Cause Of Osteogenesis Imperfecta Research Articles

Exome sequencing identified mutations in the WNT1 and COL1A2 genes in osteogenesis imperfecta cases.

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder characterized by bone deformities, fractures and reduced bone mass. OI can be inherited as a dominant, recessive, or X-linked disorder. The mutational spectrum has shown that autosomal dominant mutations in the type I collagen-encoding genes are responsible for OI in 85% of the cases. Apart from collagen genes, mutations in more than 20 other genes, such as CRTAP, CREB3L1, MBTPS2, P4HB, SEC24D, SPARC, FKBP10, LEPRE1, PLOD2, PPIB, SERPINF1, SERPINH1, SP7, WNT1, BMP1, TMEM38B, and IFITM5 have been reported in OI. To understand the genetic cause of OI in four cases, we conducted whole exome sequencing, followed by Sanger sequencing. In case #1, we identified a novel c.506delG homozygous mutation in the WNT1 gene, resulting in a frameshift and early truncation of the protein at the 197th amino acid. In cases #2, 3 and 4, we identified a heterozygous c.838G > A mutation in the COL1A2 gene, resulting in a p.Gly280Ser substitution. The clinvar frequency of this mutation is 0.000008 (GnomAD-exomes). This mutation has been identified by other studies as well and appears to be a mutational hot spot. These pathogenic mutations were found to be absent in 96 control samples analyzed for these sites. The presence of these mutations in the cases, their absence in controls, their absence or very low frequency in general population, and their evaluation using various in silico prediction tools suggested their pathogenic nature. Mutations in the WNT1 and COL1A2 genes explain these cases of osteogenesis imperfecta.

Novel pathogenic variants in SPARC as cause of osteogenesis imperfecta: Two case reports

Pathogenic variants in SPARC cause a rare autosomal recessive form of osteogenesis imperfecta (OI), classified as OI type XVII, which was first reported in 2015. Only six patient cases with this specific form of OI have been reported to date. The SPARC protein plays a crucial role in the calcification of collagen in bone, synthesis of the extracellular matrix, and the regulation of cell shape. In this case report, we describe the phenotype of two patients with SPARC-related OI, including a patient with two novel pathogenic variants in the SPARC gene. Targeted Next Generation Sequencing revealed new compound heterozygous variants (c.484G > A p.(Glu162Lys)) and c.496C > T p.(Arg166Cys)) in one patient and a homozygous nonsense pathogenic variant (c.145C > T p.(Gln49*)) in the other. In line with previously reported cases, the two OI patients presented delayed motor development, muscular weakness, scoliosis, and multiple fractures. Interestingly, our study reports for the first time the occurrence of dentinogenesis imperfecta. The study also reports the effectiveness of bisphosphonate treatment for OI type XVII. This article enhances the genetic, clinical, therapeutic, and radiological understanding of SPARC-related OI.

Effect of sclerostin inactivation in a mouse model of severe dominant osteogenesis imperfecta

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.

Jurisprudence Rulings Related to Osteogenesis Syndrome (Lobstein) in Islamic Jurisprudence

``Osteogenesis imperfecta'' and ``vitreous osteoporosis'' are genetic diseases in most of their cases, that is, it is sufficient for one of the parents to be a disease carrier in order to have one of their children suffering from it. It is the main protein source in the bone structure leading to this disorder; however, the genetic factor is the most common and accounts for about 80 to 85% of the causes of osteogenesis imperfecta. The congenital bone disorder is associated with a defect in the connective tissue, which leads to the inability to build or form bones. It leads to easy bone fractures, and the cause of these fractures is often unclear.
 Keywords: rulings, jurisprudence, syndrome, epigenetics, bone, Lobstein, jurisprudence, Islamic.

One half-century of advances in the evaluation and management of disorders of bone and mineral metabolism in children and adolescents.

