Mutations occurring during embryonic development affect only a subset of cells resulting in two or more distinct cell populations that are present at different levels, also known as postzygotic mosaicism (PZM). Although PZM is a common biological phenomenon, it is often overlooked as a source of disease due to the challenges associated with its detection and characterization, especially for very low-frequency variants. Moreover, PZM can cause a different phenotype compared to constitutional mutations. Especially, lethal mutations in receptor tyrosine kinase (RTK) pathway genes, which exist only in a mosaic state, can have completely new clinical manifestations and can look very different from the associated monogenic disorder. However, some key questions are still not addressed, such as the level of mosaicism resulting in a pathogenic phenotype and how the clinical outcome changes with the development and age. Addressing these questions is not trivial as we require methods with the sensitivity to capture some of these variants hidden away in very few cells. Recent ultra-accurate deep-sequencing approaches can now identify these low-level mosaics and will be central to understand systemic and local effects of mosaicism in the RTK pathway. The main focus of this review is to highlight the importance of low-level mosaics and the need to include their detection in studies of genomic variation associated with disease.

• Klíčová slova
• gain of function, pathogenic variants, penetrance, postzygotic mosaicisms, tyrosine kinase receptor,
• MeSH
• dítě MeSH
• embryo savčí MeSH
• exprese genu MeSH
• fenotyp MeSH
• fibrózní dysplazie polyostotická enzymologie   genetika   patologie   MeSH
• fosfatidylinositol-3-kinasy třídy I genetika   metabolismus   MeSH
• kojenec MeSH
• letální geny MeSH
• lidé MeSH
• mozaicismus * MeSH
• novorozenec MeSH
• Proteův syndrom enzymologie   genetika   patologie   MeSH
• signální transdukce MeSH
• Sturgeův-Weberův syndrom enzymologie   genetika   patologie   MeSH
• tyrosinkinasové receptory nedostatek   genetika   MeSH
• zárodečné mutace * MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• fosfatidylinositol-3-kinasy třídy I MeSH
• PIK3CA protein, human MeSH Prohlížeč
• tyrosinkinasové receptory MeSH

NME7 (non-metastatic cells 7, nucleoside diphosphate kinase 7) is a member of a gene family with a profound effect on health/disease status. NME7 is an established member of the ciliome and contributes to the regulation of the microtubule-organizing center. We aimed to create a rat model to further investigate the phenotypic consequences of Nme7 gene deletion. The CRISPR/Cas9 nuclease system was used for the generation of Sprague Dawley Nme7 knock-out rats targeting the exon 4 of the Nme7 gene. We found the homozygous Nme7 gene deletion to be semi-lethal, as the majority of SDNme7-/- pups died prior to weaning. The most prominent phenotypes in surviving SDNme7-/- animals were hydrocephalus, situs inversus totalis, postnatal growth retardation, and sterility of both sexes. Thinning of the neocortex was histologically evident at 13.5 day of gestation, dilation of all ventricles was detected at birth, and an external sign of hydrocephalus, i.e., doming of the skull, was usually apparent at 2 weeks of age. Heterozygous SDNme7+/- rats developed normally; we did not detect any symptoms of primary ciliary dyskinesia. The transcriptomic profile of liver and lungs corroborated the histological findings, revealing defects in cell function and viability. In summary, the knock-out of the rat Nme7 gene resulted in a range of conditions consistent with the presentation of primary ciliary dyskinesia, supporting the previously implicated role of the centrosomally located Nme7 gene in ciliogenesis and control of ciliary transport.

