Mutation-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles
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ABSTRACT:
PROVIDER: PRJNA1008999 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25755127.fastq.gz | Fastqsanger.gz | |||
| SRR25755128.fastq.gz | Fastqsanger.gz | |||
| SRR25755129.fastq.gz | Fastqsanger.gz | |||
| SRR25755130.fastq.gz | Fastqsanger.gz | |||
| SRR25755131.fastq.gz | Fastqsanger.gz |
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Project description:Mutation-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles
| PRJNA1033619 | ENA
Project description:We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with de novo variants in the AFF3 degron , a sequence involved in its binding to ubiquitin ligase. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative (DN) mode-of-action, wherein an increased level of AFF3 resulted in pathological effects. In line with this hypothesis, we describe an individual presenting a KINSSHIP-like phenotype carrying a partial duplication of AFF3. Further screening of intellectual disability cohorts revealed nine individuals with heterozygous and three with homozygous loss-of-function (LoF) variants, as well as two probands with compound LoF/missense and six with biallelic missense mutations in AFF3, who displayed a milder syndrome. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA confirming their association with the ablation of aff3. Conversely, the missense isoforms did not complement demonstrating the deleteriousness of the variants identified in affected individuals. To assess the different effect of these variants, we profiled the transcriptome of fibroblasts of affected individuals and isogenic cells harboring DN/DN, LoF/+, LoF/LoF or DN/LoF AFF3 genotypes. While the same pathways are affected, only one-third of the differentially expressed genes are common to both homozygote datasets, indicating that AFF3 LoF and DN mutations largely modulate transcriptomes differently. In particular, the apical junction and DNA repair pathways displayed opposite modulation. Our results and the high pleiotropy shown by this locus in GWASes suggest that even slight changes in the AFF3 function might be deleterious.
2024-02-14 | GSE246554 | GEO
Project description:We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with de novo variants in the AFF3 degron , a sequence involved in its binding to ubiquitin ligase. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative (DN) mode-of-action, wherein an increased level of AFF3 resulted in pathological effects. In line with this hypothesis, we describe an individual presenting a KINSSHIP-like phenotype carrying a partial duplication of AFF3. Further screening of intellectual disability cohorts revealed nine individuals with heterozygous and three with homozygous loss-of-function (LoF) variants, as well as two probands with compound LoF/missense and six with biallelic missense mutations in AFF3, who displayed a milder syndrome. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA confirming their association with the ablation of aff3. Conversely, the missense isoforms did not complement demonstrating the deleteriousness of the variants identified in affected individuals. To assess the different effect of these variants, we profiled the transcriptome of fibroblasts of affected individuals and isogenic cells harboring DN/DN, LoF/+, LoF/LoF or DN/LoF AFF3 genotypes. While the same pathways are affected, only one-third of the differentially expressed genes are common to both homozygote datasets, indicating that AFF3 LoF and DN mutations largely modulate transcriptomes differently. In particular, the apical junction and DNA repair pathways displayed opposite modulation. Our results and the high pleiotropy shown by this locus in GWASes suggest that even slight changes in the AFF3 function might be deleterious.
2024-02-14 | GSE241621 | GEO
Project description:BackgroundWe previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney,caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative (DN) mode-of-action, wherein an increased level of AFF3 resulted in pathological effects.MethodsEvolutionary constraints suggest that other mode-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be deleterious variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants.ResultsWe identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous LoF or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not complement. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring +/+, DN/DN, LoF/+, LoF/LoF or DN/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the DN/DN or the LoF/LoF lines. While the same pathways are affected, only about one-third of the differentially expressed genes are common to these homozygote datasets, indicating that AFF3 LoF and DN variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation.ConclusionsOur results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.
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2014-06-30 | E-GEOD-48977 | biostudies-arrayexpress
Project description:Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
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Project description:<p>Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigated how the cell state preceding <em>Tet2</em> mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we found that the epigenetic features of clones at similar differentiation status were highly heterogeneous and functionally responded differently to <em>Tet2</em> mutation. Cell differentiation stage also influenced <em>Tet2</em> mutation response indicating that the cell of origin's epigenome modulates clone-specific behaviors in CH. Molecular features associated with higher risk outcomes include <em>Sox4</em> that sensitized cells to <em>Tet2</em> inactivation, inducing dedifferentiation, altered metabolism and increasing the <em>in vivo</em> clonal output of mutant cells, as confirmed in primary GMP and HSC models. Our findings validate the hypothesis that epigenetic features can predispose specific clones for dominance, explaining why identical genetic mutations can result in different phenotypes.</p>
2024-04-30 | MTBLS9914 | MetaboLights
Project description:Cardiac pathological hypertrophy is associated with a significantly increased risk of coronary heart disease and has been observed in diabetic patients treated with rosiglitazone, whereas most published studies do not suggest a similar increase in risk of cardiovascular events in pioglitazone-treated diabetic subjects. This study sought to understand the pathophysiological mechanisms underlying the disparate cardiovascular effects of rosiglitazone and pioglitazone and yield knowledge as to the causative nature of rosiglitazone-associated cardiac hypertrophy.
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