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At least 19 recordsLinked to original sources
PubMed2022

A novel DPH5-related diphthamide-deficiency syndrome causing embryonic lethality or profound neurodevelopmental disorder.

PURPOSE: Diphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs). METHODS: Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5em1Mbp/Mmucd) was created for a DPH5 p.His260Arg homozygous variant identified in 1 family. Adenosine diphosphate-ribosylation assays in DPH5-knockout human and yeast cells and in silico modeling were performed for the identified DPH5 potential pathogenic variants. RESULTS: DPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2. CONCLUSION: We provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.

Adenosine Diphosphate↗
PubMed1992

Structure, expression, and chromosome location of the gene for the beta subunit of brain-specific Ca2+/calmodulin-dependent protein kinase II identified by transgene integration in an embryonic lethal mouse mutant.

The transgenic mouse strain CAT40 carries in its germ line one copy of a DNA construct consisting of the chloramphenicol acetyltransferase gene and the immunoglobulin heavy-chain enhancer. We show that transgene integration has resulted in a recessive lethal mutation that leads to death of homozygous CAT40 embryos shortly after implantation. The transgene has integrated adjacent to the 3' end of the gene coding for the beta subunit of the brain-specific Ca2+/calmodulin-dependent protein kinase II (Camk-2). The complete cDNA sequence of the Camk-2 gene and most of its exon/intron structure was determined. The deduced amino acid sequence is highly homologous to the previously described rat protein. The chromosomal location of the Camk-2 locus was mapped by interspecific backcross analysis to the proximal region of mouse chromosome 11. This region lacks previously identified recessive embryonic lethal mutations. During embryonic development, Camk-2-specific transcripts are first seen in the head section of 12.5-day-old embryos, and in adult mice the gene is expressed almost exclusively in the brain. Although transcription of the Camk-2 gene in heterozygous CAT40 mice is affected by transgene integration, it is unlikely that this gene is responsible for the mutant phenotype, since it is not expressed in blastocysts and the first transcripts during normal development are detected after the death of homozygous CAT40 embryos. Transgene integration is accompanied by a large deletion of cellular DNA; death is therefore most likely caused by the loss of a gene or genes that are important for early postimplantation development.

Amino Acid Sequence↗
PubMed1978

Cell culture of individual Drosophila embryos. II. Culture of X-linked embryonic lethals.

Results are reported from the culturing in vitro of cells from individual early gastrulae of the following four groups of X-linked embryonic lethal mutants of Drosophila melanogaster. (1) Notch lethals, Five Notch mutants were studied which have been reported to give similar abnormalities in whole embryos: the nervous system displays a three-fold hypertrophy as part of a shift in the pattern of differentiation within ectodermal derivatives, and mesodermal derivatives do not differentiate. An hypertrophy of nerve was found in cell cultures prepared from embryos of all five mutants. In addition, four of the five alleles consistently gave abnormalities of muscle differentiation: when compared to controls, Notch cultures had a reduced frequency of myotubes, and displayed unusual clusters of myocytes which had either failed to fuse or had fused incompletely. Results from mixed cultures prepared from two embryos were consistent with the autonomous expression of nerve and muscle abnormalities by Notch-8 cells in the presence of wild-type cells. It is argued that the Notch locus has a direct role in the differentiation of both nerve and muscle. (2) white deficiencies. Cells carrying either of two deficiencies gave a clear-cut pattern of abnormalities: initial cellular differentiations were normal, but nerve, muscle and fat-body cells progressively deteriorated during the culture period. Mixed cultures showed that wild-type cells could not 'rescue' mutant muscle and fat-body cells; however, the status of the autonomy of mutant nerve abnormalities in these cultures was unclear. Both white deficiencies remove cytological band 3C1, and this permits a comparison of results with those from cultures of cells from Notch-8 embryos (also deficient for 3C1). Abnormalities displayed in cultures of the two types of mutant show no overlap. Therefore no consistent cellular abnormality can be attributed to absence of band 3C1. (3) lethal(1)myospheroid. In contrast to earlier observations on in vitro cell cultures (Donady & Seecof, 1972) muscle was seen to differentiate, though its morphology was extremely abnormal. Observations indicated that all cell types within the cultures had poor properties of adhesion to a glass substrate. It is argued that the observed abnormalities are not consistent with a mutant lesion which is restricted to the basement membrane (contra Wright, 1960), and that all cell types carry a basic defect which may reside in the cell membrane. (4) shibirets alleles. Cultures of two temperature-sensitive lethal shibire alleles (shits1), shits3) were normal at the permissive temperature of 22 degrees C. At the restrictive temperature (29 degrees C) early cell differentiation was normal but subsequent development was blocked. This blockage could be partially reversed by shifting cultures to the permissive temperature after as much as 10 days exposure to the high temperature. It is suggested that shits cells are mutant in a process which is basic to several cell types.

