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A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity.

ABSTRACT: We previously reported a pathogenic de novo p.R342W mutation in the transcriptional corepressor CTBP1 in four independent patients with neurodevelopmental disabilities [1]. Here, we report the clinical phenotypes of seven additional individuals with the same recurrent de novo CTBP1 mutation. Within this cohort, we identified consistent CtBP1-related phenotypes of intellectual disability, ataxia, hypotonia, and tooth enamel defects present in most patients. The R342W mutation in CtBP1 is located within a region implicated in a high affinity-binding cleft for CtBP-interacting proteins. Unbiased proteomic analysis demonstrated reduced interaction of several chromatin-modifying factors with the CtBP1 W342 mutant. Genome-wide transcriptome analysis in human glioblastoma cell lines expressing -CtBP1 R342 (wt) or W342 mutation revealed changes in the expression profiles of genes controlling multiple cellular processes. Patient-derived dermal fibroblasts were found to be more sensitive to apoptosis during acute glucose deprivation compared to controls. Glucose deprivation strongly activated the BH3-only pro-apoptotic gene NOXA, suggesting a link between enhanced cell death and NOXA expression in patient fibroblasts. Our results suggest that context-dependent relief of transcriptional repression of the CtBP1 mutant W342 allele may contribute to deregulation of apoptosis in target tissues of patients leading to neurodevelopmental phenotypes.

SUBMITTER: Beck DB

PROVIDER: S-EPMC8078134 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity

Project description:We previously reported a pathogenic de novo W342 mutation in the transcriptional corepressor CtBP1 in four independent patients with neurodevelopmental disabilities. Here, we report the clinical phenotypes of seven additional individuals with the same recurrent de novo CtBP1 mutation. Within this cohort we identified consistent CtBP1-related phenotypes of intellectual disability, ataxia, hypotonia and tooth enamel defects present in all patients. The W342 mutation in CtBP1 is located within a region implicated in a high affinity-binding cleft for CtBP-interacting proteins. Unbiased proteomic analysis demonstrated reduced interaction of several chromatin modifying factors with the CtBP1 W342 mutant. Genome-wide transcriptome analysis in human glioblastoma cells lines expressing -CtBP1 R342 (wt) or W342 mutation revealed changes in the expression profiles of genes controlling multiple cellular processes. Patient-derived dermal fibroblasts were found to be more sensitive to apoptosis during acute glucose deprivation compared to controls. Glucose deprivation strongly activated the BH3-only pro-apoptotic gene NOXA, suggesting a link between enhanced cell death and NOXA expression in patient fibroblasts. Our results suggest that context-dependent relief of transcriptional repression of the CtBP1 mutant W342 allele may contribute to deregulation of apoptosis in target tissues of patients leading to neurodevelopmental phenotypes.

2019-05-09 | PXD012702 | Pride

A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity

2019-02-08 | GSE126253 | GEO

A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity

Project description:A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity

| PRJNA521403 | ENA

A missense mutation in human INSC causes peripheral neuropathy

Project description:PAR3/INSC/LGN form an evolutionarily conserved complex required for asymmetric cell division in the developing brain, but its post-developmental function and disease relevance in the peripheral nervous system (PNS) remains unknown. We mapped a new locus for axonal Charcot-Marie-Tooth disease (CMT2) and identified a missense mutation c.209T>G (p.Met70Arg) in the INSC gene. Modelling the INSCM70R variant in Drosophila, we showed that it caused proprioceptive defects in adult flies, leading to gait defects resembling those in CMT2 patients. Cellularly, PAR3/INSC/LGN dysfunction caused tubulin aggregation and necrotic neurodegeneration, with microtubule-stabilizing agents rescuing both morphological and functional defects of the INSCM70R mutation in the PNS. Our findings underscore the critical role of the PAR3/INSC/LGN machinery in the adult PNS and highlights a potential therapeutic target for INSC-associated CMT2.

| S-SCDT-10_1038-S44321-024-00062-W | biostudies-other

A missense mutation in Lama3 causes androgen alopecia.

Project description:Hair loss disorders such as androgenetic alopecia have caused serious disturbances to normal human life. Animal models play an important role in exploring pathogenesis of disease and evaluating new therapies. NIH hairless mice are a spontaneous hairless mouse discovered and bred in our laboratory. In this study, we resequenced the genomes of NIH normal mice and NIH hairless mice and obtained 3,575,560 high-quality, plausible SNP loci and 995,475 InDels. The Euclidean distance algorithm was used to assess the association of SNP loci with the hairless phenotype, at a threshold of 0.62. Two regions of chromosome 18 having the highest association with the phenotype contained 345 genes with a total length of 13.98 Mb. The same algorithm was used to assess the association of InDels with the hairless phenotype at a threshold of 0.54 and revealed a region of 25.45 Mb in length, containing 518 genes. The mutation candidate gene Lama3 (NM_010680.2: c.652C>T; NP_034810.1: p. Arg217Cys) was selected based on the results of functional gene analysis and mutation prediction screening. Lama3 (R217C) mutant mice were further constructed using CRISPR/Cas9 technology, and the relationship between Lama3 point mutations and the hairless phenotype were clarified by phenotypic observation. The results showed that male Lama3 point mutation mice started to lose hair on the 80th day after birth, and the hair loss area gradually expanded over time. H&E staining of skin sections showed that the point mutation mice had increased sebaceous glands in the dermis and missing hair follicle structure (i.e., typical symptoms of androgenetic alopecia). This study is a good extension of the current body of knowledge about the function of Lama3, and the constructed Lama3 (R217C) mutant mice may be a good animal model for studying androgenetic alopecia.

| S-EPMC10682005 | biostudies-literature

A pathogenic DYT-THAP1 dystonia mutation causes hypomyelination and loss of YY1 binding.

