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A Progeroid Syndrome with Severe Osteogenesis Imperfecta segregates with an Intronic TAPT1 homozygous Variant that Creates a knockout allele [RNA-seq]

ABSTRACT: In this study, we use transcriptomic approaches, to delineate a non-coding TAPT1 mutation (c.1237-52G>A) resulting in a protein-null allele, that segregated with a congenital recessive disease recessive consisting of Osteogenesis Imperfecta (OI) and neonatal progeria.

ORGANISM(S): Homo sapiens

PROVIDER: GSE197118 | GEO | 2023/01/20

REPOSITORIES: GEO

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A Progeroid Syndrome with Severe Osteogenesis Imperfecta segregates with an Intronic TAPT1 homozygous Variant that Creates a knockout allele [NET-seq]

Project description:In this study, we use transcriptomic approaches, to delineate a non-coding TAPT1 mutation (c.1237-52G>A) resulting in a protein-null allele, that segregated with a congenital recessive disease recessive consisting of Osteogenesis Imperfecta (OI) and neonatal progeria.

2023-01-20 | GSE197119 | GEO

A Progeroid Syndrome with Severe Osteogenesis Imperfecta segregates with an Intronic TAPT1 homozygous Variant that Creates a knockout allele

Project description:A Progeroid Syndrome with Severe Osteogenesis Imperfecta segregates with an Intronic TAPT1 homozygous Variant that Creates a knockout allele

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Multi-Omic analyses reveal aberrant differentiation trajectory with WNT1 Loss-of-Function in type XV osteogenesis imperfecta

Project description:Osteogenesis imperfecta (OI) is a serious genetic bone disorder characterized by congenital low bone mass, deformity and frequent fractures. Type XV OI is a moderate to severe form of skeletal dysplasia caused by WNT1 mutations. In this cohort study from southern China, we summarized the clinical phenotypes of patients with WNT1 mutations and found the proportion of type XV patients was around 10.3% (25 out of 243) with diverse phenotypic spectrums. Functional assays indicated that mutations of WNT1 significantly impaired its secretion and effective activity, leading to moderate to severe clinical manifestations, porous bone structure and enhanced osteoclastic activities. Analysis of proteomic data from human skeleton indicated that the expression of SOST was dramatically reduced in type XV patients. Single-cell transcriptome data generated from human tibia samples revealed aberrant differentiation trajectory of skeletal progenitors and impaired maturation of osteocytes, resulting in excessive CXCL12+ progenitors and abnormal cell populations with adipogenic characteristics. The integration of multi-omics data from human skeleton delineates how WNT1 regulates the differentiation and maturation of skeletal progenitors, which will provide a new direction for the treatment strategy of type XV osteogenesis imperfecta and relative low bone mass diseases such as early onset osteoporosis.

2024-10-17 | PXD050841 | Pride

A Progeroid Syndrome with Severe Osteogenesis Imperfecta segregates with an Intronic TAPT1 homozygous Variant that Creates a knockout allele [NET-seq]

Project description:A Progeroid Syndrome with Severe Osteogenesis Imperfecta segregates with an Intronic TAPT1 homozygous Variant that Creates a knockout allele [NET-seq]

| PRJNA809011 | ENA

A Progeroid Syndrome with Severe Osteogenesis Imperfecta segregates with an Intronic TAPT1 homozygous Variant that Creates a knockout allele [RNA-seq]

Project description:A Progeroid Syndrome with Severe Osteogenesis Imperfecta segregates with an Intronic TAPT1 homozygous Variant that Creates a knockout allele [RNA-seq]

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The osteocyte transcriptome is extensively dysregulated in mouse models of Osteogenesis Imperfecta

