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1.
Endocr Pract ; 25(3): 230-241, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30913006

RESUMO

OBJECTIVE: Osteogenesis imperfecta (OI) is a group of heritable fragile bone diseases, and the majority are caused by pathogenic variants in the COL1A1 and COL1A2 genes. We sought to identify the genetic causes and phenotypes of OI in Chinese patients without COL1A1 or COL1A2 mutations. METHODS: Twenty-three patients who were diagnosed with sporadic OI but did not carry COL1A1/2 mutations were recruited, and their genomic DNA was analyzed using targeted next-generation sequencing of rare OI-related genes. The resulting damaging mutations in the probands and their parents were verified using Sanger sequencing. Moreover, the efficacy of long-term bisphosphonate treatment was evaluated in proband 1. RESULTS: Compound heterozygous variants in the WNT1 and TMEM38B genes were identified in proband 1 and proband 2, respectively. A heterozygous mutation in the P4HB gene was identified in proband 3, and a hemizygous mutation in PLS3 was identified in proband 4. The unaffected parents of the probands (except the father of proband 4) with mutations in the WNT1, TMEM38B, and PLS3 genes were heterozygous carriers of each of the variants, respectively. Notably, proband 3 had the characteristic exophthalmos, flat nasal bridge and flat, wide forehead. None of the patients presented with dentinogenesis imperfecta or hearing loss. Furthermore, bisphosphonates exerted beneficial effects on proband 1, who carried the WNT1 mutations, by increasing bone mineral density Z-score, reshaping the compressed vertebrae and decreasing the fracture risk. CONCLUSION: We identified novel mutations and expanded the spectrum of phenotypes and genotypes of the extremely rare disorder OI. ABBREVIATIONS: BMD = bone mineral density; MIM = Mendelian Inheritance in Man; OI = osteogenesis imperfecta; PDI = protein disulfide isomerase.


Assuntos
Osteogênese Imperfeita , Grupo com Ancestrais do Continente Asiático , Colágeno Tipo I , Genótipo , Humanos , Canais Iônicos , Mutação , Osteogênese Imperfeita/genética , Fenótipo , Pró-Colágeno-Prolina Dioxigenase , Isomerases de Dissulfetos de Proteínas , Proteína Wnt1
2.
Orthop Clin North Am ; 50(2): 193-209, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30850078

RESUMO

Osteogenesis imperfecta is a genetically and phenotypically heterogeneous disorder related to a defect or deficiency in the production of type I collagen. It is characterized by brittle bones, fractures, spine and extremity deformity, and a host of extraskeletal manifestations. Type I collagen is present in bone, tendons, ligaments, skin, dentin, and the sclera of the eye and other connective tissues. Osteogenesis imperfecta includes a multitude of disease manifestations that may be present at birth or develop over time and vary depending on the severity of the disease. This article describes the disease presentation and management considerations from a pediatric orthopedic perspective.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Deformidades Congênitas dos Membros/diagnóstico , Osteogênese Imperfeita/diagnóstico , Osteogênese Imperfeita/genética , Adolescente , Doenças do Desenvolvimento Ósseo/patologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Cálcio/administração & dosagem , Cálcio/uso terapêutico , Criança , Pré-Escolar , Difosfonatos/administração & dosagem , Difosfonatos/uso terapêutico , Exercício/fisiologia , Feminino , Órtoses do Pé/normas , Fraturas Ósseas/complicações , Fraturas Ósseas/terapia , Humanos , Lactente , Comunicação Interdisciplinar , Deformidades Congênitas dos Membros/etiologia , Deformidades Congênitas dos Membros/cirurgia , Deformidades Congênitas dos Membros/terapia , Masculino , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/patologia , Escoliose/patologia , Escoliose/cirurgia , Coluna Vertebral/anormalidades , Coluna Vertebral/patologia , Vitamina D/uso terapêutico
3.
Mol Genet Genomic Med ; 7(5): e619, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30829463