Animals↗
PubMed1976

Maternally influenced embryonic lethality: allele specific genetic rescue at a female fertility locus in Drosophila melanogaster.

A new locus, mel(1)R1, with a maternal effect on embryonic development, has been mapped at about 0.5 on the X chromosome of Drosophila melanogaster and localized cytologically between bands 2D6 and 3A1. Genotypically mutant embryos die if produced by homozygous mutant females but survive if produced by heterozygous females. Two mutant alleles have been isolated. One of these is genetically rescuable: when homozygous mutant females are mated to mutant males, all the embryos die, but when these females are mated to normal males, female offspring are produced. The other allele is not rescuable. Genetic rescue is dominant at this locus since females heterozygous for the two mutant alleles produce female offspring in crosses to normal males.

Alleles↗
PubMed1976

The developmental analysis of an embryonic lethal (C6H) in the mouse.

A development study of the effects of the C6H allele at the albino locus has identified the C6H homozygote as an early postimplantation lethal. Homozygous C6H embryos can first be recognized at 6 1/2-7 days of gestation by abnormalities of the ectoplacental and parietal endodern. At 7 1/2 days, mutant embryos appear severely retarded with obvious abnormalities in all germ layers. All C6H homozygotes are dead and resorbed by 8 days of development. It is proposed that the mutation interferes with the normal differentiation of the parietal endoderm, ectoplacental cone and extra-embryonic ectoderm of the egg cyclinder.

Alleles↗
PubMed2025

Impaired hematopoiesis and embryonic lethality at midgestation of mice lacking both lipid transfer proteins VPS13A and VPS13C.

VPS13 is the founding member of a family of proteins that mediate lipid transfer at intracellular membrane contact sites by a bridge-like mechanism. Mammalian genomes comprise 4 VPS13 genes encoding proteins with distinct localizations and function. The gene duplication resulting in VPS13A and VPS13C is the most recent in evolution and, accordingly, these two proteins are the most similar to each other. However, they have distinct subcellular localizations and their loss of function mutations in humans are compatible with life but result in two different age-dependent neurodegenerative diseases, chorea-acanthocytosis and Parkinson's disease, respectively. Thus, it remains unclear whether these two proteins have overlapping functions. Here, we show that while Vps13a KO and Vps13c KO mice are viable, embryonic development of Vps13a/Vps13c double knockout (DKO) mice is arrested at midgestation. Prior to death, DKO embryos were smaller than controls, were anemic and had a smaller liver, most likely reflecting defective embryonic erythropoiesis which at this developmental stage occurs primarily in this organ. Further analyses of erythroid precursor cells showed that their differentiation was impaired and that this defect was accompanied by activation of innate immunity as revealed by upregulation of interferon stimulated genes (ISGs). Additionally, the RIG-I and MDA5 components of dsRNA triggered innate immunity were found upregulated in the DKO fetal liver. Activation of innate immunity may result from loss of integrity of the membranes of intracellular organelles, such as mitochondria and autophagic lysosomes, or to impaired autophagy, due to the absence of these lipid transport proteins. The surprising and striking synthetic effect resulting for the combined loss of VPS13A and VPS13C suggests that despite of the different localization of these two proteins, the lipid fluxes that they mediate are partially redundant.

Animals↗
PubMed1992

Developmental expression of the alpha receptor for platelet-derived growth factor, which is deleted in the embryonic lethal Patch mutation.

