Biallelic BRF2 mutations cause syndromic immunodeficiency and change RNA polymerase III-mediated transcription
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ABSTRACT:
PROVIDER: PRJNA1176264 | ENA |
REPOSITORIES: ENA
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Project description:TFIIB-related factor 2 (BRF2) crucially recruits RNA polymerase III (Pol III) to type III promoters containing a TATA box. These promoters encompass crucial components such as U6 spliceosomal RNA, tRNA processing enzyme RNase P, and selenocysteine tRNA. The results on cancer occurrence due to overexpression of BRF2 are known, but genetic disorders caused by mutations in BRF2 are still not well understood. Here, we first identified biallelic BRF2 variants exhibiting defective RNA Pol III activity to type III promoter in a familial patient presenting multiple anomalous features and primary immunodeficiency.
2024-11-06 | GSE280098 | GEO
Project description:Biallelic RNU12 noncoding variants cause CDAGS syndrome
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Project description:Intracellular calcium levels are finely tuned through intricate actions of a number of channels and transporters, including those at key endocellular stores, e.g. endoplasmic reticulum (ER), lysosomes, and mitochondria. Along with the highly homologous genes Inositol 1,4,5-trisphosphate (IP3) receptor type 1 (ITPR1) and 2 (ITPR2), ITPR3 encodes the IP3 receptor (IP3R), a key player in intracellular calcium release in animals. Here we report the first cases of ITPR3 defects in man leading to a primarily dysimmune phenotype. In four unrelated patients of diverse ethnicity, and suffering from a complex immunodeficiency syndrome, we report the same de novo pathogenic variant - c.7570C>T; p.Arg2524Cys - in ITPR3. Clinically, recurrent severe infectious episodes of viral and bacterial origins, features of ectodermal dysplasia and that of Charcot-Marie-Tooth disease were paramount. The identified variant does not affect gene transcription, yet it was structurally predicted and biologically proven to disrupt proper protein folding and function in vivo. This eventually leads to defective Calcium flux in patient cells, dysregulation of mitochondrial function and a broad dysimmune phenotype characterized primarily by a profound CD4 T cell lymphopenia associated with quasi absence of naïve CD4 and CD8 cells, itself mirrored by an increase in cognate memory cells. The Calcium signaling defect was recapitulated ex vivo through the introduction of this single variant in Jurkat cells. Moreover, site-directed mutagenesis displayed the exquisite sensitivity of Arg2524 to any amino acid change. In conclusion, a single unique recurrent de novo variant in ITPR3 leads to a novel syndromic immunodeficiency.
2023-07-05 | E-MTAB-13124 | biostudies-arrayexpress
Project description:Identifying causes of sporadic intellectual disability remains a considerable medical challenge. Here, we demonstrate that null mutations in the NONO gene, a member of the Drosophila Behavior Human Splicing (DBHS) protein family, are a novel cause of X-linked syndromic intellectual disability. Comparing humans to Nono-deficient mice revealed related behavioral and craniofacial anomalies, as well as global transcriptional dysregulation. Nono-deficient mice also showed deregulation of a large number of synaptic transcripts, causing a disorganization of inhibitory synapses, with impaired postsynaptic scaffolding of gephyrin. Alteration of gephyrin clustering could be rescued by over-expression of Gabra2 in NONO-compromised neurons. These findings link NONO to intellectual disability and first highlight the key role of DBHS proteins in functional organization of GABAergic synapses.
2015-09-02 | E-MTAB-2895 | biostudies-arrayexpress
Project description:Identifying causes of sporadic intellectual disability remains a considerable medical challenge. Here, we demonstrate that null mutations in the NONO gene, a member of the Drosophila Behavior Human Splicing (DBHS) protein family, are a novel cause of X-linked syndromic intellectual disability. Comparing humans to Nono-deficient mice revealed related behavioral and craniofacial anomalies, as well as global transcriptional dysregulation. Nono-deficient mice also showed deregulation of a large number of synaptic transcripts, causing a disorganization of inhibitory synapses, with impaired postsynaptic scaffolding of gephyrin. Alteration of gephyrin clustering could be rescued by over-expression of Gabra2 in NONO-compromised neurons. These findings link NONO to intellectual disability and first highlight the key role of DBHS proteins in functional organization of GABAergic synapses.
2015-09-02 | E-MTAB-2894 | biostudies-arrayexpress
Project description:Biallelic PAX5 mutations cause hypogammaglobulinemia,sensorimotor deficits and autism spectrum disorder
| PRJNA759253 | ENA
Project description:Autosomal recessive TPPII mutations cause a new human immunodeficiency
| PRJNA269323 | ENA
Project description:Processing of RNA polymerase II-transcribed spliceosomal small nuclear RNAs (snRNAs) initiates with cleavage by the Integrator complex, but the factors that subsequently remove 3’ end extensions from metazoan snRNAs have remained unknown. We studied human families with a unique recessive syndromic constellation of pontocerebellar atrophy with ambiguous genitalia, uncovering biallelic inactivating mutations in TOE1, which encodes a conserved unconventional deadenylase. TOE1 demonstrated tight association with snRNA-protein (snRNP) complexes with specificity for incompletely processed pre-snRNAs containing 3’ end extensions that often included post-transcriptionally added tails. Human cells deficient for TOE1 catalytic activity showed accumulation of 3’-end extended U1, U2, U4 and U5 pre-snRNAs, and TOE1 immuno-isolated from human cells was capable of processing 3’-end extended snRNPs in vitro. The missense mutations identified in patients impaired TOE1 stability and snRNA processing in patient cells, which was associated with defects in splicing. Our findings reveal the cause of a unique brain malformation and uncover a long-sought 3’ exonuclease required for snRNA processing.
2016-12-31 | GSE71536 | GEO
Project description:A single recurrent dominant variant in ITPR3 leads to a syndromic immunodeficiency
| PRJEB63615 | ENA
Project description:Cause of complex dyskinesia remains elusive in some patients. A homozygous missense variant leading to drastic decrease of PDE2A enzymatic activity was reported in one patient with childhood-onset choreodystonia preceded by paroxysmal dyskinesia and associated with cognitive impairment and interictal EEG abnormalities. Here, we report three new cases with biallelic PDE2A variants identified by trio whole-exome sequencing. Mitochondria network was analyzed after Mitotracker™ Red staining in control and mutated primary fibroblasts. Analysis of retrospective video of patients' movement disorder and refinement of phenotype was carried out. We identified a homozygous gain of stop codon variant c.1180C>T; p.(Gln394*) in PDE2A in siblings and compound heterozygous variants in young adult: a missense c.446C>T; p.(Pro149Leu) and splice-site variant c.1922+5G>A predicted and shown to produce an out of frame transcript lacking exon 22. All three patients had cognitive impairment or developmental delay. The phenotype of the two oldest patients, aged 9 and 26, was characterized by childhood-onset refractory paroxysmal dyskinesia initially misdiagnosed as epilepsy due to interictal EEG abnormalities. The youngest patient showed a proven epilepsy at the age of 4 months and no paroxysmal dyskinesia at 15 months. Interestingly, analysis of the fibroblasts with the biallelic variants in PDE2A variants revealed mitochondria network morphology changes. Together with previously reported case, our three patients confirm that biallelic PDE2A variants are a cause of childhood-onset refractory paroxysmal dyskinesia with cognitive impairment, sometimes associated with choreodystonia and interictal baseline EEG abnormalities or epilepsy.
| S-EPMC7608189 | biostudies-literature