RESUMO

BACKGROUND: Osteogenesis imperfecta (OI), a genetically determined connective tissue disorder, is characterized by increased bone fragility and reduced bone mass. Clinical presentation severity ranges from very mild types with nearly no fractures to intrauterine fractures and perinatal lethality. It can be accompanied by blue sclerae, dentinogenesis imperfecta (DI), hearing loss, muscle weakness, ligament laxity, and skin fragility. This study sought to identify pathogenic gene variants in a four-generation Han Chinese family with OI type I. METHODS: In order to unveil the molecular genetic factors underlying the disease phenotype, whole exome sequencing in a member, with OI type I, of a Han Chinese family from Hunan, China was performed. The variant identified by whole exome sequencing was further tested by Sanger sequencing in the family members. RESULTS: A heterozygous missense variant (NM_000089.3: c.3197G>T; NP_000080.2: p.Gly1066Val) in the collagen type I alpha 2 chain gene (COL1A2) was identified in four patients. It co-segregated with the disease in the family. CONCLUSION: The sequence variant may be a disease-causing factor resulting in abnormal type I procollagen synthesis and leading to OI type I. This finding has significant implications for genetic counseling and clinical monitoring of high-risk families and may be helpful for understanding pathogenic mechanism of OI and developing therapies.


Assuntos
Colágeno Tipo I/genética , Mutação de Sentido Incorreto , Osteogênese Imperfeita/genética , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteogênese Imperfeita/patologia , Linhagem
4.
Mamm Genome ; 30(3-4): 81-87, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30788588

RESUMO

A genetic disorder, osteogenesis imperfecta (OI) is broadly characterized by connective tissue abnormalities and bone fragility most commonly attributed to alterations in Type I collagen. Two Red Angus calves by the same sire presented with severe bone and dental fragility, blue sclera, and evidence of in utero fractures consistent with OI congenita. Comparative analyses with human cases suggested the OI in these calves most closely resembled that classified as OI Type II. Due to the phenotypic classification and shared paternity, a dominant, germ-line variant was hypothesized as causative although recessive genotypes were also considered due to a close relationship between the sire and dam of one calf. Whole-genome sequencing revealed the presence of a missense mutation in the alpha 1 chain of collagen Type I (COL1A1), for which both calves were heterozygous. The variant resulted in the substitution of a glycine residue with serine in the triple helical domain of the protein; in this region, glycine normally occupies every third position as is critical for correct formation of the Type I collagen molecule. Allele-specific amplification by droplet digital PCR further quantified the variant at a frequency of nearly 4.4% in the semen of the sire while it was absent in his blood, supporting the hypothesis of a de novo causative variant for which the germ line of the sire was mosaic. The identification of novel variants associated with unwanted phenotypes in livestock is critical as the high prolificacy of breeding stock has the potential to rapidly disseminate undesirable variation.


Assuntos
Doenças dos Bovinos/genética , Mutação em Linhagem Germinativa , Osteogênese Imperfeita/veterinária , Alelos , Animais , Bovinos , Doenças dos Bovinos/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Feminino , Genes Dominantes , Masculino , Mutação de Sentido Incorreto , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/metabolismo , Linhagem , Fenótipo
5.
Chin Med J (Engl) ; 132(2): 145-153, 2019 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-30614853

RESUMO

BACKGROUND: Osteogenesis imperfecta (OI), a heritable bone fragility disorder, is mainly caused by mutations in COL1A1 gene encoding α1 chain of type I collagen. This study aimed to investigate the COL1A1 mutation spectrum and quantitatively assess the genotype-phenotype relationship in a large cohort of Chinese patients with OI. METHODS: A total of 161 patients who were diagnosed as OI in Department of Endocrinology of Peking Union Medical College Hospital from January 2010 to December 2017 were included in the study. The COL1A1 mutation spectrum was identified by next generation sequencing and confirmed by Sanger sequencing. A new clinical scoring system was developed to quantitatively assess the clinical severity of OI and the genotype-phenotype relationship was analyzed. The independent sample t-test, analysis of variance, Mann-Whitney U-test, Chi-squared test, Pearson correlation, and multiple linear regression were applied for statistical analyses. RESULTS: Among 161 patients with OI, 32.9% missense mutations, 16.8% non-sense mutations, 24.2% splice-site mutations, 24.8% frameshift mutations, and 1.2% whole-gene deletions were identified, of which 38 variations were novel. These mutations led to 53 patients carrying qualitative defects and 67 patients carrying quantitative defects in type I collagen. Compared to patients with quantitative mutations, patients with qualitative mutations had lower alkaline phosphatase level (296 [132, 346] U/L vs. 218 [136, 284] U/L, P = 0.009) and higher clinical score (12.2 ±â€Š5.3 vs. 7.4 ±â€Š2.4, P < 0.001), denoting more severe phenotypes including shorter stature, lower bone mineral density, higher fracture frequency, more bone deformity, vertebral compressive fractures, limited movement, and dentinogenesis imperfecta (DI). Patients would not present with DI if the glycine substitutions happened before the 79th amino acid in triple helix of α1 chains. CONCLUSIONS: This presented distinctive COL1A1 mutation spectrum in a large cohort of Chinese patients with OI. This new quantitative analysis of genotype-phenotype correlation would be helpful to predict the prognosis of OI and genetic counseling.