The alpha receptor of PDGF (Pdgfra) is expressed in primitive endoderm and mesoderm derivatives throughout embryogenesis. In the early primitive streak stage the gene is transcribed in the visceral and parietal endoderm. Later it is expressed in the presomitic mesoderm, yolk sac and amnion. During somitogenesis its transcription localizes to the heart and the somites. Subsequently, it is transcribed in the dermatome, the sclerotome, the developing limb and in various mesenchymal tissues of visceral organs. Its wild-type expression pattern correlates well with the phenotype of homozygous mutant Patch (Ph) embryos, where the Pdgfra gene is deleted. The Ph phenotype is first detectable at the primitive streak stage with convoluted and hypertrophic visceral yolk sac, deformed neural plate and disorganized or missing mesoderm. Most Ph/Ph embryos die before the 11th day of gestation. Those that survive till early organogenesis are very small, have hypertrophic yolk sacs, small and undifferentiated somites, convoluted neural tubes, large heart and pericardium, rudimentary limb buds and branchial arches. Our observations together suggest that the alpha PDGF receptor may be required for the normal development of visceral endoderm and mesoderm derivatives.

Animals↗
PubMed1979

In vivo and in vitro studies on the early embryonic lethal oligosyndactylism (Os) in the mouse.

The development of mouse embryos homozygous for oligosyndactylism (Os) is arrested during implantation. Histological investigations confirm a previous report that cells become blocked in mitosis, and air-dried spreads of the mutant embryos reveal that large numbers of cells accumulate in metaphase. Trophoblastic giant cells appear unaffected by the action of the mutant gene both in utero and during culture over the lethal phase. It is proposed that the form of endoreduplication undergone by giant cells renders them refractory to the metaphase block.

Animals↗
PubMed2026

Development and optimization of T-ARMS PCR assays for detection of lethal haplotypes of TADA2A, UR1B, and PORL1B in pigs in Vietnam.

Marker-assisted selection has increasingly relied on single-nucleotide polymorphisms (SNPs) as robust genetic markers, particularly in livestock breeding programs. In pig farming, embryonic mortality significantly affects litter size, and SNPs in reference genes have been implicated as potential causal factors. We developed and optimized a tetra-primer amplification refractory mutation system (T-ARMS) PCR assay for rapid, cost-effective detection of SNPs in 3 candidate genes-TADA2A, PORL1B, URB1-that are associated with embryonic lethality and reproductive performance. Primer sets were designed based on known mutation sites and validated using synthetic gene constructs and porcine genomic DNA from pigs of Duroc and Landrace breeds. Optimization of annealing temperatures and primer concentration ratios yielded distinct and reproducible allele-specific amplicon patterns that were corroborated by PCR-RFLP and Sanger sequencing. Our T-ARMS PCR protocol, which requires minimal equipment and reduces processing time to <3&#x2009;h, had high specificity and efficiency in differentiating wild-type, heterozygous, and homozygous mutant genotypes in 20 Duroc and 20 Landrace pigs. Our Tetra-ARMS PCR assay is a robust and economically viable tool for SNP genotyping in pig breeding programs, potentially contributing to the reduction of embryonic lethality and the improvement of overall reproductive outcomes.

Sus scrofa↗
PubMed1978

Developmental analysis of the tumorous head mutation in Drosophila melanogaster.

The extent and type of adult transformations in the tumorous head (tuh) mutation of Drosophila melanogaster were studied. The observations indicate homeotic transformations, duplications and deficiencies of eye antennal disc derivatives. Contrary to previous observations there is no transformation of eye to abdomen and the only homeotic transformations identifiable are antenna to leg and rostralhaut to genitalia. Embryonic and post-embryonic lethality was also examined. Specific anterior abnormalities were found in embryos leading to early death. The amount of embryonic lethality was not affected by increased temperature during oogenesis. When analysing the adult phenotype, however, the whole period of oogenesis was sensitive to pulses of increased temperature; the pulses however did not have to be restricted to any particular stage of oogenesis to be effective in increasing tuh penetrance. The increase in the penetrance of the adult transformations is also exhibited when eggs are moved from 25 degrees C to 29 degrees C from the 8th to the 12th hour of embryonic development. Experiments indicate that the tuh-3 gene is active before the 8th hour of embryogenesis.

