIEW: Peutz-Jeghers syndrome is a rare, autosomal dominant, hereditary polyposis syndrome defined by gastrointestinal hamartomas and mucocutaneous pigmentations, caused by a germline mutation in the serine/ threonine kinase 11 or liver kinase B1 (STK11/LKB1) genes. Hamartomatous polyps located throughout the gastrointestinal tract can be complicated by bleeding and small bowel intussusception, potentially leading to the need for emergency surgery. Individuals suffering from Peutz-Jeghers syndrome have an increased lifetime risk of various forms of cancer (gastrointestinal, pancreatic, lung, breast, uterine, ovarian and testicular). Surveillance should lead to the prevention of complications and thus a reduction in mortality and morbidity of patients. RECENT FINDINGS: A combined approach based on wireless capsule endoscopy, magnetic resonance enterography and device-assisted enteroscopy is effective in reduction of the polyp burden and thus decreasing the risk of bleeding and intussusception. Current guidelines for screening and surveillance are mostly based on expert opinion rather than evidence. SUMMARY: Peutz-Jeghers syndrome is an emerging disease that significantly affects the quality of life enjoyed by patients. Despite of all the progress in improved early diagnostics, options for advanced endoscopic therapy and elaborate surveillance, acute and chronic complications decrease the life expectancy of patients suffering from Peutz-Jeghers syndrome.
BACKGROUND: 'Braun' is an illegal injectable dihydrocodeinone-enriched drug mixture of semi-synthetic opioids. It is prepared by palladium-catalysed hydrogenation from codeine-containing tablets. OBJECTIVE: We aimed to characterize the dermatologic consequences of long-term abuse of 'Braun'. METHODS: Skin biopsies of two long-term 'Braun' abusers were evaluated histopathologically, immunohistochemically and ultrastructurally. Palladium skin content was assessed by X-ray fluorescence (XRF) spectrometry. RESULTS: Both patients showed generalized diffuse dark blue-grey hyperpigmentation of the skin. In both, an abnormal population of cells containing intracytoplasmic brownish granular material was identified in the papillary dermis by light microscopy. Electron microscopy revealed a dense and minimally structured material that predominantly accumulated in macrophages, fibroblasts and vascular endothelial cells. XRF analysis confirmed elevated levels of palladium in the patient's skin in comparison to healthy controls. CONCLUSION: Long-term abuse of palladium-contaminated dihydrocodeinone ('Braun') results in excessive accumulation of granular material in various dermal cell types and causes generalized diffuse skin hyperpigmentation.
- MeSH
- fluorescenční spektrometrie MeSH
- hydrokodon škodlivé účinky MeSH
- hyperpigmentace chemicky indukované metabolismus patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- narkotika škodlivé účinky MeSH
- palladium škodlivé účinky metabolismus MeSH
- poruchy způsobené užíváním narkotik komplikace MeSH
- syntetická léčiva škodlivé účinky MeSH
- zakázané drogy škodlivé účinky MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- Názvy látek
- hydrokodon MeSH
- narkotika MeSH
- palladium MeSH
- syntetická léčiva MeSH
- zakázané drogy MeSH
BACKGROUND: Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder that is associated with oculocutaneous albinism, bleeding diathesis, granulomatous colitis, and highly penetrant pulmonary fibrosis in some subtypes. Homozygous or compound heterozygous pathological variants in HPS1, HPS3, HPS4, and several other genes lead to clinical manifestation of the disease. CASE PRESENTATION: A 57-year-old female was admitted with congenital oculocutaneous albinism, thrombocytopathy and late-onset accelerated pulmonary fibrosis (first symptoms from age 50 onwards). Chest high-resolution computed tomography identified thickening of peribronchovascular interstitium, bronchiectasis, reticulations, honeycombing, ground glass opacities and lung parenchyma consolidations. HPS was clinically suspected. We performed whole exome sequencing (WES), a form of massive parallel sequencing, of proband-parents trio. Whole exome libraries were processed using KAPA Hyper Prep Kit, SeqCap EZ MedExome Enrichment Kit and HyperCap Bead Kit according to the SeqCap EZ HyperCap Workflow. The paired-end 2 × 75 bp sequencing was performed on the Illumina NextSeq 500 Sequencer (Illumina Inc., USA). Furthermore, obtained variants by WES were evaluated using a virtual panel of genes: HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, and PLDN. We identified a compound heterozygous genotype in HPS1 gene in the proband. We identified a pathogenic frameshift variant c.1189delC; p.(Gln397Serfs*2), resulting in a premature stop codon. This variant has been previously associated with HPS. Furthermore, we characterized previously undescribed nonsense variant c.1507C > T; p.(Gln503*), resulting in a premature stop codon and mRNA degradation through nonsense-mediated decay. Sanger sequencing validated the presence of both variants and simultaneously confirmed the heterozygous carrier status of parents. Unfortunately, the patient died due to fulminant progression of pulmonary fibrosis 2 months after diagnostics. CONCLUSIONS: Compound heterozygous mutations in HPS1 in the proband lead to disruption of HPS1 gene and clinical manifestation of HPS with severe pulmonary fibrosis. This case illustrates the need to consider HPS in differential diagnostics of pulmonary fibrosis. Pulmonary fibrosis is a common cause of death in HPS patients. Earlier diagnosis may enable better treatment for these patients.
