scholarly journals Modern classification and molecular-genetic aspects of osteogenesis imperfecta

2020 ◽  
Vol 24 (2) ◽  
pp. 219-227
Author(s):  
A. R. Zaripova ◽  
R. I. Khusainova
Keyword(s):  
Osteogenesis Imperfecta ◽  
Bone Tissue ◽  
Autosomal Recessive ◽  
Type I Collagen ◽  
Autosomal Dominant ◽  
Clinical Severity ◽  
Type I ◽  
New Genes ◽  
Wide Range

Osteogenesis imperfecta (imperfect osteogenesis in the Russian literature) is the most common hereditary form of bone fragility, it is a genetically and clinically heterogeneous disease with a wide range of clinical severity, often leading to disability from early childhood. It is based on genetic disorders leading to a violation of the structure of bone tissue, which leads to frequent fractures, impaired growth and posture, with the development of characteristic disabling bone deformities and associated problems, including respiratory, neurological, cardiac, renal impairment, hearing loss. Osteogenesis imperfecta occurs in both men and women, the disease is inherited in both autosomal dominant and autosomal recessive types, there are sporadic cases of the disease due to de novomutations, as well as X-linked forms. The term “osteogenesis imperfecta” was coined by W. Vrolick in the 1840s. The first classification of the disease was made in 1979 and has been repeatedly reviewed due to the identification of the molecular cause of the disease and the discovery of new mechanisms for the development of osteogenesis imperfecta. In the early 1980s, mutations in two genes of collagen type I (COL1A1and COL1A2) were first associated with an autosomal dominant inheritance type of osteogenesis imperfecta. Since then, 18 more genes have been identified whose products are involved in the formation and mineralization of bone tissue.  The degree of genetic heterogeneity of the disease has not yet been determined, researchers continue to identify new genes involved in its pathogenesis, the number of which has reached 20. In the last decade, it has become  known that autosomal recessive, autosomal dominant and X-linked mutations in a wide range of genes, encoding  proteins that are involved in the synthesis of type I collagen, its processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells, cause imperfect  osteogenesis. A large number of causative genes complicated the classical classification of the disease and, due to new advances in the molecular basis of the disease, the classification of the disease is constantly being improved.  In this review, we systematized and summarized information on the results of studies in the field of clinical and genetic aspects of osteogenesis imperfecta and reflected the current state of the classification criteria for diagnosing the disease.

scholarly journals Genotype-Phenotype Correlations in Autosomal Dominant Osteogenesis Imperfecta

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
I. Mouna Ben Amor ◽  
Francis H. Glorieux ◽  
Frank Rauch
Keyword(s):  
Osteogenesis Imperfecta ◽  
Autosomal Dominant ◽  
Collagen Type ◽  
Collagen Type I ◽  
Bone Fragility ◽  
Clinical Severity ◽  
Type I ◽  
Review Of The Literature ◽  
Single Centre ◽  
Wide Range

Osteogenesis imperfecta, discussed in Baldridge et al. 2008 is an inherited bone fragility disorder with a wide range of clinical severity that in the majority of cases is caused by mutations in COL1A1 or COL1A2, the genes that encode the two collagen type I alpha chains. Here we describe genotype-phenotype correlations in OI patients who have mutations affecting collagen type I. This paper is based on findings in a large single-centre OI population and a review of the literature.