Animals↗
PubMed1992

The locus Om, responsible for the DDK syndrome, maps close to Sigje on mouse chromosome 11.

The DDK inbred strain of mouse has a striking particularity: when DDK females are crossed to males of other strains they exhibit a reduced fertility, whereas the reciprocal crosses (non-DDK females x DDK males) are fertile (Wakasugi et al. 1967; Wakasugi 1973). The low fertility results from an early embryonic lethality, the F1 embryos dying near the late morula-early blastocyst stage. Genetic analyses (Wakasugi 1974) and nuclear and cytoplasmic transfers (Renard and Babinet 1986; Babinet et al. 1990; Mann 1986), have shown that the failure of the embroys to develop is due to an incompatibility between a DDK maternally encoded cytoplasmic product and the non-DDK paternal genome. In order to elucidate the genetic determinism of this embryonic lethality, we have analyzed the fertility of male progeny from a backcross BALB/c females x (BALB/c x DDK)F1 males and that of males from a set of recombinant inbred (RI) strains, established from DDK and BALB/c progenitors, when mated with DDK females. Our results indicate that a single locus, Om, is responsible for the DDK syndrome and is located on Chromosome (Chr) 11, very close to the Sigje locus.

Animals↗
PubMed2025

Kin17 promotes rDNA transcription, ribosomal biogenesis, and cortical lamination.

During brain development, neural progenitor cells (NPCs) undergo rapid division, necessitating efficient ribosomal biogenesis for proliferation. Yet, the regulatory mechanisms remain largely elusive. Here, we report that the DNA binding protein Kin17 exhibits development-dependent expression and plays a vital role in embryonic development. Complete loss of Kin17 in mice leads to embryonic lethality, while Kin17 depletion specifically in NPCs allows embryonic survival but results in reduced brain size and cortical lamination defects. Our findings demonstrate that these cortical malformation stems from impaired NPC proliferation and differentiation. Mechanistically, we show that Kin17 binds to the promoter region of rDNA, sequentially recruiting NCL and Polr1a, thereby promoting rDNA transcription. Consequently, Kin17 facilitates ribosome biogenesis and protein translation in NPCs. This study underscores a critical role of Kin17 in promoting rDNA transcription and ribosomal biogenesis in NPCs during brain development, which is essential for proper cortical lamination.

Animals↗
PubMedDate not supplied

Chondrodystrophy: an inherited lethal condition in turkey embryos.

Chondrodystrophy was found to occur as an embryonic lethal in a special line of turkeys. Inheritance of the condition was studied in embryos produced parthenogenetically from virgin dams and also in embryos from the same dams in bisexual matings. Expression was similar to other forms of the disorder encountered in various avian species. Micromelia and brachycephaly were recognized in affected embryos after 9 days while lethality occurred mainly after 16 days of incubation. A few affected embryos expressed modified phenotypes and these were also nonviable. Modified phenotypes were not observed in parthenogenetic production, and it was thus inferred that such embryos may have been heterozygotes. No changes were evident when the genetic background was altered. The condition was inherited as a single, autosomal, recessive lethal, in both parthenogenetic progeny and in progeny from bisexual matings. The symbol ch is designated for the mutant allele.

Achondroplasia↗
PubMed1979

Aberrations of holokinetic chromosomes and associated lethality after x-irradiation of meiotic stages in Tetranychus urticae Koch (acari, tetranychidae).