- Klíčová slova
- Exome sequencing, Hermansky-Pudlak syndrome, Pulmonary fibrosis,
- MeSH
- fatální výsledek MeSH
- Heřmanského-Pudlákův syndrom * diagnóza genetika patofyziologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- membránové proteiny genetika MeSH
- mutace MeSH
- plíce diagnostické zobrazování patologie MeSH
- plicní fibróza * diagnóza genetika patofyziologie MeSH
- počítačová rentgenová tomografie metody MeSH
- progrese nemoci MeSH
- sekvenování exomu metody MeSH
- stupeň závažnosti nemoci MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- Názvy látek
- HPS1 protein, human MeSH Prohlížeč
- membránové proteiny MeSH
The authors declare they have no potential conflicts of interest concerning drugs, pro-ducts, or services used in the study. The Editorial Board declares that the manu-script met the ICMJE recommendation for biomedical papers. Submitted: 17. 6. 2017 Accepted: 1. 11. 2018.
Mutagenesis is a hallmark and enabling characteristic of cancer cells. The E3 ubiquitin ligase RAD18 and its downstream effectors, the 'Y-family' Trans-Lesion Synthesis (TLS) DNA polymerases, confer DNA damage tolerance at the expense of DNA replication fidelity. Thus, RAD18 and TLS polymerases are attractive candidate mediators of mutagenesis and carcinogenesis. The skin cancer-propensity disorder xeroderma pigmentosum-variant (XPV) is caused by defects in the Y-family DNA polymerase Pol eta (Polη). However it is unknown whether TLS dysfunction contributes more generally to other human cancers. Recent analyses of cancer genomes suggest that TLS polymerases generate many of the mutational signatures present in diverse cancers. Moreover biochemical studies suggest that the TLS pathway is often reprogrammed in cancer cells and that TLS facilitates tolerance of oncogene-induced DNA damage. Here we review recent evidence supporting widespread participation of RAD18 and the Y-family DNA polymerases in the different phases of multi-step carcinogenesis.
- Klíčová slova
- DNA damage, RAD18, cancer, genome maintenance, mutagenesis, trans-lesion synthesis (TLS),
- MeSH
- DNA vazebné proteiny genetika metabolismus MeSH
- DNA-dependentní DNA-polymerasy genetika metabolismus MeSH
- genom lidský MeSH
- karcinogeneze genetika metabolismus patologie MeSH
- lidé MeSH
- multigenová rodina MeSH
- mutageneze MeSH
- nádorové proteiny genetika metabolismus MeSH
- nádory genetika metabolismus patologie MeSH
- poškození DNA MeSH
- regulace genové exprese u nádorů * MeSH
- signální transdukce MeSH
- ubikvitinligasy genetika metabolismus MeSH
- xeroderma pigmentosum genetika metabolismus patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
- Názvy látek
- DNA vazebné proteiny MeSH
- DNA-dependentní DNA-polymerasy MeSH
- nádorové proteiny MeSH
- RAD18 protein, human MeSH Prohlížeč
- Rad30 protein MeSH Prohlížeč
- ubikvitinligasy MeSH