Search for mutations of the interferon-induced transmembrane protein 5 (IFITM5) gene in patients with osteogenesis imperfecta

2019 ◽  
pp. 21-29
Author(s):  
А.Р. Зарипова ◽  
Л.Р. Нургалиева ◽  
А.В. Тюрин ◽  
И.Р. Минниахметов ◽  
Р.И. Хусаинова
Keyword(s):  
Osteogenesis Imperfecta ◽  
De Novo ◽  
Transmembrane Protein ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Heterozygous Mutation ◽  
Type I ◽  
New Genes ◽  
Wide Range ◽  
Type V

Проведено исследование гена интерферон индуцированного трансмембранного белка 5 (IFITM5) у 99 пациентов с несовершенным остеогенезом (НО) из 86 неродственных семей. НО - клинически и генетически гетерогенное наследственное заболевание соединительной ткани, основное клиническое проявление которого - множественные переломы, начиная с неонатального периода жизни, зачастую приводящие к инвалидизации с детского возраста. К основным клиническим признакам НО относятся голубые склеры, потеря слуха, аномалия дентина, повышенная ломкость костей, нарушения роста и осанки с развитием характерных инвалидизирующих деформаций костей и сопутствующих проблем, включающих дыхательные, неврологические, сердечные, почечные нарушения. НО встречается как у мужчин, так и у женщин. До сих пор не определена степень генетической гетерогенности заболевания. На сегодняшний день известно 20 генов, вовлеченных в патогенез НО, и исследователи разных стран продолжают искать новые гены. В последнее десятилетие стало известно, что аутосомно-рецессивные, аутосомно-доминантные и Х-сцепленные мутации в широком спектре генов, кодирующих белки, которые участвуют в синтезе коллагена I типа, его процессинге, секреции и посттрансляционной модификации, а также в белках, которые регулируют дифференцировку и активность костеобразующих клеток, вызывают НО. Мутации в гене IFITM5, также называемом BRIL (bone-restricted IFITM-like protein), участвующем в формировании остеобластов, приводят к развитию НО типа V. До 5% пациентов имеют НО типа V, который характеризуется образованием гиперпластического каллуса после переломов, кальцификацией межкостной мембраны предплечья и сетчатым рисунком ламелирования, наблюдаемого при гистологическом исследовании кости. В 2012 г. гетерозиготная мутация (c.-14C> T) в 5’-нетранслируемой области (UTR) гена IFITM5 была идентифицирована как основная причина НО V типа. В представленной работе проведен анализ гена IFITM5 и идентифицирована мутация c.-14C>T, возникшая de novo, у одного пациента с НО, которому впоследствии был установлен V тип заболевания. Также выявлены три известных полиморфных варианта: rs57285449; c.80G>C (p.Gly27Ala) и rs2293745; c.187-45C>T и rs755971385 c.279G>A (p.Thr93=) и один ранее не описанный вариант: c.128G>A (p.Ser43Asn) AGC>AAC (S/D), которые не являются патогенными. В статье уделяется внимание особенностям клинических проявлений НО V типа и рекомендуется определение мутации c.-14C>T в гене IFITM5 при подозрении на данную форму заболевания. A study was made of interferon-induced transmembrane protein 5 gene (IFITM5) in 99 patients with osteogenesis imperfecta (OI) from 86 unrelated families and a search for pathogenic gene variants involved in the formation of the disease phenotype. OI is a clinically and genetically heterogeneous hereditary disease of the connective tissue, the main clinical manifestation of which is multiple fractures, starting from the natal period of life, often leading to disability from childhood. The main clinical signs of OI include blue sclera, hearing loss, anomaly of dentin, increased fragility of bones, impaired growth and posture, with the development of characteristic disabling bone deformities and associated problems, including respiratory, neurological, cardiac, and renal disorders. OI occurs in both men and women. The degree of genetic heterogeneity of the disease has not yet been determined. To date, 20 genes are known to be involved in the pathogenesis of OI, and researchers from different countries continue to search for new genes. In the last decade, it has become known that autosomal recessive, autosomal dominant and X-linked mutations in a wide range of genes encoding proteins that are involved in the synthesis of type I collagen, its processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells cause OI. Mutations in the IFITM5 gene, also called BRIL (bone-restricted IFITM-like protein), involved in the formation of osteoblasts, lead to the development of OI type V. Up to 5% of patients have OI type V, which is characterized by the formation of a hyperplastic callus after fractures, calcification of the interosseous membrane of the forearm, and a mesh lamellar pattern observed during histological examination of the bone. In 2012, a heterozygous mutation (c.-14C> T) in the 5’-untranslated region (UTR) of the IFITM5 gene was identified as the main cause of OI type V. In the present work, the IFITM5 gene was analyzed and the de novo c.-14C> T mutation was identified in one patient with OI who was subsequently diagnosed with type V of the disease. Three known polymorphic variants were also identified: rs57285449; c.80G> C (p.Gly27Ala) and rs2293745; c.187-45C> T and rs755971385 c.279G> A (p.Thr93 =) and one previously undescribed variant: c.128G> A (p.Ser43Asn) AGC> AAC (S / D), which were not pathogenic. The article focuses on the features of the clinical manifestations of OI type V, and it is recommended to determine the c.-14C> T mutation in the IFITM5 gene if this form of the disease is suspected.