Chromosomes of the holokinetic organization type were irradiated with X-rays in various stages of meiosis in unfertilized eggs of Tetranychus urticae Koch. Visible cytological aberrations, lethality and sterility were investigated in subsequent generations. Chromosome fragments are the most frequently occurring light-microscopically visible chromosome aberrations; bridges are not formed. Contrary to expectations, the presence of fragments appears to be positively correlated with the occurrence of lethality; loss of fragments, mis-segregation and the measure of damage to the broken chromosome parts are involved. In contrast with monokinetic chromosomes the earliest lethality occurs only after about 10 divisions. The ratios between different embryonic lethality types (early vs. late) differ depending on the stage irradiated: in more compact chromatin, more serious damage (i.e. more early lethality syndromes) is induced than in less compact chromatin. In the progeny of the surviving males, neither translocations nor independent fragments are found; indirect evidence indicated the occasional presence of inversions. The presumptive inversions are induced more frequently in a chromatin-compact stage (metaphase I) than in a less compact one (telophase I).

Animals↗
PubMed1979

A region of the Drosophila genome necessary for CNS development.

Mutations in genes involved in essential aspects of central nervous system development in Drosophila melanogaster are expected to be lethal. Thus, when searching for neurogenic mutants attention should be focused on embryonic lethal point mutants, for many of these might affect neural development. However, this approach can be very time consuming, for the location of neurogenic genes is unknown. A more convenient approach, which allows a faster screening of the genome, is to use relatively small chromosome deletions to determine whether the lack of a definite part of the genome affects neurogenesis. Once any region producing an interesting neural phenotype is found, it can be further analysed by the use of smaller deletions or point lethal mutants mapping within it, until the gene(s) responsible can be more precisely localised. We report here on a region of the Drosophila genome which has been found necessary for normal neurogenesis.

Animals↗
PubMed2026

RNA Binding Protein PCBP1 Functions in the Endothelial-to-Hematopoietic Transition During Hematopoietic Stem Cell Formation.

Two paralogous RNA-binding proteins, PCBP1 and PCBP2, are individually essential for mouse development. Pcbp2-null embryos lose viability at midgestation, whereas Pcbp1-null embryos have an earlier, peri-implantation lethality. Inactivation of each gene alone in the differentiating erythroid lineage failed to impact embryonic viability, whereas combined Pcbp1/Pcbp2 inactivation resulted in repression of erythroid/hematopoietic gene expression midgestation, decreased blood cell formation, and fetal demise. Here, we assess the impacts of individual and combined conditional inactivation of Pcbp1 and Pcbp2 in endothelial cells on embryonic hematopoietic stem and progenitor cell (HSPC) formation. Inactivation of Pcbp1 in endothelial cells is embryonic lethal and reduces the number of HSPCs, whereas loss of Pcbp2 has no impact. Combined deletion of Pcbp1 and Pcbp2 in endothelial cells results in a more severe phenotype than loss of Pcbp1 alone. These results demonstrate that although Pcbp1 is a major regulator of HSPC formation, the two genes have nonredundant roles in endothelial cells.

Animals↗
PubMed2025

EZH2 variants derived from cryptic splice sites govern distinct epigenetic patterns during embryonic development.

EZH2 catalyzes H3K27me3&#xa0;and is essential for embryonic development. Although multiple EZH2 variants have been identified, the functional implications and physiological significance of its heterogeneity remain unclear. Here, we revealed that conserved cryptic splice sites generated two EZH2 variants with (EZH2A) or without (EZH2B) a 27-nt region, coding for a 9-aa segment. Structural modeling showed that splice-in or splice-off of the 9-aa segment caused a topological change in EZH2 structure. The 9-aa surplus in EZH2A strengthened its interaction with other PRC2 components, particularly in PRC2.2 holocomplex. We developed point-mutation mouse lines specifically depleting EZH2A or EZH2B (Ezh2amut or Ezh2bmut). Biallelic deletion of Ezh2a caused developmental defects and embryonic lethality between E12.5 and E15.5, while the Ezh2bmut mice were fertile and developed normally. Combined RNA-seq and CUT&Tag analyses in mouse embryonic fibroblasts revealed that EZH2A and EZH2B bound to different genomic loci and affected H3K27me3 deposition in different subsets of genes related to development or the innate immune system, respectively. EZH2A depletion specifically suppressed the expression of genes involved in the development-related Hippo-Yap1 pathway, which might be attributable to a compensatory process mediated by JARID2. Our findings demonstrate that EZH2 heterogeneity from the 9-aa splicing event plays a crucial role in development.

Animals↗