• Klíčová slova
• Nme7, cilia, hydrocephalus, infertility, knock-out rat,
• MeSH
• cilie metabolismus   ultrastruktura   MeSH
• fenotyp MeSH
• genetická predispozice k nemoci * MeSH
• genetické asociační studie MeSH
• genotyp MeSH
• genový knockdown MeSH
• imunohistochemie MeSH
• krysa rodu Rattus MeSH
• letální geny * MeSH
• modely nemocí na zvířatech MeSH
• nukleosiddifosfátkinasa nedostatek   genetika   metabolismus   MeSH
• poruchy ciliární motility diagnóza   genetika   MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• regulace genové exprese MeSH
• rentgenová mikrotomografie MeSH
• stanovení celkové genové exprese MeSH
• transkriptom MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• nukleosiddifosfátkinasa MeSH

Maintenance of genome stability is essential for every living cell as genetic information is repeatedly challenged during DNA replication in each cell division event. Errors, defects, delays, and mistakes that arise during mitosis or meiosis lead to an activation of DNA repair processes and in case of their failure, programmed cell death, i.e. apoptosis, could be initiated. Fam208a is a protein whose importance in heterochromatin maintenance has been described recently. In this work, we describe the crucial role of Fam208a in sustaining the genome stability during the cellular division. The targeted depletion of Fam208a in mice using CRISPR/Cas9 leads to embryonic lethality before E12.5. We also used the siRNA approach to downregulate Fam208a in zygotes to avoid the influence of maternal RNA in the early stages of development. This early downregulation increased arresting of the embryonal development at the two-cell stage and occurrence of multipolar spindles formation. To investigate this further, we used the yeast two-hybrid (Y2H) system and identified new putative interaction partners Gpsm2, Amn1, Eml1, Svil, and Itgb3bp. Their co-expression with Fam208a was assessed by qRT-PCR profiling and in situ hybridisation [1] in multiple murine tissues. Based on these results we proposed that Fam208a functions within the HUSH complex by interaction with Mphosph8 as these proteins are not only able to physically interact but also co-localise. We are bringing new evidence that Fam208a is multi-interacting protein affecting genome stability on the level of cell division at the earliest stages of development and also by interaction with methylation complex in adult tissues. In addition to its epigenetic functions, Fam208a appears to have an additional role in zygotic division, possibly via interaction with newly identified putative partners Gpsm2, Amn1, Eml1, Svil, and Itgb3bp.

• Klíčová slova
• Fam208a, Genome stability, HUSH, Multipolar spindle apparatus,
• MeSH
• aparát dělícího vřeténka metabolismus   MeSH
• buněčné dělení genetika   fyziologie   MeSH
• CRISPR-Cas systémy MeSH
• embryonální vývoj genetika   fyziologie   MeSH
• fosfoproteiny metabolismus   MeSH
• HEK293 buňky MeSH
• jaderné proteiny fyziologie   MeSH
• letální geny MeSH
• lidé MeSH
• malá interferující RNA genetika   farmakologie   MeSH
• multiproteinové komplexy MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• nestabilita genomu MeSH
• RNA interference MeSH
• vývojová regulace genové exprese * MeSH
• zvířata MeSH
• zygota metabolismus   MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• publikace stažené z tisku MeSH
• Názvy látek
• Fam208a protein, mouse MeSH Prohlížeč
• fosfoproteiny MeSH
• jaderné proteiny MeSH
• malá interferující RNA MeSH
• MPHOSPH8 protein, human MeSH Prohlížeč
• Mphosph8 protein, mouse MeSH Prohlížeč
• multiproteinové komplexy MeSH
• TASOR protein, human MeSH Prohlížeč

In 1994, the field of bone biology was significantly advanced by the discovery that activating mutations in the fibroblast growth factor receptor 3 (FGFR3) receptor tyrosine kinase (TK) account for the common genetic form of dwarfism in humans, achondroplasia (ACH). Other conditions soon followed, with the list of human disorders caused by FGFR3 mutations now reaching at least 10. An array of vastly different diagnoses is caused by similar mutations in FGFR3, including syndromes affecting skeletal development (hypochondroplasia [HCH], ACH, thanatophoric dysplasia [TD]), skin (epidermal nevi, seborrhaeic keratosis, acanthosis nigricans), and cancer (multiple myeloma [MM], prostate and bladder carcinoma, seminoma). Despite many years of research, several aspects of FGFR3 function in disease remain obscure or controversial. As FGFR3-related skeletal dysplasias are caused by growth attenuation of the cartilage, chondrocytes appear to be unique in their response to FGFR3 activation. However, the reasons why FGFR3 inhibits chondrocyte growth while causing excessive cellular proliferation in cancer are not clear. Likewise, the full spectrum of molecular events by which FGFR3 mediates its signaling is just beginning to emerge. This article describes the challenging journey to unravel the mechanisms of FGFR3 function in skeletal dysplasias, the extraordinary cellular manifestations of FGFR3 signaling in chondrocytes, and finally, the progress toward therapy for ACH and cancer.