The past 50years of research in pediatric bone and mineral metabolism have led to remarkable progress in the identification and characterization of disorders that affect the developing skeleton. Progress has been facilitated through advances in both technology and biology and this paper provides a brief description of some but not all of the key findings, including identification of the calcium sensing receptor and the polypeptides parathyroid hormone and parathyroid hormone-related protein as well as their shared receptor and signal generating pathways; the elucidation of vitamin D metabolism and actions; discovery of fibroblast growth factor 23 (FGF23), the sodium-phosphate co-transporters and the other components that regulate phosphate metabolism. Moreover, the past half-century of research has led to the delineation of the molecular bases for genetic forms ofhypoparathyroidism, pseudohypoparathyroidism, and primary hyperparathyroidism as well as the determination of the genetic causes of osteogenesis imperfecta, osteopetrosis, hypophosphatasia, and other disorders of mineral/bone homeostasis. During the next decade we expect that many of these fundamental discoveries will lead to the development of innovative treatments that will improve thelives of children with these disorders.

An Update on Animal Models of Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a heterogeneous disorder characterized by bone fragility, multiple fractures, bone deformity, and short stature. In recent years, the application of next generation sequencing has triggered the discovery of many new genetic causes for OI. Until now, more than 25 genetic causes of OI and closely related disorders have been identified. However, the mechanisms of many genes on skeletal fragility in OI are not entirely clear. Animal models of OI could help to understand the cellular, signaling, and metabolic mechanisms contributing to the disease, and how targeting these pathways can provide therapeutic targets. To date, a lot of animal models, mainly mice and zebrafish, have been described with defects in 19 OI-associated genes. In this review, we summarize the known genetic causes and animal models that recapitulate OI with a main focus on engineered mouse and zebrafish models. Additionally, we briefly discuss domestic animals with naturally occurring OI phenotypes. Knowledge of the specific molecular basis of OI will advance clinical diagnosis and potentially stimulate targeted therapeutic approaches.

Dental Treatment Approach in Two Patients with Osteogenesis Imperfecta: Case Report

Osteogenesis imperfecta (OI) is a very common, inherited autosomal dominant disease. It is characterized by deformity and fragility in bone structure, blue sclera, hearing loss, scoliosis, and dentinogenesis imperfecta. Molecular studies have shown that the cause of OI is a mutation of genes named COLIA1 and COLIA2 in both chains of collagen. Biochemical tests that examine the collagen structure or molecular tests that examine the DNA structure are used for making a definite diagnosis of the disease. It is reported that the prevalence of OI is between 1: 5000 and 1: 20000 in newborns, regardless of ethnic and racial discrimination. In addition to hard tissue involvement, tissues commonly contain collagen such as tendons, ligaments, skin, sclera, dental tissue, the middle and inner ear may be affected. Common dental anomalies in patients are dentinogenesis imperfecta (DI) and malocclusion. In this case report, two male patients, 18 and 19 years old, that have changes in the mouth, teeth and body tissues of were examined. The dental treatment of the patients was completed by applying resin-based composite restorations to affected hard dental tissues with a minimally invasive treatment approach.

Detection of a Recurrent TMEM38B Gene Deletion Associated with Recessive Osteogenesis Imperfecta.

Osteogenesis imperfecta is a clinically and genetically group of heterogeneous disorders associated with decreased bone density, brittle bones, bone deformity, recurrent fractures, and growth retardation. Osteogenesis imperfecta is commonly associated with mutations of the genes encoding for type I collagen (COL1A1/COL1A2). Mutations in other genes, some associated with type I collagen post-translational processing, have also been identified as the cause of osteogenesis imperfecta. Mutations in the transmembrane protein 38B (TMEM38B) gene have been reported in a rare autosomal recessive form of osteogenesis imperfecta. TMEM38B encodes TRIC-B - a trimeric intracellular cation channel type B which is essential to modulate intracellular calcium signaling. In this study, we are reporting a case of osteogenesis imperfecta type XIV from a Saudi consanguineous family. Our patient was an eight-month-old child with short limbs, club feet, and lower limb deformities with developmental delay. Radiological findings were consistent with the evidence of osteogenesis imperfecta. There was no evidence of impaired hearing or blue sclera and based on the clinical assessment, we classified our patient as a non-syndromic osteogenesis imperfecta. A pathogenic deletion in the chromosome 9q31.2 region, partially encompassing the TMEM38B gene, was detected using chromosomal microarray analysis. This study expands our knowledge about the rare type of osteogenesis imperfecta in our consanguineous population. Besides, it emphasizes the use of genomic medicine in clinical practices to formulate early interventions to clinically improve the patient’s condition.