Assuntos
Colágeno Tipo I/genética , Mutação/genética , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Adulto Jovem
6.
Mol Genet Genomic Med ; 7(3): e559, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30675999

RESUMO

BACKGROUND: Osteogenesis imperfecta (OI) is a rare genetic bone fragility disorder. In the current study, differences between the genotypes and phenotypes of de novo and inherited collagen-related OI were investigated. METHODS: A comparative analysis was performed of the genotypes and phenotypes of 146 unrelated inherited and de novo collagen I OI cases from Estonia, Ukraine, and Vietnam. Mutational analysis of the subjects and all available parents were performed with Sanger sequencing. RESULTS: Results showed that 56.16% of the OI cases were caused by de novo pathogenic variants. The proportion of OI types OI1, OI4, and OI3 among subjects with inherited OI was 45.31%, 46.88%, and 7.81%, respectively. Among subjects with de novo OI, the proportions of OI types (OI1, OI4, and OI3) were almost equal. Both inherited and de novo OI pathogenic variants occurred more often in the COL1A1 gene than in the COL1A2. The majority of de novo cases were missense pathogenic variants, whereas inherited OI was mostly caused by loss of function pathogenic variants. CONCLUSION: In summary, there were significant differences between the phenotypes and genotypes of subjects with de novo and inherited OI. These findings may promote the further understanding of OI etiology, and assist with diagnostics procedures, as well as with family planning.


Assuntos
Colágeno Tipo I/genética , Mutação , Osteogênese Imperfeita/genética , Adolescente , Feminino , Humanos , Masculino , Osteogênese Imperfeita/epidemiologia
7.
Nat Med ; 25(3): 439-447, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30692697

RESUMO

Current non-invasive prenatal screening is targeted toward the detection of chromosomal abnormalities in the fetus1,2. However, screening for many dominant monogenic disorders associated with de novo mutations is not available, despite their relatively high incidence3. Here we report on the development and validation of, and early clinical experience with, a new approach for non-invasive prenatal sequencing for a panel of causative genes for frequent dominant monogenic diseases. Cell-free DNA (cfDNA) extracted from maternal plasma was barcoded, enriched, and then analyzed by next-generation sequencing (NGS) for targeted regions. Low-level fetal variants were identified by a statistical analysis adjusted for NGS read count and fetal fraction. Pathogenic or likely pathogenic variants were confirmed by a secondary amplicon-based test on cfDNA. Clinical tests were performed on 422 pregnancies with or without abnormal ultrasound findings or family history. Follow-up studies on cases with available outcome results confirmed 20 true-positive, 127 true-negative, zero false-positive, and zero-false negative results. The initial clinical study demonstrated that this non-invasive test can provide valuable molecular information for the detection of a wide spectrum of dominant monogenic diseases, complementing current screening for aneuploidies or carrier screening for recessive disorders.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Acondroplasia/diagnóstico , Acondroplasia/genética , Acrocefalossindactilia/diagnóstico , Acrocefalossindactilia/genética , Adulto , Osso e Ossos/anormalidades , Ácidos Nucleicos Livres , Colágeno Tipo I/genética , Síndrome de Lange/diagnóstico , Síndrome de Lange/genética , Feminino , Doenças Genéticas Inatas/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hidropisia Fetal/diagnóstico por imagem , Hidropisia Fetal/genética , Linfangioma Cístico/diagnóstico por imagem , Linfangioma Cístico/genética , Medição da Translucência Nucal , Osteogênese Imperfeita/diagnóstico , Osteogênese Imperfeita/genética , Valor Preditivo dos Testes , Gravidez , Diagnóstico Pré-Natal , Análise de Sequência de DNA , Displasia Tanatofórica/diagnóstico , Displasia Tanatofórica/genética , Ultrassonografia Pré-Natal
8.
J Hum Genet ; 64(4): 291-296, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30692598

RESUMO

A rare form of osteogenesis imperfecta (OI) caused by Wingless-type MMTV integration site family 1 (WNT1) mutations combines central nervous system (CNS) anomalies with the characteristic increased susceptibility to fractures. We report an additional case where arachnoid cysts extend the phenotype, and that also confirms the association of intellectual disabilities with asymmetric cerebellar hypoplasia here. Interestingly, if the cerebellum is normal in this disorder, intelligence is as well, analogous to an association with similar delays in a subset of patients with sporadic unilateral cerebellar hypoplasia. Those cases typically appear to represent vascular disruptions, and we suggest that most brain anomalies in WNT1-associated OI have vascular origins related to a role for WNT1 in CNS angiogenesis. This unusual combination of benign cerebellar findings with effects on higher functions in these two situations raises the possibility that WNT1 is involved in the pathogenesis of the associated sporadic cases as well. Finally, our patient reacted poorly to pamidronate, which appears ineffective with this form of OI, so that a lack of improvement is an indication for molecular testing that includes WNT1.