• MeSH
• chondrocyty metabolismus   patologie   MeSH
• chrupavka abnormality   metabolismus   MeSH
• fibroblastové růstové faktory genetika   metabolismus   MeSH
• fosfatidylinositol-3-kinasy genetika   metabolismus   MeSH
• kosti a kostní tkáň abnormality   metabolismus   MeSH
• kůže metabolismus   patologie   MeSH
• letální geny MeSH
• lidé MeSH
• MAP kinasový signální systém genetika   MeSH
• mezibuněčná komunikace MeSH
• mutace MeSH
• nádory kůže genetika   metabolismus   patologie   MeSH
• natriuretický peptid typu C genetika   metabolismus   MeSH
• osteochondrodysplazie genetika   metabolismus   patologie   MeSH
• proliferace buněk MeSH
• receptor fibroblastových růstových faktorů, typ 3 * genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• signální transdukce MeSH
• transkripční faktor STAT1 genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• FGFR3 protein, human MeSH Prohlížeč
• fibroblastové růstové faktory MeSH
• fosfatidylinositol-3-kinasy MeSH
• natriuretický peptid typu C MeSH
• receptor fibroblastových růstových faktorů, typ 3 * MeSH
• STAT1 protein, human MeSH Prohlížeč
• transkripční faktor STAT1 MeSH

The interleukin-18 (IL-18) gene on chromosome 11q22 has been suggested as a susceptibility factor for allergies. To test for a possible role of IL-18 polymorphisms in Czech population, case-control study including 958 subjects (633 allergic patients and 325 healthy controls) was performed. An allele-specific polymerase chain reaction was used to analyze variants at positions -607 C/A (rs1946518) and -137 G/C (rs187238) in the promoter region together with the polymerase chain reaction-restriction fragment length polymorphism method for the detection of polymorphism at position -140 C/G (previously -133 C/G, rs360721) in intron 1 of the IL-18 gene. The -1297 C/T (rs360719) polymorphism was genotyped by real-time-polymerase chain reaction, using a predevelopment TaqMan allele discrimination assay. There were no significant differences in distribution of alleles or genotypes in any of four single nucleotide polymorphisms in the IL-18 gene between controls and patients. However, subsequent analysis revealed a significant difference in haplotype frequencies between the allergic patients and healthy subjects (p < 0.01). Haplotype formed by -1297 C/-607 A/-137 C/-140 C alleles occurred significantly more frequently in patients than controls (0.0433 vs 0.0129; p < 0.0003; p(corr)< 0.01, OR = 3.37; 95% CI = 1.59-7.14). In contrast, there was no relationship among the IL-18 variants and total serum IgE level. Our results indicate that promoter polymorphisms in the IL-18 gene act in interaction and could play a role in allergic disorders.