Plastin 3 in X-Linked Osteoporosis: Imbalance of Ca2+-Dependent Regulation Is Equivalent to Protein Loss.

Osteogenesis imperfecta is a genetic disorder disrupting bone development and remodeling. The primary causes of osteogenesis imperfecta are pathogenic variants of collagen and collagen processing genes. However, recently variants of the actin bundling protein plastin 3 have been identified as another source of osteogenesis imperfecta. Plastin 3 is a highly conserved protein involved in several important cellular structures and processes and is controlled by intracellular Ca2+ which potently inhibits its actin-bundling activity. The precise mechanisms by which plastin 3 causes osteogenesis imperfecta remain unclear, but recent advances have contributed to our understanding of bone development and the actin cytoskeleton. Here, we review the link between plastin 3 and osteogenesis imperfecta highlighting in vitro studies and emphasizing the importance of Ca2+ regulation in the localization and functionality of plastin 3.

Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2

Osteogenesis imperfecta (OI) is characterized primarily by susceptibility to fractures with or without bone deformation. OI is genetically heterogeneous: over 20 genetic causes are recognized. We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in four families. KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2, which recycles ER-resident proteins with a KDEL-like peptide from the cis-Golgi to the ER through COPI retrograde transport. Analysis of patient primary fibroblasts showed intracellular decrease of HSP47 and FKBP65 along with reduced procollagen type I in culture media. Electron microscopy identified an abnormal quality of secreted collagen fibrils with increased amount of HSP47 bound to monomeric and multimeric collagen molecules. Mapping the identified KDELR2 variants onto the crystal structure of G.gallus KDELR2 indicated that these lead to an inactive receptor resulting in impaired KDELR2-mediated Golgi-ER transport. Therefore, in KDELR2-deficient individuals, OI most likely occurs because of the inability of HSP47 to bind KDELR2 and dissociate from collagen type I. Instead, HSP47 remains bound to collagen molecules extracellularly, disrupting fiber formation. This highlights the importance of intracellular recycling of ER-resident molecular chaperones for collagen type I and bone metabolism and a crucial role of HSP47 in the KDELR2-associated pathogenic mechanism leading to OI.

Femur Fracture Caused by Falling of a Boy with Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is the most common hereditable cause of bone fragility in children. A Japanese 2-year-old boy fell accidentally from a slide, sustaining a femur shaft fracture. Several maternal family members had experienced episodes of hearing impairment and bone fracture. The injury mechanism was clear and competent. Child abuse was unlikely. Strong family history and presence of blue sclera confirmed the OI diagnosis. Any doctor treating pediatric femur fractures should recall the rare cause of OI. Clinical evaluation alone without a family interview might not complete the diagnosis with OI. We continued proposing to his parents the benefit of receiving bisphosphonate treatment.

Osteogenesis imperfecta: advancements in genetics and treatment.

The purpose of this review is to outline the current understanding of the molecular mechanisms and natural history of osteogenesis imperfecta, and to describe the development of new treatments for this disorder. The introduction of next-generation sequencing technology has led to better understanding of the genetic cause of osteogenesis imperfecta and enabled cost-effective and timely diagnosis via expanded gene panels and exome or genome sequencing. Clinically, despite genetic heterogeneity, different forms of osteogenesis imperfecta share similar features that include connective tissue and systemic manifestations in addition to bone fragility. Thus, the goals of treatment in osteogenesis imperfecta extend beyond decreasing the risk of fracture, to include the maximization of growth and mobility, and the management of extraskeletal complications. The standard of care in pediatric patients is bisphosphonates therapy. Ongoing preclinical studies in osteogenesis imperfecta mouse models and clinical studies in individuals with osteogenesis imperfecta have been instrumental in the development of new and targeted therapeutic approaches, such as sclerostin inhibition and transforming growth factor-β inhibition. Osteogenesis imperfecta is a skeletal dysplasia characterized by bone fragility and extraskeletal manifestations. Better understanding of the mechanisms of osteogenesis imperfecta will enable the development of much needed targeted therapies to improve the outcome in affected individuals.