scholarly journals A novel Gly to Arg substitution at position 388 of the alpha1 chain of type I collagen in lethal form of osteogenesis imperfecta.

2002 ◽  
Vol 49 (2) ◽  
pp. 443-450 ◽  
Author(s):  
Anna Galicka ◽  
Slawomir Wolczynski ◽  
Ryszard Lesniewicz ◽  
Lech Chyczewski ◽  
Andrzej Gindzienski
Keyword(s):  
Osteogenesis Imperfecta ◽  
Type I Collagen ◽  
Peptide Mapping ◽  
Novel Mutation ◽  
Direct Sequencing ◽  
Base Change ◽  
Clinical Severity ◽  
Restriction Enzyme Digestion ◽  
Type I ◽  
Cultured Skin

Cultured skin fibroblasts from a proband with a lethal form of osteogenesis imperfecta produce two forms of type I collagen chains, with normal and delayed electrophoretic migration; collagen of the proband's mother was normal. Peptide mapping experiments localized the structural defect in the proband to alpha1(I) CB8 peptide in which residues 123 to 402 are spaned. Direct sequencing of amplified cDNA covering this region revealed a G to A single base change in one allele of the alpha1(I) chain, that converted glycine 388 to arginine. Restriction enzyme digestion of the RT-PCR product was consistent with a heterozygous COL1A1 mutation. The novel mutation conforms to the linear gradient of clinical severity for the alpha1(I) chain and results in reduced thermal stability by 3 degrees C and intracellular retention of abnormal molecules.

Management of Multiple Mandibular Fractures in a Child with Osteogenesis Imperfecta Using Arch Bar Retained Thermoformed Splints: A Novel Technique

2016 ◽  
Vol 40 (4) ◽  
pp. 322-327 ◽  
Author(s):  
Kumar Nilesh ◽  
Ashwini Sawant ◽  
Swapnil Taur ◽  
M I Parkar
Keyword(s):  
Osteogenesis Imperfecta ◽  
Type I Collagen ◽  
Autosomal Dominant ◽  
Bone Fractures ◽  
Invasive Technique ◽  
Mandibular Fractures ◽  
Type I ◽  
Inherited Disorders ◽  
Arch Bar ◽  
Blue Sclerae

Osteogenesis Imperfecta (OI) is a heterogeneous group of autosomal dominant and recessive inherited disorders of type I collagen metabolism. Clinical features of OI include multiple bone fractures, muscle weakness, joint laxity, skeletal deformities, blue sclerae, hearing loss, and dentinogenesis imperfecta. This report presents a challenging case of multiple mandibular fractures in a five years old child with OI, which was successfully treated with a new, minimally invasive technique of closed reduction with arch bar retained thermoformed splint.

scholarly journals New Genes in Bone Development: What's New in Osteogenesis Imperfecta