Project description:Osteocytes are long-lived, highly interconnected, terminally differentiated osteoblasts which reside within mineralized bone matrix. They constitute about 95% of adult bone cells and play important functions in the regulation of bone remodeling, phosphate homeostasis, and mechanical stimuli sensing and response. However, the role of osteocytes in the pathogenesis of congenital diseases of bone such as osteogenesis imperfecta (OI) is poorly understood. This study characterized in vivo transcriptional changes in osteocytes from the CrtapKO and oim/oim mouse models of OI, using RNA-sequencing on osteocyte-enriched cortical bone from femur and tibia. These models were chosen because they mimic two types of OI with different genetic mutations which result in distinct type I collagen defects. Hundreds of transcripts were dysregulated in either model of OI compared to WT, but 281 of these were similarly up- or down-regulated in both. Conversely, very few transcripts were differentially expressed between the CrtapKO and oim/oim mice, indicating that distinct alterations in type I collagen can lead to shared pathogenic processes and similar phenotypic outcomes. Bioinformatics analyses identified several critical hubs of dysregulation that were enriched in annotation terms such as development and differentiation, ECM and collagen fibril organization, cell adhesion, signaling, regulatory processes, pattern binding, chemotaxis, and cell projections. The data further indicated alterations in important signaling pathways such as WNT and TGF-β. Overall, our study suggested that the osteocyte transcriptome is broadly dysregulated in OI, that transcriptomic alterations in OI can be strikingly similar despite arising from different genetic mutations, and that the potential consequences of osteocyte dysregulation deserve further investigation.

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Effect of Sclerostin Inactivation in a Mouse Model of Severe Dominant Osteogenesis Imperfecta

Project description:Osteogenesis imperfecta (OI) is a rare bone disease that is associated with fractures and low bone mass. Sclerostin inhibition is being evaluated as a potential approach to increase bone mass in OI. We had previously found that in Col1a1Jrt/+ mice, a model of severe OI, treatment with an anti-sclerostin antibody had a minor effect on the skeletal phenotype. In the present study, we assessed the effect of genetic sclerostin inactivation in the Col1a1Jrt/+ mouse. We crossed Col1a1Jrt/+ mice with Sost knockout mice to generate Sost-deficient Col1a1Jrt/+ mice and assessed differences between Col1a1Jrt/+ mice with homozygous Sost deficiency and Col1a1Jrt/+ mice with heterozygous Sost deficiency. We found that Col1a1Jrt/+ mice with homozygous Sost deficiency had higher body mass, femur length, trabecular bone volume, cortical thickness and periosteal diameter as well as increased biomechanical parameters of bone strength. Differences between genotypes were larger at the age of 14 weeks than at 8 weeks of age. Transcriptome analysis of RNA extracted from the tibial diaphysis revealed only 5 differentially regulated genes. Thus, genetic inactivation of Sost increased bone mass and strength in the Col1a1Jrt/+ mouse. It appears from these observations that the degree of Sost suppression that is required for eliciting a beneficial response can vary with the genetic cause of OI.

2023-04-04 | GSE220601 | GEO

A Progeroid Syndrome with Severe Osteogenesis Imperfecta segregates with an Intronic TAPT1 homozygous Variant that Creates a knockout allele

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-01-19 | GSE197120 | GEO

Trancsriptomic analyses reveal aberrant differentiation trajectory with WNT1 Loss-of-Function in type XV osteogenesis imperfecta

2024-08-13 | GSE262092 | GEO

XBP1s-Mediated Endoplasmic Reticulum Proteostasis Network Enhancement Can Selectively Improve Folding and Secretion of an Osteogenesis Imperfecta-Causing Collagen-I Variant

Project description:Osteogenesis imperfecta (OI) is most commonly caused by autosomal dominant mutations in genes encoding collagen type-I. Here, we test the hypothesis that modulation of the endoplasmic reticulum (ER) proteostasis network via the unfolded protein response (UPR) can improve the folding and secretion of the lethal osteogenesis imperfecta (OI)-causing G425S a1(I) variant. We show that specific induction of the UPR’s XBP1s transcriptional response enhances G425S a1(I) secretion up to ~300% of basal levels. Notably, the effect is selective – WT a1(I) secretion is unaltered by XBP1s. XBP1s pathway activation appears to post-translationally enhance the folding/assembly and secretion of G425S a1(I). Consistent with this notion, we find that the stable, triple-helical collagen-I secreted by XBP1s-activated G425S a1(I) patient fibroblasts includes a higher proportion of the mutant a1(I) polypeptide than the collagen-I secreted under basal ER proteostasis conditions.

2023-12-19 | GSE163812 | GEO

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