Newly identified ZNHIT3 variants, which cause intrauterine fetal loss, disrupt snoRNP assembly
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB78345 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR13388219.fastq.gz | Fastqsanger.gz | |||
| ERR13388220.fastq.gz | Fastqsanger.gz | |||
| ERR13388221.fastq.gz | Fastqsanger.gz | |||
| ERR13388222.fastq.gz | Fastqsanger.gz | |||
| ERR13388223.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:ZNHIT3 (zinc finger HIT type containing protein 3) is an evolutionarily conserved protein required for ribosome biogenesis by mediating the assembly of small nucleolar RNAs (snoRNAs) of class C/D into ribonucleoprotein complexes (snoRNPs). Missense mutations in the gene encoding ZNHIT3 protein have been previously reported to cause PEHO syndrome, a severe neurodevelopmental disorder typically presenting after birth. We present here the case of two fetuses from a single family who presented with isolated hydrops during the early second trimester of pregnancy, resulting in intrauterine demise. Autopsy revealed no associated malformation. Through whole-genome quartet analysis, we identified two novel variants within the ZNHIT3 gene, both inherited from healthy parents and occurring as compound heterozygotes in both fetuses. The c.40T>C p.Cys14Arg variant originated from the father, while the c.251_254delAAGA r.? p.? variant was of maternal origin. Western capillary analysis of ZNHIT3 protein in lymphoblastoid cell lines of the parents shows that the parental c.40T>C p.Cys14Arg variant causes a significant drop in steady-state ZNHIT3 protein level. Analysis of the variants in human cell culture models reveals that both variants reduce cell growth, albeit to different extents, and impact the protein's stability and function in distinct ways. The c.251_254delAAGA results in production of a stable form of ZNHIT3 that lacks a domain required for mediating snoRNP biogenesis, whereas the c.40T>C p.Cys14Arg variation behaves similarly to the previously described PEHO-associated ZNHIT3 variants that destabilize the protein. Interestingly, both variations lead to a marked decrease in specific box C/D snoRNA levels, reduced rRNA levels and cellular translation. Analysis of rRNA methylation pattern in fetus samples reveals distinct sites of hypo 2’-O-methylation. RNA-seq analysis of undifferentiated and differentiated SHSY5Y cells transfected with the ZNHIT3 variants reveals differential expression of a set of genes, many of which are associated with developmental processes and RNA binding compared to cells expressing wild-type ZNHIT3. In summary, this work adds two novel ZNHIT3 variants to the other human disease-linked variants of this protein and describes the molecular defects caused by these pathogenic variants.
2024-10-08 | GSE273112 | GEO
Project description:Newly identified ZNHIT3 variants, which cause intrauterine fetal loss, disrupt snoRNP assembly
| PRJNA1140199 | ENA
Project description:Upon fertilization, the mouse zygotic genome is activated and maternal RNAs as well as proteins are degraded. Early developmental programs are built on proteins encoded by zygotic mouse genes that are needed to guide early cell fate commitment. The box C/D snoRNA ribonucleoprotein (snoRNP) complex is required for rRNA biogenesis, ribosome assembly and pre-mRNA splicing essential for protein translation. Zinc finger, HIT type 3 (encoded by Znhit3) is previously identified as a component in the assembly of the box C/D snoRNP complex. Using gene-edited mice, it identifies Znhit3 as an early embryonic gene whose ablation reduces protein translation and prevents mouse embryos development beyond the morula stage. The absence of ZNHIT3 leads to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development.
2025-11-18 | GSE267991 | GEO
Project description:Upon fertilization, the mouse zygotic genome is activated and maternal RNAs as well as proteins are degraded. Early developmental programs are built on proteins encoded by zygotic mouse genes that are needed to guide early cell fate commitment. The box C/D snoRNA ribonucleoprotein (snoRNP) complex is required for rRNA biogenesis, ribosome assembly and pre-mRNA splicing essential for protein translation. Zinc finger, HIT type 3 (encoded by Znhit3) is previously identified as a component in the assembly of the box C/D snoRNP complex. Using gene-edited mice, it identifies Znhit3 as an early embryonic gene whose ablation reduces protein translation and prevents mouse embryos development beyond the morula stage. The absence of ZNHIT3 leads to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development.
2025-11-18 | GSE267997 | GEO
Project description:Upon fertilization, the mouse zygotic genome is activated and maternal RNAs as well as proteins are degraded. Early developmental programs are built on proteins encoded by zygotic mouse genes that are needed to guide early cell fate commitment. The box C/D snoRNA ribonucleoprotein (snoRNP) complex is required for rRNA biogenesis, ribosome assembly and pre-mRNA splicing essential for protein translation. Zinc finger, HIT type 3 (encoded by Znhit3) is previously identified as a component in the assembly of the box C/D snoRNP complex. Using gene-edited mice, it identifies Znhit3 as an early embryonic gene whose ablation reduces protein translation and prevents mouse embryos development beyond the morula stage. The absence of ZNHIT3 leads to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development.