OR13-5 The Molecular Landscape of Osteogenesis Imperfecta in a Brazilian Tertiary Service Cohort

Osteogenesis imperfecta (OI) is clinically and genetically heterogeneous. Defects in collagen type 1 are reportedly the main cause of OI (85-90%), but most available data has arisen from developed countries. Massively parallel sequencing (MPS) technologies now allow for systematic and comprehensive analysis of OI genes simultaneously. Our objective was to obtain the molecular diagnosis of OI through targeted MPS in a single tertiary center cohort of Brazilian adults with OI. After informed consent, DNA samples were obtained from 52 cases of OI (9 families and 43 sporadic; total of 64 sequenced individuals, 96% adults). Sixty-nine percent of the cohort had moderate to severe OI, and consanguinity was common (22%). Coding regions and 25-bp boundaries of 15 OI genes (COL1A1, COL1A2, IFITM5 [plus 5’UTR], SERPINF1, CRTAP, P3H1, PPIB, SERPINH1, FKBP10, PLOD2, BMP1, SP7, TMEM38B, WNT1, CREB3L1) were captured with Agilent SureSelectXT and sequenced in Illumina NextSeq. Identified variants were classified according to ACMG/AMP guidelines and those considered to be disease-causing were confirmed by Sanger sequencing. Segregation analysis was pursued when familial samples were available. A molecular diagnosis was obtained in 92% of cases. Altogether, 55 variants were identified, 21 of which had never been previously reported in international databases. Variants in COL1A1 or COL1A2 were identified in 77%, whereas 23% had variants in other candidate genes. Amongst these, variants in SERPINF1, FKBP10 and PLOD2 were more prevalent. Only one case had the previously described IFITM5 c.-14C>T variant. A peculiar combination of four heterozygous P3H1 and WNT1 variants was detected in a non-consanguineous case, where one variant in each gene was inherited from each parent. In two cases, potentially modifier variants in LRP5 were identified. Surprisingly, in four consanguineous families the molecular cause was still related to COL1A1 or COL1A2, and two non-consanguineous cases had compound heterozygous PLOD2 variants. In conclusion, targeted MPS has effectively allowed establishing the molecular basis of OI in this Brazilian cohort, unraveling novel disease-causing variants in 29% of cases, and potentially reflecting new aspects of OI pathogenesis in Brazil. Non-collagen defects were found in 23% of cases, with a higher prevalence of P3H1, FKBP10, PLOD2 and SERPINF1 defects, with potential digenic interactions, and a lower prevalence of IFITM5-related OI. Inferring the molecular diagnosis from a family history of consanguinity was misleading in this setting. Obtaining a precise diagnosis of OI in underrepresented populations allows expanding our understanding of its molecular landscape and may lead to improved personalized care in the future.

Osteogenesis imperfecta: diagnosis and treatment.

Here we summarize the diagnosis of osteogenesis imperfecta, discuss newly discovered genes involved in osteogenesis imperfecta, and review the management of this disease in children and adults. Mutations in the two genes coding for collagen type I, COL1A1 and COL1A2, are the most common cause of osteogenesis imperfecta. In the past 10 years, defects in at least 17 other genes have been identified as responsible for osteogenesis imperfecta phenotypes, with either dominant or recessive transmission. Intravenous bisphosphonate infusions are the most widely used medical treatment. This has a marked effect on vertebra in growing children and can lead to vertebral reshaping after compression fractures. However, bisphosphonates are less effective for preventing long-bone fractures. At the moment, new therapies are under investigation. Despite advances in the diagnosis and treatment of osteogenesis imperfecta, more research is needed. Bisphosphonate treatment decreases long-bone fracture rates, but such fractures are still frequent. New antiresorptive and anabolic agents are being investigated but efficacy and safety of these drugs, especially in children, need to be better established before they can be used in clinical practice.