• MeSH
• alergie genetika   imunologie   patofyziologie   MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• genetické asociační studie MeSH
• haplotypy MeSH
• interleukin-18 genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• letální geny MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutační analýza DNA MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• interleukin-18 MeSH

The positive transcription elongation factor b (P-TEFb) is essential for the elongation of transcription and cotranscriptional processing by RNA polymerase II. In mammals, it contains predominantly the C-type cyclin cyclin T1 (CycT1) or CycT2 and cyclin-dependent kinase 9 (Cdk9). To determine if these cyclins have redundant functions or affect distinct sets of genes, we genetically inactivated the CycT2 gene (Ccnt2) using the beta-galactosidase-neomycin gene (beta-geo) gene trap technology in the mouse. Visualizing beta-galactosidase during mouse embryogenesis revealed that CycT2 is expressed abundantly during embryogenesis and throughout the organism in the adult. This finding was reflected in the expression of CycT2 in all adult tissues and organs. However, despite numerous matings of heterozygous mice, we observed no CycT2(-/-) embryos, pups, or adult mice. This early lethality could have resulted from decreased expression of critical genes, which were revealed by short interfering RNAs against CycT2 in embryonic stem cells. Thus, CycT1 and CycT2 are not redundant, and these different P-TEFb complexes regulate subsets of distinct genes that are important for embryonic development.

• MeSH
• cyklin T antagonisté a inhibitory   nedostatek   genetika   metabolismus   MeSH
• cykliny antagonisté a inhibitory   nedostatek   genetika   metabolismus   MeSH
• DNA primery genetika   MeSH
• embryonální kmenové buňky metabolismus   MeSH
• embryonální vývoj genetika   fyziologie   MeSH
• letální geny MeSH
• malá interferující RNA genetika   MeSH
• mutantní kmeny myší MeSH
• myši knockoutované MeSH
• myši MeSH
• sekvence nukleotidů MeSH
• těhotenství MeSH
• tkáňová distribuce MeSH
• transkripční faktor B aktivující elongaci metabolismus   MeSH
• vývojová regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• Ccnt1 protein, mouse MeSH Prohlížeč
• cyklin T MeSH
• cykliny MeSH
• DNA primery MeSH
• malá interferující RNA MeSH
• transkripční faktor B aktivující elongaci MeSH

A novel Arabidopsis thaliana mutant of one member of the pentatricopeptide repeat (PPR) gene family has been identified among T-DNA insertion lines. Tagging of the At1g53330 gene caused the appearance of a semi-lethal mutation with a complex phenotypic expression from embryo lethality associated with the abnormal pattern of cell division during globular to heart transition to fertile plants with just subtle phenotypic changes. The PPR protein At1g53330.1 was predicted to be targeted to mitochondria by TargetP and MitoProt programs. Complementation analysis confirmed that the phenotype is a result of a single T-DNA integration. A thorough functional analysis of this mutant aimed at finding a particular organelle target of At1g53330.1 protein will follow.

• MeSH
• aminokyselinové motivy MeSH
• Arabidopsis genetika   MeSH
• DNA bakterií genetika   MeSH
• DNA rostlinná genetika   MeSH
• fenotyp MeSH
• letální geny MeSH
• mapování chromozomů MeSH
• molekulární sekvence - údaje MeSH
• mutace MeSH
• proteiny huseníčku genetika   MeSH
• repetitivní sekvence aminokyselin MeSH
• rostlinné geny * MeSH
• sekvence aminokyselin MeSH
• sekvence nukleotidů MeSH
• testy genetické komplementace MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA bakterií MeSH
• DNA rostlinná MeSH
• proteiny huseníčku MeSH
• T-DNA MeSH Prohlížeč

Steroid signaling underlies developmental processes in animals. Mutations that impair steroidogenesis in the fruit fly Drosophila melanogaster provide tools to dissect steroid hormone action genetically. The widely used temperature-sensitive mutation ecdysoneless(1) (ecd(1)) disrupts production of the steroid hormone ecdysone, and causes developmental and reproductive defects. These defects cannot be satisfactorily interpreted without analysis of the ecd gene. Here, we show that ecd encodes an as yet functionally undescribed protein that is conserved throughout eukaryotes. The ecd(1) conditional allele contains an amino acid substitution, whereas three non-conditional larval lethal mutations result in truncated Ecd proteins. Consistent with its role in steroid synthesis, Ecd is expressed in the ecdysone-producing larval ring gland. However, development of ecd-null early larval lethal mutants cannot be advanced by Ecd expression targeted to the ring gland or by hormone feeding. Cell-autonomous ecd function, suggested by these experiments, is evidenced by the inability of ecd(-) clones to survive within developing imaginal discs. Ecd is also expressed in the ovary, and is required in both the follicle cells and the germline for oocyte development. These defects, induced by the loss of ecd, provide the first direct evidence for a cell-autonomous function of this evolutionarily conserved protein.

