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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE197120 | GEO | 2023/01/19

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 [RNA-seq]

2023-01-20 | GSE197118 | 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

| PRJNA809010 | ENA

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]

| PRJNA809007 | ENA

Monoallelic and biallelic CREB3L1 variant causes mild and severe osteogenesis imperfecta, respectively.

Project description:PurposeOsteogenesis imperfecta (OI) is a heritable skeletal dysplasia. Dominant pathogenic variants in COL1A1 and COL1A2 explain the majority of OI cases. At least 15 additional genes have been identified, but those still do not account for all OI phenotypes that present. We sought the genetic cause of mild and lethal OI phenotypes in an unsolved family.MethodsWe performed exome sequencing on seven members of the family, both affected and unaffected.ResultsWe identified a variant in cyclic AMP responsive element binding protein 3-like 1 (CREB3L1) in a consanguineous family. The variant caused a prenatal/perinatal lethal OI in homozygotes, similar to that seen in OI type II as a result of mutations in type I collagen genes, and a mild phenotype (fractures, blue sclerae) in multiple heterozygous family members. CREB3L1 encodes old astrocyte specifically induced substance (OASIS), an endoplasmic reticulum stress transducer. The variant disrupts a DNA-binding site and prevents OASIS from acting on its transcriptional targets including SEC24D, which encodes a component of the coat protein II complex.ConclusionThis report confirms that CREB3L1 is an OI-related gene and suggests the pathogenic mechanism of CREB3L1-associated OI involves the altered regulation of proteins involved in cellular secretion.

| S-EPMC5816725 | biostudies-literature

PPIB mutations cause severe osteogenesis imperfecta.

Project description:Deficiency of cartilage-associated protein (CRTAP) or prolyl 3-hydroxylase 1(P3H1) has been reported in autosomal-recessive lethal or severe osteogenesis imperfecta (OI). CRTAP, P3H1, and cyclophilin B (CyPB) form an intracellular collagen-modifying complex that 3-hydroxylates proline at position 986 (P986) in the alpha1 chains of collagen type I. This 3-prolyl hydroxylation is decreased in patients with CRTAP and P3H1 deficiency. It was suspected that mutations in the PPIB gene encoding CyPB would also cause OI with decreased collagen 3-prolyl hydroxylation. To our knowledge we present the first two families with recessive OI caused by PPIB gene mutations. The clinical phenotype is compatible with OI Sillence type II-B/III as seen with COL1A1/2, CRTAP, and LEPRE1 mutations. The percentage of 3-hydroxylated P986 residues in patients with PPIB mutations is decreased in comparison to normal, but it is higher than in patients with CRTAP and LEPRE1 mutations. This result and the fact that CyPB is demonstrable independent of CRTAP and P3H1, along with reported decreased 3-prolyl hydroxylation due to deficiency of CRTAP lacking the catalytic hydroxylation domain and the known function of CyPB as a cis-trans isomerase, suggest that recessive OI is caused by a dysfunctional P3H1/CRTAP/CyPB complex rather than by the lack of 3-prolyl hydroxylation of a single proline residue in the alpha1 chains of collagen type I.

| S-EPMC2756556 | biostudies-literature

Case Report: A Novel Homozygous Variant of the <i>SERPINF1</i> Gene in Rare Osteogenesis Imperfecta Type VI.

Project description:Osteogenesis imperfecta (OI) is a group of connective tissue disorders with different types of inheritance. OI is characterized by bone fragility and deformities, frequent fractures, low bone-mineral density, and impaired bone micro-architectonics. We described here a case of a one-year-old Tuvan patient with multiple fractures. The disease manifestation occurred first at 12 weeks of age as a shoulder joint bruise, and during the year, the patient sustained 27 fractures. Genetic testing revealed a novel homozygous mutation, c.259_260insCGGCC (p.T87fs), in the SERPINF1 gene. This insertion leads to an open-reading frameshift, and the mutation is not represented in the databases. Mutations in SERPINF1 lead to type VI OI, the clinical picture of which is similar to the disease phenotype manifestation of the patient. Thus, the patient's diagnosis was established by finding a novel pathogenic variant in the SERPINF1 gene.

| S-EPMC10095092 | biostudies-literature

Severe osteogenesis imperfecta in cyclophilin B-deficient mice.

Project description:Osteogenesis Imperfecta (OI) is a human syndrome characterized by exquisitely fragile bones due to osteoporosis. The majority of autosomal dominant OI cases result from point or splice site mutations in the type I collagen genes, which are thought to lead to aberrant osteoid within developing bones. OI also occurs in humans with homozygous mutations in Prolyl-3-Hydroxylase-1 (LEPRE1). Although P3H1 is known to hydroxylate a single residue (pro-986) in type I collagen chains, it is unclear how this modification acts to facilitate collagen fibril formation. P3H1 exists in a complex with CRTAP and the peptidyl-prolyl isomerase cyclophilin B (CypB), encoded by the Ppib gene. Mutations in CRTAP cause OI in mice and humans, through an unknown mechanism, while the role of CypB in this complex has been a complete mystery. To study the role of mammalian CypB, we generated mice lacking this protein. Early in life, Ppib-/- mice developed kyphosis and severe osteoporosis. Collagen fibrils in Ppib-/- mice had abnormal morphology, further consistent with an OI phenotype. In vitro studies revealed that in CypB-deficient fibroblasts, procollagen did not localize properly to the golgi. We found that levels of P3H1 were substantially reduced in Ppib-/- cells, while CRTAP was unaffected by loss of CypB. Conversely, knockdown of either P3H1 or CRTAP did not affect cellular levels of CypB, but prevented its interaction with collagen in vitro. Furthermore, knockdown of CRTAP also caused depletion of cellular P3H1. Consistent with these changes, post translational prolyl-3-hydroxylation of type I collagen by P3H1 was essentially absent in CypB-deficient cells and tissues from CypB-knockout mice. These data provide significant new mechanistic insight into the pathophysiology of OI and reveal how the members of the P3H1/CRTAP/CypB complex interact to direct proper formation of collagen and bone.

| S-EPMC2777385 | biostudies-literature

OSTEOGENESIS IMPERFECTA

Project description:In this study, our objective is to broaden the understanding of the genetic and clinical characteristics of OI by investigating rare pathogenic variants (PVs) not only within the well-established COL1A1 and COL1A2, which are responsible for more than 85-90% of all cases but also in other genes involved in OI. To achieve this, we performed next-generation sequencing (NGS) analysis on OI patients from the Puglia Region in South Italy, a population with limited genetic data on OI

| PRJEB66425 | ENA

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