2013 ◽  
Vol 98 (8) ◽  
pp. 3095-3103 ◽  
Author(s):  
Joan C. Marini ◽  
Angela R. Blissett
Keyword(s):  
Osteogenesis Imperfecta ◽  
Type I Collagen ◽  
Bone Development ◽  
Clinical Manifestations ◽  
Autosomal Recessive Inheritance ◽  
Bone Dysplasia ◽  
Protein Product ◽  
Type I ◽  
Related Condition ◽  
New Genes

Osteogenesis imperfecta (OI) is a heritable bone dysplasia characterized by bone fragility and deformity and growth deficiency. Most cases of OI (classical types) have autosomal dominant inheritance and are caused by mutations in the type I collagen genes. During the past several years, a number of noncollagenous genes whose protein products interact with collagen have been identified as the cause(s) of rare forms of OI. This has led to a paradigm shift for OI as a collagen-related condition. The majority of the non-classical OI types have autosomal recessive inheritance and null mutations in their respective genes. The exception is a unique dominant defect in IFITM5, which encodes Bril and leads to hypertrophic callus and interosseous membrane ossification. Three recessive OI types arise from defects in any of the components of the collagen prolyl 3-hydroxylation complex (CRTAP, P3H1, CyPB), which modifies the collagen α1(I)Pro986 residue. Complex dysfunction leads to delayed folding of the procollagen triple helix and increased helical modification. Next, defects in collagen chaperones, HSP47 and FKBP65, lead to improper procollagen folding and deficient collagen cross-linking in matrix, respectively. A form of OI with a mineralization defect is caused by mutations in SERPINF1, whose protein product, PEDF, is a well-known antiangiogenesis factor. Defects in the C-propeptide cleavage enzyme, BMP1, also cause recessive OI. Additional genes, including SP7 and TMEM38B, have been implicated in recessive OI but are as yet unclassified. Elucidating the mechanistic pathways common to dominant and recessive OI may lead to novel therapeutic approaches to improve clinical manifestations.

scholarly journals Osteogênese Imperfeita em cão jovem da raça pinscher

2018 ◽  
Vol 46 ◽  
pp. 5
Author(s):  
Paula Priscila Correa Costa ◽  
Juliana Custódio ◽  
Fernanda Sayuri Ebina ◽  
Liliane Lima Da Silva ◽  
Pedro Ernesto Da Cunha ◽  
...  
Keyword(s):  
Osteogenesis Imperfecta ◽  
Type I Collagen ◽  
Clinical Signs ◽  
Corneal Opacity ◽  
Type I ◽  
Osteogenesis Imperfecta Type ◽  
Multiple Fractures ◽  
Triangular Face ◽  
Type Iii ◽  
Wide Range