Assuntos
Sistema Nervoso Central/fisiopatologia , Deficiência Intelectual/genética , Osteogênese Imperfeita/genética , Proteína Wnt1/genética , Cistos Aracnóideos/diagnóstico por imagem , Cistos Aracnóideos/fisiopatologia , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/diagnóstico por imagem , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Cerebelo/fisiopatologia , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/fisiopatologia , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/fisiopatologia , Mutação , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/fisiopatologia , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/fisiopatologia , Pamidronato/administração & dosagem , Pamidronato/efeitos adversos
9.
Biochem Biophys Res Commun ; 509(1): 235-240, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30579604

RESUMO

Osteogenesis imperfecta (OI) is a hereditary bone disorder most commonly caused by autosomal dominant mutations in genes encoding type I collagen. In addition to bone fragility, patients suffer from impaired longitudinal bone growth. It has been demonstrated that in OI, an accumulation of mutated type I collagen in the endoplasmic reticulum (ER) induces ER stress in osteoblasts, causing osteoblast dysfunction leading to bone fragility. We hypothesize that ER stress is also induced in the growth plate where bone growth is initiated, and examined a mouse model of dominant OI that carries a G610C mutation in the procollagen α2 chain. The results demonstrated that G610C OI mice had significantly shorter long bones with growth plate abnormalities including elongated total height and hypertrophic zone. Moreover, we found that mature hypertrophic chondrocytes expressed type I collagen and ER dilation was more pronounced compared to wild type littermates. The results from in vitro chondrocyte cultures demonstrated that the maturation of G610C OI hypertrophic chondrocytes was significantly suppressed and ER stress related genes were upregulated. Given that the alteration of hypertrophic chondrocyte activity often causes dwarfism, our findings suggest that hypertrophic chondrocyte dysfunction induced by ER stress may be an underlying cause of growth deficiency in G610C OI mice.


Assuntos
Condrócitos/patologia , Colágeno Tipo I/genética , Estresse do Retículo Endoplasmático , Lâmina de Crescimento/anormalidades , Osteogênese Imperfeita/genética , Mutação Puntual , Animais , Condrócitos/metabolismo , Modelos Animais de Doenças , Lâmina de Crescimento/metabolismo , Lâmina de Crescimento/patologia , Masculino , Camundongos Endogâmicos C57BL , Osteogênese Imperfeita/patologia
10.
Osteoporos Int ; 30(2): 461-468, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30569229

RESUMO

In this large-sample study, we demonstrated that osteogenesis imperfecta (OI) significantly impaired the quality of life (QoL) in children. Moderate/severe OI patients had worse QoL scores than patients with mild OI. Furthermore, the QoL for OI patients was correlated with the presence of pathogenic gene mutations. INTRODUCTION: Osteogenesis imperfecta (OI) is a hereditary disease characterized by multiple fragility fractures and progressive skeletal deformities. No detailed investigations about the quality of life (QoL) have been carried out in a large sample of patients with OI. We evaluated the QoL and its influencing factors in a large and well-characterized OI cohort. METHODS: We used a validated questionnaire of PedsQL 4.0 to evaluate the health-related quality of life (HRQoL) of children and adolescents with OI. We compared HRQoL among patients with OI types I, III, and IV. The relationship between HRQoL and pathogenic mutations in candidate OI genes was investigated. We also evaluated the influencing factors of HRQoL in OI patients. RESULTS: A total of 138 children with OI and 138 healthy controls were enrolled in this study. The HRQoL scores of OI patients were 64.4 ± 30.0, 71.9 ± 22.2, 75.7 ± 24.8, 63.7 ± 24.5, and 68.9 ± 22.0 in physical, emotional, social, school functioning, and total score, respectively, which were significantly lower than those of healthy children (86.5 ± 12.7, 83.3 ± 16.0, 92.1 ± 11.8, 87.5 ± 11.8, and 87.3 ± 10.7, all p < 0.01). Moderate and severe OI (type III/IV) patients had poorer HRQoL scores than patients with mild OI (type I). Gene mutations inducing qualitative defects in type I collagen led to worse HRQoL scores than those with quantitative defects in type I collagen, except in emotional functioning. The total HRQoL score was positively correlated with family income, lumbar, and femoral bone mineral density (BMD) Z-scores and negatively correlated with disease severity and fracture frequency. CONCLUSION: HRQoL was significantly impaired in OI patients, and patients with more severe OI had poorer HRQoL scores. For the first time, we found that children with qualitative defects in type I collagen had poorer HRQoL scores than those with quantitative defects in type I collagen.