2025-11-18 | GSE267993 | GEO
Project description:ZNHIT3 (zinc finger HIT type containing protein 3) is an evolutionarily conserved protein required for ribosome biogenesis by mediating the assembly of small nucleolar RNAs (snoRNAs) of class C/D into ribonucleoprotein complexes (snoRNPs). Missense mutations in the gene encoding ZNHIT3 protein have been previously reported to cause PEHO syndrome, a severe neurodevelopmental disorder typically presenting after birth. We discuss here the case of two fetuses from a single family who presented with isolated hydrops during the early second trimester of pregnancy, resulting in intrauterine demise. Autopsy revealed no associated malformation. Through whole-genome quartet analysis, we identified two novel variants within the ZNHIT3 gene, both inherited from healthy parents and occurring as compound heterozygotes in both fetuses. The c.40T>C p.Cys14Arg variant originated from the father, while the c.251_254delAAGA variant was of maternal origin. Analysis of the variants in human cell culture models reveals that both variants reduce cell growth, albeit to different extents, and impact the protein's stability and function in distinct ways. The c.251_254delAAGA results in production of a stable form of ZNHIT3 that lacks a domain required for mediating snoRNP biogenesis, whereas the c.40T>C p.Cys14Arg variation behaves similarly to the previously described PEHO-associated ZNHIT3 variants that destabilize the protein. Interestingly, both variations lead to a marked decrease in specific box C/D snoRNA levels, reduced rRNA levels and cellular translation. Analysis of rRNA methylation pattern in fetus samples reveals distinct sites of hypo 2'-O-methylation. RNA-seq analysis of undifferentiated and differentiated SHSY5Y cells transfected with the ZNHIT3 variants reveals differential expression of a set of genes, many of which are associated with developmental processes and RNA binding compared to cells expressing wild-type ZNHIT3. In summary, this work extends the phenotype of PEHO syndrome to include antenatal manifestations and describe the molecular defects induced by two novel ZNHIT3 variants.
| S-EPMC11383450 | biostudies-literature
Project description:Retinitis pigmentosa (RP) is the most common inherited retinal disease (IRD) and is characterized by photoreceptor degeneration and progressive vision loss. We report 4 patients presenting with RP from 3 unrelated families with variants in TBC1D32, which to date has never been associated with an IRD. To validate TBC1D32 as a putative RP causative gene, we combined Xenopus in vivo approaches and human induced pluripotent stem cell-derived (iPSC-derived) retinal models. Our data showed that TBC1D32 was expressed during retinal development and that it played an important role in retinal pigment epithelium (RPE) differentiation. Furthermore, we identified a role for TBC1D32 in ciliogenesis of the RPE. We demonstrated elongated ciliary defects that resulted in disrupted apical tight junctions, loss of functionality (delayed retinoid cycling and altered secretion balance), and the onset of an epithelial-mesenchymal transition-like phenotype. Last, our results suggested photoreceptor differentiation defects, including connecting cilium anomalies, that resulted in impaired trafficking to the outer segment in cones and rods in TBC1D32 iPSC-derived retinal organoids. Overall, our data highlight a critical role for TBC1D32 in the retina and demonstrate that TBC1D32 mutations lead to RP. We thus identify TBC1D32 as an IRD-causative gene.
| S-EPMC10721274 | biostudies-literature
Project description:PEHO syndrome is characterized by Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy, which was first described in Finnish patients. A homozygous missense substitution p.Ser31Leu in ZNHIT3 was recently identified as the primary cause of PEHO syndrome in Finland. Variants in ZNHIT3 have not been identified in patients with PEHO or PEHO-like syndrome in other populations. It has therefore been suggested that PEHO syndrome caused by ZNHIT3 variants does not occur outside of the Finnish population. We describe the first patient outside Finland who carries compound heterozygous variants in ZNHIT3 gene causing PEHO syndrome. Trio genome sequencing was carried out and the identified variants were confirmed by Sanger sequencing. The patient filled all diagnostic clinical criteria of PEHO syndrome. We identified biallelic missense variants in ZNHIT3 gene: the c.92C > T p.(Ser31Leu) variant (NM_004773.3), which is described previously as causing PEHO syndrome and the second novel variant c.41G > T p.(Cys14Phe). There are only eight heterozygous carriers of c.41G > T variant in the gnomAD database and it is predicted damaging by multiple in silico algorithms. The ZNHIT3-associated PEHO syndrome exists outside of the Finnish population.
| S-EPMC6819237 | biostudies-literature
Project description:BackgroundDetermining the cause of intrauterine fetal death is essential for patients to manage their next pregnancy. However, in the majority of cases of fetal death, the cause remains unexplained despite comprehensive evaluation, especially in the cases of twins. Among twin pregnancies, conditions of monochorionic twinning, commonly regarded as monozygotic, are more complicated than dichorionic ones.Case summaryWe systematically evaluated the cause of fetal death for a Han Chinese woman with monochorionic twinning following in vitro fertilization/embryo transfer. Discrepant karyotypes were unexpectedly discovered between the twins. One fetus had an aneuploid male karyotype (46, XY), dup (9) (p24.3-q13), and the other had a normal female karyotype (46, XX). We considered that the male died of aberration of chromosome 9 and the female died of subsequent acute exsanguination through vascular anastomosis.ConclusionThis study demonstrated the importance of recognizing the presence of monochorionic dizygotic twinning and the challenges of clinical management for twins following in vitro fertilization/double embryo transfer.
| S-EPMC9846037 | biostudies-literature
Project description:Cellular distribution and dynamics of mitochondria are regulated by several motor proteins and a microtubule network. In neurons, mitochondrial trafficking is crucial because of high energy needs and calcium ion buffering along axons to synapses during neurotransmission. The trafficking kinesin proteins (TRAKs) are well characterized for their role in lysosomal and mitochondrial trafficking in cells, especially neurons. Using whole exome sequencing, we identified homozygous truncating variants in TRAK1 (NM_001042646:c.287-2A > C), in six lethal encephalopathic patients from three unrelated families. The pathogenic variant results in aberrant splicing and significantly reduced gene expression at the RNA and protein levels. In comparison with normal cells, TRAK1-deficient fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced mitochondrial membrane potential, and diminished mitochondrial respiration. This study confirms the role of TRAK1 in mitochondrial dynamics and constitutes the first report of this gene in association with a severe neurodevelopmental disorder.
| S-EPMC6075218 | biostudies-literature