Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The phenotype of the most common human ADAR1p150 Za domain mutation P193A in mice is incompletely penetrant

ABSTRACT: ADAR1 mediated A-to-I RNA editing is a self/non-self discrimination mechanism for cellular double stranded RNAs. ADAR mutations are one cause of Aicardi-Goutières Syndrome, an inherited paediatric encephalopathy, classed as a “Type I interferonopathy”. The most common ADAR1 mutation is a proline 193 alanine (p.P193A) mutation, mapping to the ADAR1p150 isoform specific Za domain. We report the development of an independent murine P195A knock-in mouse, homologous to the human P193A mutation. The Adar1P195A/P195A mice are largely normal and the mutation is well tolerated. Contrasting with previous reports when the P195A mutation was compounded with an ADAR1 null allele (Adar1P195A/-), we find a partially penetrant phenotype, with approximately half the animals being runted with a shortened lifespan and the remaining animals normal. Severe runting and shortened survival of Adar1P195A/- animals were partly associated with the parental genotype. The P195A mutation is well tolerated in vivo and the loss of MDA5 is sufficient to completely rescue phenotypes in the Adar1P195A/- mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE220628 | GEO | 2023/02/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

RNA-sequencing of lung RNA from mice with compound mutations in ADAR1 and MAVS, ZBP1 or RIPK3.

Project description:The purpose of this study was to examine the role of MAVS, ZBP1 and RIPK3 in the phenotype that develops when ADAR1 activity is impaired, in particular when the Za domain of ADAR1 is mutated. Mice homozygous for a Za domain-mutant allele of Adar1 (Adar1mZa/mZa mice) and mice carrying one mZa and one null Adar1 allele (Adar1-/mZa mice) were compared with control mice that were either wild type or heterozygous for the Adar1 mZa allele (Adar1wt/mZa mice). The effects of MAVS deficiency, RIPK3 deficiency, ZBP1 deficiency or ZBP1 Za domain mutations were assessed by analysing compound mutant mice. Given the early postnatal lethal phenotype that develops in Adar1-/mZa mice, comparisons were made in RNA isolated from lung tissue from newborn mice of each genotype (5 mice per genotype). As Adar1-/mZa mice additionally lacking Mavs or Zbp1 are viable, adult mice (15-20 weeks of age) were also used for several compound mutations as donors of lung tissue.

2022-06-09 | E-MTAB-11540 | biostudies-arrayexpress

RNA-sequencing of brain RNA from mice with compound mutations in ADAR1 and MAVS or ZBP1

Project description:The purpose of this study was to examine the role of MAVS and ZBP1 in the phenotype that develops when ADAR1 activity is missing, in particular when the Za domain of ADAR1 is mutated. Mice homozygous for a Za domain-mutant allele of Adar1 (Adar1mZa/mZa mice) were compared with control mice carrying one mZa allele and one wild type allele of Adar1 (Adar1wt/mZa mice) and with mice carrying one mZa and one null Adar1 allele (Adar1-/mZa mice). Adar1-/mZa mice were also compared with mice additionally deficient in ZBP1 (Adar1-/mZa Zbp1-/- mice) or MAVS (Adar1-/mZa Mavs-/- mice). Given the early postnatal lethal phenotype that develops in Adar1-/mZa mice, comparisons were made in RNA isolated from brain tissue from newborn mice of each genotype (4 mice per genotype).

2022-04-27 | E-MTAB-11537 | biostudies-arrayexpress

2022_de Reuver_ADAR1 +/+ vs ADAR1 Za/Za HEK293 cells (deep-seq)

Project description:ADAR1 +/+ vs ADAR1 Za/Za HEK293 cells (deep-seq)

| PRJEB52618 | ENA

ADAR1 Zα domain P195A mutation activates the MDA-5 dependent RNA-sensing signaling pathway in the brain enhanced by haploinsufficiency without overall RNA editing level decrease.

Project description:The A-to-I RNA editing enzyme ADAR1 critically regulates the cellular RNA sensing signaling pathway, as the RNA-sensing signaling pathway recognizes unedited RNAs as “non-self” to activate the innate immune response. Mutations of ADAR1 cause severe inflammatory tissue injury, as shown in Aicardi-Goutières syndrome (AGS), in which severe inflammation occurs in the brain. The most frequent ADAR1 mutation in AGS is the P193A mutation in the Za domain, which exists in the AGS families coupling with an additional ADAR1 mutation. How this mutation alters the cellular RNAs leading to innate immune activation, has not been fully understood. This study analyzed RNA editing status and innate immune activation in the brains of a mouse model that carries the human ADAR1 P193A-equivalent mouse P195A mutation. We found that this mutation alone can cause excessive ISG expression in the brains, especially in the periventricular areas reflecting the pathologic feature of AGS. Furthermore, we found that ADAR1 P195A mutation did not affect the RNA editing activity in the overall RNA editing level; however, it leads to ISG expression in a dose-dependent manner, causing severer innate immune activation in haploinsufficiency status, whereas wildtype ADAR1 is redundant to suppress innate immune activation. The finding from this study indicated that the intact Z-RNA binding activity of ADAR1 plays a critical role in suppressing self-cellular RNA sensing, and innate immune homeostasis requires a minimum Z-RNA binding capacity of ADAR1.

2023-05-31 | GSE229884 | GEO

The phenotype of the most common human ADAR1p150 Za domain mutation P193A in mice is incompletely penetrant

Project description:The phenotype of the most common human ADAR1p150 Za domain mutation P193A in mice is incompletely penetrant

| PRJNA910555 | ENA

Prevalence of incompletely penetrant Huntington's disease alleles among individuals with major depressive disorder.