Project description:Dystonia is a disabling disease that manifests as prolonged involuntary twisting movements. DYT-THAP1 is an inherited form of isolated dystonia caused by mutations in THAP1 encoding the transcription factor THAP1. The phe81leu (F81L) missense mutation is representative of a category of poorly understood mutations that do not occur on residues critical for DNA binding. Here, we demonstrate that the F81L mutation (THAP1F81L) impairs THAP1 transcriptional activity and disrupts CNS myelination. Strikingly, THAP1F81L exhibits normal DNA binding but causes a significantly reduced DNA binding of YY1, its transcriptional partner that also has an established role in oligodendrocyte lineage progression. Our results suggest a model of molecular pathogenesis whereby THAP1F81L normally binds DNA but is unable to efficiently organize an active transcription complex.

| S-EPMC8976427 | biostudies-literature

MAFA missense mutation causes familial insulinomatosis and diabetes mellitus.

Project description:The ?-cell-enriched MAFA transcription factor plays a central role in regulating glucose-stimulated insulin secretion while also demonstrating oncogenic transformation potential in vitro. No disease-causing MAFA variants have been previously described. We investigated a large pedigree with autosomal dominant inheritance of diabetes mellitus or insulinomatosis, an adult-onset condition of recurrent hyperinsulinemic hypoglycemia caused by multiple insulin-secreting neuroendocrine tumors of the pancreas. Using exome sequencing, we identified a missense MAFA mutation (p.Ser64Phe, c.191C>T) segregating with both phenotypes of insulinomatosis and diabetes. This mutation was also found in a second unrelated family with the same clinical phenotype, while no germline or somatic MAFA mutations were identified in nine patients with sporadic insulinomatosis. In the two families, insulinomatosis presented more frequently in females (eight females/two males) and diabetes more often in males (12 males/four females). Four patients from the index family, including two homozygotes, had a history of congenital cataract and/or glaucoma. The p.Ser64Phe mutation was found to impair phosphorylation within the transactivation domain of MAFA and profoundly increased MAFA protein stability under both high and low glucose concentrations in ?-cell lines. In addition, the transactivation potential of p.Ser64Phe MAFA in ?-cell lines was enhanced compared with wild-type MAFA. In summary, the p.Ser64Phe missense MAFA mutation leads to familial insulinomatosis or diabetes by impacting MAFA protein stability and transactivation ability. The human phenotypes associated with the p.Ser64Phe MAFA missense mutation reflect both the oncogenic capacity of MAFA and its key role in islet ?-cell activity.

| S-EPMC5798333 | biostudies-literature

A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-11-25 | E-GEOD-75358 | biostudies-arrayexpress

The transcriptional cofactor MIER1-beta negatively regulates histone acetyltransferase activity of the CREB-binding protein.

Project description:BackgroundMier1 encodes a novel transcriptional regulator and was originally isolated as a fibroblast growth factor early response gene. Two major protein isoforms have been identified, MIER1alpha and beta, which differ in their C-terminal sequence. Previously, we demonstrated that both isoforms recruit histone deacetylase 1 (HDAC1) to repress transcription. To further explore the role of MIER1 in chromatin remodeling, we investigated the functional interaction of MIER1 with the histone acetyltransferase (HAT), Creb-binding protein (CBP).FindingsUsing GST pull-down assays, we demonstrate that MIER1 interacts with CBP and that this interaction involves the N-terminal half (amino acids 1-283) of MIER1, which includes the acidic activation and ELM2 domains and the C-terminal half (amino acids 1094-2441) of CBP, which includes the bromo-, HAT, C/H3 and glutamine-rich domains. Functional analysis, using HEK293 cells, shows that the CBP bound to MIER1 in vivo has no detectable HAT activity. Histone 4 peptide binding assays demonstrate that this inhibition of HAT activity is not the result of interference with histone binding.ConclusionOur data indicate that an additional mechanism by which MIER1 could repress transcription involves the inhibition of histone acetyltransferase activity.

| S-EPMC2546418 | biostudies-literature

A p.C343S missense mutation in PJVK causes progressive hearing loss.

Project description:Mutations in PJVK, encoding Pejvakin, cause autosomal recessive nonsyndromic hearing loss in humans at the DFNB59 locus on chromosome 2q31.2. Pejvakin is involved in generating auditory and neural signals in the inner ear. We have identified a consanguineous Pakistani family segregating sensorineural progressive hearing loss as a recessive trait, consistent with linkage to DFNB59. We sequenced PJVK and identified a novel missense mutation, c.1028G>C in exon 7 (p.C343S) co-segregating with the phenotype in the family. The p.C343 residue is fully conserved among orthologs from different vertebrate species. We have also determined that mutations in PJVK are not a common cause of hearing loss in families with moderate to severe hearing loss in Pakistan. This is the first report of PJVK mutation in a Pakistani family and pinpoints an important residue for PJVK function.

| S-EPMC3534776 | biostudies-literature

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