Assuntos
Osteogênese Imperfeita/reabilitação , Qualidade de Vida , Adolescente , Densidade Óssea/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Colágeno Tipo I/genética , Estudos Transversais , Feminino , Genótipo , Humanos , Masculino , Mutação , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/fisiopatologia , Osteogênese Imperfeita/psicologia , Fraturas por Osteoporose/genética , Fraturas por Osteoporose/fisiopatologia , Fraturas por Osteoporose/psicologia , Fraturas por Osteoporose/reabilitação , Fenótipo , Psicometria , Índice de Gravidade de Doença , Fatores Socioeconômicos
11.
Cornea ; 37(12): 1561-1565, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30272615

RESUMO

PURPOSE: The goal of this study was to evaluate corneal profiles of patients with osteogenesis imperfecta (OI) due to a collagen I gene mutation. METHODS: This was a cross-sectional comparative study. There were 84 eyes from 42 patients with OI types I, III, and IV who were recruited from the OI Clinic at the Clinical Hospital of Porto Alegre, Brazil. All cases presented either COL1A1 or A2 gene mutations. Controls were matched by sex, age, and refractive error. Corneal Scheimpflug tomography was used to determine curvature and thickness parameters in both groups. RESULTS: Quantitative collagen mutations were found only in OI type I. Qualitative mutations were responsible for all mutations observed in type III and IV patients. Each OI type presented significantly lower pachymetric values at the thinnest point compared with controls (443.7-505.1 vs. 541.9-548.5 µm; P < 0.001). In addition, significantly lower pachymetric values were observed in patients with OI compared with controls in all positions between the central and corneal periphery (581.4-657.0 vs. 704.5-720.7 µm at an 8.0-mm-diameter circle; P < 0.001). Differences in anterior and posterior radii of curvatures, respectively, between patients with OI and controls were not statistically significant (7.64-7.80 vs. 7.65-7.69 mm; P > 0.05) except for a lower anterior radii of curvatures in type III (7.33 vs. 7.72 mm; P < 0.01). CONCLUSIONS: Although patients with OI have homogenously thinner corneas compared with controls, we observed that a collagen I chain mutation was not responsible for corneal curvature alterations in OI.


Assuntos
Colágeno Tipo I/genética , Córnea/metabolismo , Doenças da Córnea/genética , DNA/genética , Mutação , Osteogênese Imperfeita/genética , Adolescente , Adulto , Colágeno Tipo I/metabolismo , Córnea/patologia , Doenças da Córnea/etiologia , Doenças da Córnea/patologia , Topografia da Córnea , Estudos Transversais , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Masculino , Osteogênese Imperfeita/diagnóstico , Osteogênese Imperfeita/metabolismo , Adulto Jovem
12.
Proc Natl Acad Sci U S A ; 115(34): E8037-E8046, 2018 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-30082390

RESUMO

The type I collagenopathies are a group of heterogeneous connective tissue disorders, that are caused by mutations in the genes encoding type I collagen and include specific forms of osteogenesis imperfecta (OI) and the Ehlers-Danlos syndrome (EDS). These disorders present with a broad disease spectrum and large clinical variability of which the underlying genetic basis is still poorly understood. In this study, we systematically analyzed skeletal phenotypes in a large set of zebrafish, with diverse mutations in the genes encoding type I collagen, representing different genetic forms of human OI, and a zebrafish model resembling human EDS, which harbors a number of soft connective tissues defects, typical of EDS. Furthermore, we provide insight into how zebrafish and human type I collagen are compositionally and functionally related, which is relevant in the interpretation of human type I collagen-related disease models. Our studies reveal a high degree of intergenotype variability in phenotypic expressivity that closely correlates with associated OI severity. Furthermore, we demonstrate the potential for select mutations to give rise to phenotypic variability, mirroring the clinical variability associated with human disease pathology. Therefore, our work suggests the future potential for zebrafish to aid in identifying unknown genetic modifiers and mechanisms underlying the phenotypic variability in OI and related disorders. This will improve diagnostic strategies and enable the discovery of new targetable pathways for pharmacological intervention.