Project description:Presymptomatic individuals with the Huntingtin (HTT) CAG expansion mutation that causes Huntington's disease may have higher levels of depressive symptoms than healthy comparison populations. However, the prevalence of HTT CAG repeat expansions among individuals diagnosed with major depressive disorder has not been established.This was a case-control genetic association study of HTT CAG allele size in two discovery cohorts of individuals with major depressive disorder and comparison subjects without major depression as well as a replication cohort of individuals with major depression and comparison subjects without major depression.CAG repeat lengths of 36 or greater were observed in six of 3,054 chromosomes from individuals with major depression, compared with none of 4,155 chromosomes from comparison subjects. In a third cohort, one expanded allele was observed among 1,202 chromosomes in the major depression group, compared with none of 2,678 chromosomes in comparison subjects. No clear pattern of clinical features was shared among individuals with the expanded repeats.In clinical populations of individuals diagnosed with major depression, approximately 3 in 1,000 carried expanded HTT CAG alleles.

| S-EPMC3114558 | biostudies-literature

Evidence that mutations in the X-linked DDP gene cause incompletely penetrant and variable skewed X inactivation.

Project description:X chromosome inactivation results in the random transcriptional silencing of one of the two X chromosomes early in female development. After random inactivation, certain deleterious X-linked mutations can create a selective disadvantage for cells in which the mutation is on the active X chromosome, leading to X inactivation patterns with the mutation on the inactive X chromosome in nearly 100% of the individual's cells. In contrast to the homogeneous patterns of complete skewed inactivation noted for many X-linked disorders, here we describe a family segregating a mutation in the dystonia-deafness peptide (DDP) gene, in which female carriers show incompletely penetrant and variable X inactivation patterns in peripheral blood leukocytes, ranging between 50:50 and >95:5. To address the genetic basis for the unusual pattern of skewing in this family, we first mapped the locus responsible for the variable skewing to the proximal long arm (Xq12-q22) of the X chromosome (Z=5. 7, P=.002, LOD score 3.57), a region that includes both the DDP and the XIST genes. Examination of multiple cell types from women carrying a DDP mutation and of peripheral blood leukocytes from women from two unrelated families who carry different mutations in the DDP gene suggests that the skewed X inactivation is the result of selection against cells containing the mutant DDP gene on the active X chromosome, although skewing is apparently not as severe as that seen for many other deleterious X-linked mutations. Thus, DDP is an example of an X-linked gene for which mutations cause partial cell selection and thus incompletely skewed X inactivation in peripheral blood leukocytes.

| S-EPMC1377793 | biostudies-other

Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease.

Project description:Autosomal dominant polycystic kidney disease (ADPKD) caused by mutations in PKD1 is significantly more severe than PKD2. Typically, ADPKD presents in adulthood but is rarely diagnosed in utero with enlarged, echogenic kidneys. Somatic mutations are thought crucial for cyst development, but gene dosage is also important since animal models with hypomorphic alleles develop cysts, but are viable as homozygotes. We screened for mutations in PKD1 and PKD2 in two consanguineous families and found PKD1 missense variants predicted to be pathogenic. In one family, two siblings homozygous for R3277C developed end stage renal disease at ages 75 and 62 years, while six heterozygotes had few cysts. In the other family, the father and two children with moderate to severe disease were homozygous for N3188S. In both families homozygous disease was associated with small cysts of relatively uniform size while marked cyst heterogeneity is typical of ADPKD. In another family, one patient diagnosed in childhood was found to be a compound heterozygote for the PKD1 variants R3105W and R2765C. All three families had evidence of developmental defects of the collecting system. Three additional ADPKD families with in utero onset had a truncating mutation in trans with either R3277C or R2765C. These cases suggest the presence of incompletely penetrant PKD1 alleles. The alleles alone may result in mild cystic disease; two such alleles cause typical to severe disease; and, in combination with an inactivating allele, are associated with early onset disease. Our study indicates that the dosage of functional PKD1 protein may be critical for cyst initiation.

| S-EPMC2813773 | biostudies-literature

ADAR1 mutation causes ZBP1-dependent immunopathology II

Project description:The RNA editing enzyme ADAR1 is essential for suppression of innate immune activation and pathology caused by aberrant recognition of self-RNA, a role it carries out by disrupting the duplex structure of endogenous double-stranded RNA species. A point mutation in the Z-nucleic-acid binding domain (ZBD) of ADAR1 is associated with severe autoinflammatory disease. ZBP1 is the only other ZBD-containing mammalian protein and its activation can trigger both cell death and transcriptional responses via the kinases RIPK1 and RIPK3, and the protease caspase-8. Here, we show that the pathology caused by ADAR1 ZBD mutation is driven by activation of ZBP1. We found that ablation of ZBP1 fully rescued the overt pathology caused by ADAR1 mutation, without reversing the underlying inflammatory program caused by this mutation. While loss of RIPK3 partially phenocopied the protective effects of ZBP1 ablation, combined deletion of caspase-8 and RIPK3, or of caspase-8 and MLKL, unexpectedly exacerbated the pathogenic effects of ADAR1 mutation. These findings indicate that ADAR1 is a negative regulator of sterile ZBP1 activation, and that ZBP1-dependent signaling underlies the autoinflammatory pathology caused by mutation of ADAR1.

2022-08-10 | GSE200986 | GEO

ADAR1 mutation causes ZBP1-dependent immunopathology I

2022-08-10 | GSE200985 | GEO