Structural Consequences of Glycine Missense Mutations in Osteogenesis Imperfecta

Brodsky, Barbara; Persikov, Anton V.

doi:10.1016/b978-0-12-397165-4.00011-3

Cited by 4 publications

(4 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Conversely, other mutations in COL1A1 or COL1A2 , most often glycine substitutions in the Gly-X-Y collagen repeat, cause structural defects of the collagen triple helix that have a dominant negative action on the normal collagen chains, and result in moderate, severe or lethal OI [30]. These structural mutations often cause protracted collagen folding with over-modification of lysine residues in the endoplasmic reticulum (ER), enlargement of the ER due to accumulation of misfolded chains, abnormal collagen trafficking, and delayed secretion in the ECM [29].…”

Section: Genetics Of Oi: An Evolving Storymentioning

confidence: 99%

Osteogenesis imperfecta and therapeutics

Morello

2018

Matrix Biology

View full text Add to dashboard Cite

Osteogenesis imperfecta, or brittle bone disease, is a congenital disease that primarily causes low bone mass and bone fractures but it can negatively affect other organs. It is usually inherited in an autosomal dominant fashion, although rarer recessive and X-chromosome-linked forms of the disease have been identified. In addition to type I collagen, mutations in a number of other genes, often involved in type I collagen synthesis or in the differentiation and function of osteoblasts, have been identified in the last several years. Seldom, the study of a rare disease has delivered such a wealth of new information that have helped our understanding of multiple processes involved in collagen synthesis and bone formation. In this short review I will describe the clinical features and the molecular genetics of the disease, but then focus on how OI dysregulates all aspects of extracellular matrix biology. I will conclude with a discussion about OI therapeutics.

show abstract

Section: Genetics Of Oi: An Evolving Storymentioning

confidence: 99%

Osteogenesis imperfecta and therapeutics

Morello

2018

Matrix Biology

View full text Add to dashboard Cite

show abstract

“…Phenotypes resulting from COL1A1 missense variants may be more severe than those caused by COL1A2 variants because 75% of the procollagen molecules in the heterozygotes of COL1A1 mutants are expected to have ≥1 mutant pro‐α1(I) chain. In contrast, in the case of COL1A2 variants, only 50% of the molecules presumably contain the mutant pro‐α2(I) chain (Brodsky & Persikov, 2014). Glycine substitutions to branched or charged amino acids are highly disruptive to helix stability and are mainly confined to the region near the N ‐terminal of COL1A1 .…”

Section: Discussionmentioning

confidence: 99%

Genetic analysis in Japanese patients with osteogenesis imperfecta: Genotype and phenotype spectra in 96 probands

Higuchi

Hasegawa

Futagawa

et al. 2021

Molec Gen & Gen Med

View full text Add to dashboard Cite

show abstract

“…(6) In up to 85% of cases, OI is caused by a mutation in the COL1A1 or COL1A2 encoding the α1 or α2 chain of type I collagen, respectively, resulting in an underproduction of normal collagen or secretion of defective collagen chains depending on the mutation. (7)(8)(9) More recently, other proteins localized in the matrix, endoplasmic reticulum (ER), ER-Golgi, and nucleus have been identified in the pathogenesis of OI and makeup the remaining 15% of cases. (3,(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) This spectrum of genotype-phenotype variability has made both the diagnosis and management of the disease challenging; as such, no cure for OI exists, there is no United States Food and Drug Administration-or European Medicines Agency-approved pharmacological treatment, and consensus on an appropriate treatment strategy has yet to be achieved.…”

Section: Introductionmentioning

confidence: 99%

“…Further, patients with the same OI‐causing mutation can present with different clinical phenotypes . In up to 85% of cases, OI is caused by a mutation in the COL1A1 or COL1A2 encoding the α1 or α2 chain of type I collagen, respectively, resulting in an underproduction of normal collagen or secretion of defective collagen chains depending on the mutation . More recently, other proteins localized in the matrix, endoplasmic reticulum (ER), ER‐Golgi, and nucleus have been identified in the pathogenesis of OI and makeup the remaining 15% of cases .…”

Section: Introductionmentioning

confidence: 99%

Gene Expression Profile and Acute Gene Expression Response to Sclerostin Inhibition in Osteogenesis Imperfecta Bone

et al. 2020

View full text Add to dashboard Cite

Sclerostin antibody (SclAb) therapy has been suggested as a novel therapeutic approach toward addressing the fragility phenotypic of osteogenesis imperfecta (OI). Observations of cellular and transcriptional responses to SclAb in OI have been limited to mouse models of the disorder, leaving a paucity of data on the human OI osteoblastic cellular response to the treatment. Here, we explore factors associated with response to SclAb therapy in vitro and in a novel xenograft model using OI bone tissue derived from pediatric patients. Bone isolates (approximately 2 mm3) from OI patients (OI type III, type III/IV, and type IV, n = 7; non‐OI control, n = 5) were collected to media, randomly assigned to an untreated (UN), low‐dose SclAb (TRL, 2.5 μg/mL), or high‐dose SclAb (TRH, 25 μg/mL) group, and maintained in vitro at 37°C. Treatment occurred on days 2 and 4 and was removed on day 5 for TaqMan qPCR analysis of genes related to the Wnt pathway. A subset of bone was implanted s.c. into an athymic mouse, representing our xenograft model, and treated (25 mg/kg s.c. 2×/week for 2/4 weeks). Implanted OI bone was evaluated using μCT and histomorphometry. Expression of Wnt/Wnt‐related targets varied among untreated OI bone isolates. When treated with SclAb, OI bone showed an upregulation in osteoblast and osteoblast progenitor markers, which was heterogeneous across tissue. Interestingly, the greatest magnitude of response generally corresponded to samples with low untreated expression of progenitor markers. Conversely, samples with high untreated expression of these markers showed a lower response to treatment. in vivo implanted OI bone showed a bone‐forming response to SclAb via μCT, which was corroborated by histomorphometry. SclAb induced downstream Wnt targets WISP1 and TWIST1, and elicited a compensatory response in Wnt inhibitors SOST and DKK1 in OI bone with the greatest magnitude from OI cortical bone. Understanding patients' genetic, cellular, and morphological bone phenotypes may play an important role in predicting treatment response. This information may aid in clinical decision‐making for pharmacological interventions designed to address fragility in OI. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

show abstract

Structural Consequences of Glycine Missense Mutations in Osteogenesis Imperfecta

Cited by 4 publications

References 55 publications

Osteogenesis imperfecta and therapeutics

Osteogenesis imperfecta and therapeutics

Genetic analysis in Japanese patients with osteogenesis imperfecta: Genotype and phenotype spectra in 96 probands

Gene Expression Profile and Acute Gene Expression Response to Sclerostin Inhibition in Osteogenesis Imperfecta Bone

Contact Info

Product

Resources

About