• MeSH
• Drosophila genetika   růst a vývoj   MeSH
• ekdyson farmakologie   MeSH
• endokrinní žlázy růst a vývoj   metabolismus   MeSH
• larva MeSH
• letální geny MeSH
• molekulární sekvence - údaje MeSH
• mutace MeSH
• oogeneze účinky léků   genetika   MeSH
• ovarium růst a vývoj   metabolismus   MeSH
• proteiny Drosophily genetika   metabolismus   MeSH
• sekvence aminokyselin MeSH
• sekvenční homologie aminokyselin MeSH
• steroidy metabolismus   MeSH
• vývojová regulace genové exprese * MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• ecd protein, Drosophila MeSH Prohlížeč
• ekdyson MeSH
• proteiny Drosophily MeSH
• steroidy MeSH

The Thp deletion on mouse chromosome 17 is lethal when inherited from the mother, because it deletes the T-associated maternal effect (Tme) locus, the paternal copy of which is inactivated by genomic imprinting. We have found a paternally nonimprinted Tme variant in crosses of Thp females with Mus m. musculus males. The data are consistent with the existence of a single Tme-unlinked gene, Imprintor-1 (Imp-1), with two alleles, one of which only causes imprinting at the Tme locus. Imp-1 is unlinked to the gene for cation-dependent Man-6-P receptor and acts prezygotically. Although Tme and Igf2r were thought to be identical, they show different patterns of imprinting in interspecies hybrids. The apparent nonequivalence of the Igf2r gene and Tme results in occurrence of viable mice lacking an active Igf2r gene. These mice are bigger at birth than their normal littermates, in accord with the proposed function of the IGF-II/Man-6-P receptor.

• MeSH
• chromozomální delece MeSH
• dominantní geny MeSH
• fertilizace MeSH
• genetická variace MeSH
• hybridizace genetická MeSH
• insulinu podobný růstový faktor II genetika   fyziologie   MeSH
• letální geny MeSH
• mannosafosfáty metabolismus   MeSH
• messenger RNA metabolismus   MeSH
• modely genetické MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• northern blotting MeSH
• receptor IGF typ 2 MeSH
• receptory buněčného povrchu genetika   fyziologie   MeSH
• regulace genové exprese * MeSH
• Southernův blotting MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• insulinu podobný růstový faktor II MeSH
• mannosafosfáty MeSH
• messenger RNA MeSH
• receptor IGF typ 2 MeSH
• receptory buněčného povrchu MeSH

The potential mutagenic activity of three carbamate derivatives with local anaesthetic activity was investigated. Genotoxic activity was observed after application of Carbisocaine on Euglena gracilis, whereas no activity was detected by Carbisocaine, Heptacaine and Pentacaine on Salmonella typhimurium, Escherichia coli and Drosophila melanogaster.

• MeSH
• anestetika lokální toxicita   MeSH
• Drosophila melanogaster genetika   MeSH
• Escherichia coli účinky léků   genetika   MeSH
• Euglena účinky léků   genetika   MeSH
• geny recesivní účinky léků   MeSH
• karbamáty toxicita   MeSH
• letální geny účinky léků   MeSH
• mutageny * MeSH
• oprava DNA účinky léků   MeSH
• piperidiny toxicita   MeSH
• Salmonella typhimurium genetika   MeSH
• testy genotoxicity MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anestetika lokální MeSH
• carbizocaine MeSH Prohlížeč
• heptacaine MeSH Prohlížeč
• karbamáty MeSH
• mutageny * MeSH
• pentacaine MeSH Prohlížeč
• piperidiny MeSH