Background: Osteogenesis imperfecta is a severe genetic disease rarely described in veterinary medicine. This multisystemic condition is caused by a defect in the production and metabolization of collagen, which implicates in bone fragility. This disease has been described in cattle, sheep, domestic felines, mouse and dogs of different breeds, including collie, golden retriever, beagle, dachshund and chow chow. Animals affected by this condition present multiple fractures without previous occurrence of trauma. Therefore, this report aimed to describe a case of osteogenesis imperfecta type III in a miniature pinscher dog.Case: A 1-year-old male miniature pinscher dog, was admitted for clinical evaluation in Fortaleza, Brazil, with a history of spontaneous fractures without known causes. This animal was maintained indoors, fed on dry feed and presented recurrent events of claudication and pain. In the physical examination, the individual walked solely with the forelimbs, avoiding the use of the hind limbs and presented pain behavior. Bulging of the skull was observed laterally, which promoted a triangular appearance of head and face. Fontanelles were soft, and the eyes presented blueish sclera and corneal opacity. Teeth were small, translucid, fragile and deformed. Radiography images revealed bulging of the calvaria and persistent fontanelles with open cranial sutures. In addition, cranial convolutions were less clear, which was compatible with hydrocephalus. Dental roots were narrow, short and presented partial pulp obliteration. The radiographic contrast of the dentin was low with a reduction of periapical radiolucency. Bone radiopacity was low in the bones of the abdomen and pelvis, in addition to femur. Metaphysis of the right tibia was enlarged and angular. Multiple fractures were identified in the pelvis with the formation of opaque bony calluses and bone marrow sclerosis. Physiological parameters and blood test results were unaltered. After the diagnosis of osteogenesis imperfecta type III, treatment was performed with meloxicam 0.1 mg/kg, SID, VO) and tramadol (2 mg/kg, TID, VO) until pain was controlled. When the patient was stable, the treatment was halted until the next event of fractures followed by pain.Discussion: Type I collagen is considered the most abundant protein in connective tissue, accounting for 95% of the various types of collagen found in bone tissue. In osteogenesis imperfecta, there is a shortage in coding of type I collagen, which prevents this protein from exerting its structural functions properly. In addition, it is subjected to intra and extracellular degradation, affecting cell migration and differentiation and, concomitantly, cell-matrix interaction. Hence, these changes are considered the main pathophysiological factors of osteogenesis imperfecta. There is a wide range of phenotypic presentations in individuals with osteogenesis imperfecta. However, there is a pattern of fractures and features that aid clinically and radiologically in the characterization of the disease and form the basis for case identification and diagnosis. In this case, the diagnosis was concluded primarily considering significant clinical signs, such as: repetitive fractures, triangular face, bulging of the skull, bluish sclera and corneal opacity. Radiographic examinations were used to confirm the diagnosis and to aid in treating the fractures. Although the genetic test provides a better understanding of the disease, it was not performed in this case, as it is routinely unavailable in many treatment centers. In conclusion, we described a case of osteogenesis imperfecta in a miniature pinscher dog.

scholarly journals Osteogenesis imperfecta: current issues of etiology, pathogenesis, classification (systematic review)

2021 ◽  
Vol 27 (4) ◽  
pp. 453-460
Author(s):  
S.O. Ryabykh ◽  
◽  
D.A. Popkov ◽  
E.N. Shchurova ◽  
P.V. Ochirova ◽  
...  
Keyword(s):  
Systematic Review ◽  
Osteogenesis Imperfecta ◽  
Recent Literature ◽  
Bone Diseases ◽  
Clinical Severity ◽  
Inclusion Criteria ◽  
New Genes ◽  
Review Articles ◽  
Literature Reviews

The constantly changing information about the genetic nature of osteogenesis imperfecta (OI), new approaches to classification and diagnosis, and the growing interest in this pathology require careful analysis and generalization of the available data in the recent literature. Purpose Analysis of recent literature on epidemiology, pathogenesis, etiology, classification of osteogenesis imperfecta. Materials and methods The literature search was carried out in the scientific literature databases of PubMed, Web of Science, Scopus, eLIBRARY, RSCI, and references of the key works. The following inclusion criteria were used: literature reviews, review articles, multicenter studies, cohort studies of patients with osteogenesis imperfecta. Results This systematic review included 18 publications that met the inclusion criteria. All selected publications were published within the period from 2012 to 2020. The study designs were review articles or literature reviews. Discussion Osteogenesis imperfecta is one of the most common types of skeletal dysplasia, a phenotypically and genetically heterogeneous group of hereditary bone diseases. OI is characterized by high variability of manifestations, even within the same type and one family. The results of the analysis of the prevalence of this disease in different population groups remain not fully covered. The degree of genetic heterogeneity of the disease has not yet been determined. Research is ongoing to identify new genes involved in the pathogenesis of OI. The introduction of modern methods for determining mutations in genes contributed to the progress of research into the molecular pathogenesis of osteogenesis imperfecta, and identification of new genes, mutations in which lead to OI. The large number of causative genes complicates the process of creating an optimal classification of OI. The difficulty of creating a comprehensive classification of OI subtypes is the fact that there is no clear phenotype-genotype relationship; based on the mutation, conclusions about its clinical severity cannot be drawn. Conclusion The classification of various types of osteogenesis imperfecta is still the subject of ongoing debate and research.