Assuntos
Colágeno Tipo I , Modelos Animais de Doenças , Síndrome de Ehlers-Danlos , Osteogênese Imperfeita , Peixe-Zebra , Animais , Animais Geneticamente Modificados , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/metabolismo , Síndrome de Ehlers-Danlos/patologia , Humanos , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/metabolismo , Osteogênese Imperfeita/patologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
13.
Clin Chim Acta ; 484: 141-147, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29807018

RESUMO

BACKGROUND: Osteogenesis imperfecta (OI) is a rare genetic bone disease characterized by bone fragility and low bone mass. OI was mainly caused by genetic mutations in collagen genes, COL1A1 and COL1A2. Nevertheless, new genes have been identified to be causally linked to OI. The clinical features between each OI groups share great similarities and it is sometimes difficult for clinicians to diagnose the disease accurately. Here, we identify the genetic mutations of OI patients from Malaysia and correlate the genetic mutations with the clinical features. METHOD: Targeted sequencing of fourteen genes panel was performed to identify the mutations in 29 OI patients with type I, III, IV and V disease. The mutations were determined using Ion Torrent Suite software version 5 and variant annotation was conducted using ANNOVAR. The identified mutations were confirmed using Sanger sequencing and in silico analysis was performed to evaluate the effects of the candidate mutations at protein level. RESULTS: Majority of patients had mutations in collagen genes, 48% (n = 14) in COL1A1 and 14% (n = 4) in COL1A2. Type I OI was caused by quantitative mutations in COL1A1 whereas most of type III and IV were due to qualitative mutations in both of the collagen genes. Those with quantitative mutations had milder clinical severity compared to qualitative mutations in terms of dentinogenesis imperfecta (DI), bone deformity and the ability to walk with aid. Furthermore, a few patients (28%, n = 8) had mutations in IFITM5, BMP1, P3H1 and SERPINF1. CONCLUSION: Majority of our OI patients have mutations in collagen genes, similar to other OI populations worldwide. Genotype-phenotype analysis revealed that qualitative mutations had more severe clinical characteristics compared to quantitative mutations. It is crucial to identify the causative mutations and the clinical severity of OI patients may be predicted based on the types of mutations.


Assuntos
Osteogênese Imperfeita/genética , Feminino , Variação Genética/genética , Genótipo , Humanos , Malásia , Masculino , Osteogênese Imperfeita/diagnóstico , Fenótipo
14.
J Hum Genet ; 63(7): 811-820, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29636545

RESUMO

We report a Thai father (patient 1) and his daughter (patient 2) affected with osteogenesis imperfecta type IV and dentinogenesis imperfecta. Both were heterozygous for the c.1451G>A (p.Gly484Glu) mutation in COL1A2. The father, a Thai boxer, had very mild osteogenesis imperfecta with no history of low-trauma bone fractures. Scanning electron micrography of the primary teeth with DI of the patient 2, and the primary teeth with DI of another OI patient with OI showed newly recognized dental manifestations of teeth with DI. Normal dentin and cementum might have small areas of ectopic mineralizations. Teeth affected with DI have well-organized ectopic mineralizations in dentin and cementum. The "French-fries-appearance" of the crystals at the cemento-dentinal junction and abnormal cementum have never been reported to be associated with dentinogenesis imperfecta, either isolated or osteogenesis imperfecta-associated. Our study shows for the first time that abnormal collagen fibers can lead to ectopic mineralization in dentin and cementum and abnormal cementum can be a part of osteogenesis imperfecta.


Assuntos
Colágeno Tipo I/genética , Dentinogênese Imperfeita/genética , Mutação , Osteogênese Imperfeita/genética , Adulto , Pré-Escolar , Colágeno Tipo I/metabolismo , Cemento Dentário/diagnóstico por imagem , Cemento Dentário/metabolismo , Cemento Dentário/patologia , Dentina/diagnóstico por imagem , Dentina/metabolismo , Dentina/patologia , Dentinogênese Imperfeita/diagnóstico por imagem , Dentinogênese Imperfeita/metabolismo , Dentinogênese Imperfeita/patologia , Família , Feminino , Expressão Gênica , Heterozigoto , Humanos , Masculino , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/metabolismo , Osteogênese Imperfeita/patologia , Tailândia , Sequenciamento Completo do Exoma
15.
Acta Biochim Pol ; 65(1): 79-86, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29543922