Genetic causes and mechanisms of Osteogenesis Imperfecta

Osteogenesis Imperfecta (OI) is a genetic disorder characterized by various clinical features including bone deformities, low bone mass, brittle bones, and connective tissue manifestations. The predominant cause of OI is due to mutations in the two genes that encode type I collagen. However, recent advances in sequencing technology has led to the discovery of novel genes that are implicated in recessive and dominant OI. These include genes that regulate the post-translational modification, secretion and processing of type I collagen as well as those required for osteoblast differentiation and bone mineralization. As such, OI has become a spectrum of genetic disorders informing about the determinants of both bone quantity and quality. Here we summarize the known genetic causes of OI, animal models that recapitulate the human disease and mechanisms that underlie disease pathogenesis. Additionally, we discuss the effects of disrupted collagen networks on extracellular matrix signaling and its impact on disease progression.

Pigment epithelium-derived factor restoration increases bone mass and improves bone plasticity in a model of osteogenesis imperfecta type VI via Wnt3a blockade.

Null mutations in for pigment epithelium-derived factor (PEDF), the protein product of the SERPINF1 gene, are the cause of osteogenesis imperfecta (OI) type VI. The PEDF-knockout (KO) mouse captures crucial elements of the human disease, including diminished bone mineralization and propensity to fracture. Our group and others have demonstrated that PEDF directs human mesenchymal stem cell (hMSC) commitment to the osteoblast lineage and modulates Wnt/β-catenin signaling, a major regulator of bone development; however, the ability of PEDF to restore bone mass in a mouse model of OI type VI has not been determined. In this study, PEDF delivery increased trabecular bone volume/total volume by 52% in 6-mo-old PEDF-KO mice but not in wild-type mice. In young (19-d-old) PEDF-KO mice, PEDF restoration increased bone volume fraction by 35% and enhanced biomechanical parameters of bone plasticity. A Wnt-green fluorescent protein reporter demonstrated dynamic changes in Wnt/β-catenin signaling characterized by early activation and marked suppression during terminal differentiation of hMSCs. Continuous Wnt3a exposure impeded mineralization of hMSCs, whereas the combination of Wnt3a and PEDF potentiated mineralization. Interrogation of the PEDF sequence identified a conserved motif found in other Wnt modulators, such as the dickkopf proteins. Mutation of a single amino acid on a 34-mer PEDF peptide increased mineralization of hMSC cultures compared with the native peptide sequence. These results indicate that PEDF counters Wnt signaling to allow for osteoblast differentiation and provides a mechanistic insight into how the PEDF null state results in OI type VI.-Belinsky, G. S., Sreekumar, B., Andrejecsk, J. W., Saltzman, W. M., Gong, J., Herzog, R. I., Lin, S., Horsley, V., Carpenter, T. O., Chung, C. Pigment epithelium-derived factor restoration increases bone mass and improves bone plasticity in a model of osteogenesis imperfecta type VI via Wnt3a blockade.

The application of high-resolution melting analysis in gene mutation screening of osteogenesis imperfecta