scholarly journals Restoration of Osteogenesis by CRISPR/Cas9 Genome Editing of the Mutated COL1A1 Gene in Osteogenesis Imperfecta

2021 ◽  
Vol 10 (14) ◽  
pp. 3141
Author(s):  
Hyerin Jung ◽  
Yeri Alice Rim ◽  
Narae Park ◽  
Yoojun Nam ◽  
Ji Hyeon Ju
Keyword(s):  
Osteogenesis Imperfecta ◽  
Type I Collagen ◽  
Disease Modeling ◽  
Bone Fragility ◽  
Osteogenic Potential ◽  
Type I ◽  
Gene Correction ◽  
Col1a1 Gene ◽  
Collagen Formation

Osteogenesis imperfecta (OI) is a genetic disease characterized by bone fragility and repeated fractures. The bone fragility associated with OI is caused by a defect in collagen formation due to mutation of COL1A1 or COL1A2. Current strategies for treating OI are not curative. In this study, we generated induced pluripotent stem cells (iPSCs) from OI patient-derived blood cells harboring a mutation in the COL1A1 gene. Osteoblast (OB) differentiated from OI-iPSCs showed abnormally decreased levels of type I collagen and osteogenic differentiation ability. Gene correction of the COL1A1 gene using CRISPR/Cas9 recovered the decreased type I collagen expression in OBs differentiated from OI-iPSCs. The osteogenic potential of OI-iPSCs was also recovered by the gene correction. This study suggests a new possibility of treatment and in vitro disease modeling using patient-derived iPSCs and gene editing with CRISPR/Cas9.

scholarly journals Intracellular and Extracellular Markers of Lethality in Osteogenesis Imperfecta: A Quantitative Proteomic Approach

2021 ◽  
Vol 22 (1) ◽  
pp. 429
Author(s):  
Luca Bini ◽  
Domitille Schvartz ◽  
Chiara Carnemolla ◽  
Roberta Besio ◽  
Nadia Garibaldi ◽  
...  
Keyword(s):  
Osteogenesis Imperfecta ◽  
Type I Collagen ◽  
Type I ◽  
Tandem Mass ◽  
Type Ii ◽  
Type Iii ◽  
Bioinformatic Tools ◽  
Proteomic Approach ◽  
Fibrillin 1 ◽  
Heritable Disorder

Osteogenesis imperfecta (OI) is a heritable disorder that mainly affects the skeleton. The inheritance is mostly autosomal dominant and associated to mutations in one of the two genes, COL1A1 and COL1A2, encoding for the type I collagen α chains. According to more than 1500 described mutation sites and to outcome spanning from very mild cases to perinatal-lethality, OI is characterized by a wide genotype/phenotype heterogeneity. In order to identify common affected molecular-pathways and disease biomarkers in OI probands with different mutations and lethal or surviving phenotypes, primary fibroblasts from dominant OI patients, carrying COL1A1 or COL1A2 defects, were investigated by applying a Tandem Mass Tag labeling-Liquid Chromatography-Tandem Mass Spectrometry (TMT LC-MS/MS) proteomics approach and bioinformatic tools for comparative protein-abundance profiling. While no difference in α1 or α2 abundance was detected among lethal (type II) and not-lethal (type III) OI patients, 17 proteins, with key effects on matrix structure and organization, cell signaling, and cell and tissue development and differentiation, were significantly different between type II and type III OI patients. Among them, some non–collagenous extracellular matrix (ECM) proteins (e.g., decorin and fibrillin-1) and proteins modulating cytoskeleton (e.g., nestin and palladin) directly correlate to the severity of the disease. Their defective presence may define proband-failure in balancing aberrances related to mutant collagen.

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