RESUMO

Although over 85% of osteogenesis imperfecta (OI) cases are associated with mutations in the procollagen type I genes (COL1A1 or COL1A2), no hot spots for the mutations were associated with particular clinical phenotypes. Eight patients that were studied here, diagnosed with OI by clinical standards, are from the Polish population with no ethnic background indicated. Previously unpublished mutations were found in six out of those eight patients. Genotypes for polymorphisms (Sp1 - rs1800012 and PvuII - rs412777), linked to bone formation and metabolism were determined. Mutations were found in exons 2, 22, 50 and in introns 13 and 51 of the COL1A1 gene. In COL1A2, one mutation was identified in exon 22. Deletion type mutations in COL1A1 that resulted in OI type I had no effect on collagen type I secretion, nor on its intracellular accumulation. Also, a single base substitution in I13 (c.904-9 G>T) was associated with the OI type I. The OI type III was associated with a single base change in I51 of COL1A1, possibly causing an exon skipping. Also, a missense mutation in COL1A2 changing Gly→Cys in the central part of the triple helical domain of the collagen type I molecule caused OI type III. It affected secretion of the heterotrimeric form of procollagen type I. However, no intracellular accumulation of procollagen chains could be detected. Mutation in COL1A2 affected its incorporation into procollagen type I. The results obtained shall help in genetic counseling of OI patients and provide a rational support for making informed, life important decisions by them and their families.


Assuntos
Colágeno Tipo I/genética , Mutação , Osteogênese Imperfeita/genética , Éxons , Humanos , Íntrons , Osteogênese , Polimorfismo Genético , Pró-Colágeno/metabolismo
16.
Int J Mol Med ; 41(6): 3662-3670, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29512769

RESUMO

The aim of the present study was to characterize the clinical manifestations and identify the mutations of Serpin family F member 1 (SERPINF1) and FK506 binding protein 10 (FKBP10) genes in Chinese patients with osteogenesis imperfecta (OI). Using whole­exome sequencing in the first and third probands, a novel mutation was identified in SERPINF1 and a novel compound heterozygous mutation was revealed in FKBP10. Using Sanger sequencing, an additional novel mutation in SERPINF1 was identified in a proband of family 2. In family 1, the proband presented with a novel homozygous missense mutation of the SERPINF1 gene, c.1067T>A (V356E). In family 2, the proband had a novel homozygous deletion mutation of the SERPINF1 gene, c.283+473_643+104del (p.Ala96_Gly215del). Serum pigment­epithelium­derived factor concentration was not detected in probands with OI type VI. For both families, the proband's father was demonstrated to have a heterozygous mutation of SERPINF1, whereas no mutations was detected in the probands' mothers. An assessment of allelic copy numbers revealed a deletion of SERPINF1 in the mother of family 1. The results of the present study demonstrate that patients may have mild symptoms of OI with a large fragment deletion in the SERPINF1 gene. Thus, the phenotype of Chinese patients with type VI OI is milder than that of Caucasian and Korean patients. In family 3, the proband displayed a novel compound heterozygous mutation in FKBP10, c.813_814delGA (p.Glu271AspfsX101) and c.831delC (p.Gly278AlafsX20), and did not have Bruck syndrome. Codon 831 of the FKBP10 gene may represent a mutation hotspot for human OI. These results extend both the phenotypic and the genotypic contents of OI patients with SERPINF1 or FKBP10 mutations.


Assuntos
Proteínas do Olho/genética , Fatores de Crescimento Neural/genética , Osteogênese Imperfeita/genética , Osteopetrose/congênito , Serpinas/genética , Proteínas de Ligação a Tacrolimo/genética , Grupo com Ancestrais do Continente Asiático , Densidade Óssea/genética , Densidade Óssea/fisiologia , Criança , Pré-Escolar , Exoma/genética , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Mutação/genética , Osteopetrose/genética , Deleção de Sequência/genética
17.
Orthod Craniofac Res ; 21(2): 71-77, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29388328