Objective To explore the application of high-resolution melting analysis (HRMA) in gene mutations screening of osteogenesis imperfecta (OI). Methods Clinical data of five children with OI was collected from March to December 2012 in Tianjin Hospital. Blood samples from five children with OI and their parents with a family history of OI were collected as well as normal controls. All exons and their flanking sequences of COL1A1 and COL1A2 gene were screened using PCR-HRMA and validated by the gene sequencing. Results PCR-HRMA showed abnormal results from five children in the COL1A1 gene exon 11, exon 39, exon 8 and the COL1A2 gene exon 19 screening area, respectively. Melting curves of children with OI were differences from normal controls, which showed the mutations of genes. Standard melting curve showed five children with mutations of heterozygous mutation. Sequencing analysis showed that children with COL1A1 gene mutation, c.768dupC, c.2644C> T, c.635G> A and COL1A2 gene mutation c.982G> A, c.948C>T, respectively. COL1A1 gene mutation caused a premature stop codon in children 1, 2 and clinical diagnosis with typeⅠOI. Genetic mutations in children 3, 4 with OI in alpha helix structure domain Gly alternative, and clinical diagnosis with type Ⅳ OI. Children 5 gene mutation was nonsense mutations. This variation is not the cause of OI, Which possible causes need to be researched. Conclusions PCR-HRMA has a low cost, easy operation, fast, high flux, pollution-free advantages. PCR-HRMA is a new effective method for OI mutation screening. The study found a new mutation of COL1A1 gene, c.768dupC. (Chin J Lab Med, 2015, 38: 35-39) Key words: Osteogenesis imperfecta; Collagen type Ⅰ; Collagen type Ⅱ; High resolution melting

Diagnosis of Fetal Osteogenesis imperfecta by Multidisciplinary Assessment: A Retrospective Study of 10 Cases

Objective: To describe our 2 year experience in diagnosing prenatal-onset osteogenesis imperfecta (OI) by multidisciplinary assessment. Methods: We retrospectively analyzed 10 cases of fetal OI by using prenatal ultrasound evaluation, postnatal radiographic diagnosis, and molecular genetic testing of COL1A1/2. Results: By postnatal radiographic examination, five patients were diagnosed with type II OI and five were diagnosed with type III OI. A causative variant in the COL1A1 gene was found in four cases of type II and one case of type III OI; a causative variant in the COL1A2 gene was found in two cases of type III OI. Conclusion: The definitive diagnosis of fetal OI should be accomplished using a multidisciplinary assessment, which is paramount for proper genetic counseling. With the discovery of COL1A1/2 gene variants as a cause of OI, sequence analysis of these genes will add to the diagnostic process.

Osteogenesis imperfecta: Clinical diagnosis, nomenclature and severity assessment

Recently, the genetic heterogeneity in osteogenesis imperfecta (OI), proposed in 1979 by Sillence et al., has been confirmed with molecular genetic studies. At present, 17 genetic causes of OI and closely related disorders have been identified and it is expected that more will follow. Unlike most reviews that have been published in the last decade on the genetic causes and biochemical processes leading to OI, this review focuses on the clinical classification of OI and elaborates on the newly proposed OI classification from 2010, which returned to a descriptive and numerical grouping of five OI syndromic groups. The new OI nomenclature and the pre-and postnatal severity assessment introduced in this review, emphasize the importance of phenotyping in order to diagnose, classify, and assess severity of OI. This will provide patients and their families with insight into the probable course of the disorder and it will allow physicians to evaluate the effect of therapy. A careful clinical description in combination with knowledge of the specific molecular genetic cause is the starting point for development and assessment of therapy in patients with heritable disorders including OI. © 2014 The Authors. American Journal of Medical Genetics Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution–NonCommercial–NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

A novel splicing mutation in COL1A1 gene caused type I osteogenesis imperfecta in a Chinese family

To study a family affected with osteogenesis imperfecta for potential mutations in COL1A1 gene. Clinical data of an affected family was collected. Potential mutation of the COL1A1 gene was screened using polymerase chain reaction and direct sequencing. Suspected mutation was detected in 20 unaffected relatives and 200 unrelated healthy controls. Analysis of RNA splicing has revealed a c.3208G/A mutation, which created a new splice sites and led to a frameshift mutation. The same mutation was not detected in the unaffected relatives or the 200 healthy controls. Mutations of the COL1A1 gene are one of the major causes of osteogenesis imperfecta in Chinese population. Our finding has enriched the mutation spectrum of type I collagen genes.