RESUMO

OBJECTS: To investigate the relationship between genotype and severity of malocclusion in osteogenesis imperfecta (OI). SETTING AND SAMPLE POPULATION: A total of 49 patients participated in this cross-sectional study (age range: 5-19 years; 28 females; diagnoses: OI type I, N = 7; OI type III, N = 11; OI type IV, N = 27; OI type V, N = 2; OI type VI, N = 2). MATERIALS AND METHODS: Sequence analysis of COL1A1/COL1A2 and other OI-related genes was compared to the Peer Assessment Rating (PAR), an index reflecting the severity of malocclusion. RESULTS: The mutation spectrum was as follows: COL1A1, N = 22; COL1A2, N = 22, IFITM5, N = 2; SERPINF1, N = 2; no mutation detected, N = 1). Compared to patients with COL1A1 mutations, patients with COL1A2 mutations had significantly higher scores for total PAR, anterior cross-bite, anterior open bite and anteroposterior buccal occlusion. Males with COL1A2 mutations had significantly higher total PAR scores than females (median 36 vs 30, P = .047, Mann-Whitney test). Exploratory correlation between age and buccal vertical occlusion was noted in patients with COL1A2 mutations (Spearman correlation: r = .46, P = .03, power = .50). Two patients with OI type V (caused by IFITM5 mutations) had total PAR scores of 44 and 21. Both patients scored high for "segment." Patients with OI type VI (due to SERPINF1 mutations) scored similar to OI type V for "centreline." Considerable difference was observed in the total PAR score between the 2 patients with OI type VI. They had total PAR of 43 and 2. CONCLUSION: Type of disease-causing mutation affects the severity of malocclusion in individuals with OI.


Assuntos
Genótipo , Má Oclusão/complicações , Má Oclusão/genética , Osteogênese Imperfeita/complicações , Osteogênese Imperfeita/genética , Adolescente , Fatores Etários , Criança , Pré-Escolar , Estudos Transversais , Humanos , Masculino , Mutação , Fatores Sexuais , Adulto Jovem
18.
Eur J Med Genet ; 61(7): 369-371, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29481978

RESUMO

Osteogenesis imperfecta (OI) is an inherited disorder with osteoporosis and recurrent fractures. Children presenting with recurrent fractures and bowing of limbs have severe form of the disorder. Patients carrying homozygous WNT1 mutations have more frequent fractures while heterozygous carriers of the mutation in WNT1 gene are also found to have early onset osteoporosis. We identified a family with novel WNT1 mutation. The index case, a 6 month old child presented with fractures from early infancy. Next generation sequencing (NGS)done for the child didn't show any variations in other OI genes including COL1A1, COL1A2, SERPINH1, CRTAP, LEPRE1, PP1B, 1F1TM5 and BMP1 genes. Sanger sequencing showed 41bp deletion in splice region following exon 1 of WNT1 gene in homozygous state. The mutation was found to be likely pathogenic on bioinformatic analysis. To further characterize the significance of the mutation we studied his mother who is 30 year old with blue sclera and history of backache but no fractures. Her DXA scan of lumber spine showed osteoporosis and she was heterozygous for the mutation. The child's DXA scan showed T-score of -6.4 at lumbar spine level. Father also has history of backache and was carrier for the same deletion variant. The child was given 3 doses of zoledronate and did not have any further fractures. Thus, we conclude that this novel variant identified in the child with OI is likely cause for the disease and possibly zoledronate has a role in prevention of fractures in this case.


Assuntos
Fraturas Ósseas/genética , Osteogênese Imperfeita/genética , Proteína Wnt1/genética , Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Variação Genética , Humanos , Imidazóis/uso terapêutico , Lactente , Masculino , Mutação , Osteogênese Imperfeita/tratamento farmacológico , Ácido Zoledrônico
19.
Biochim Biophys Acta Mol Basis Dis ; 1864(5 Pt A): 1642-1652, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29432813

RESUMO

The clinical phenotype in osteogenesis imperfecta (OI) is attributed to the dominant negative function of mutant type I collagen molecules in the extracellular matrix, by altering its structure and function. Intracellular retention of mutant collagen has also been reported, but its effect on cellular homeostasis is less characterized. Using OI patient fibroblasts carrying mutations in the α1(I) and α2(I) chains we demonstrate that retained collagen molecules are responsible for endoplasmic reticulum (ER) enlargement and activation of the unfolded protein response (UPR) mainly through the eukaryotic translation initiation factor 2 alpha kinase 3 (PERK) branch. Cells carrying α1(I) mutations upregulate autophagy, while cells with α2(I) mutations only occasionally activate the autodegradative response. Despite the autophagy activation to face stress conditions, apoptosis occurs in all mutant fibroblasts. To reduce cellular stress, mutant fibroblasts were treated with the FDA-approved chemical chaperone 4-phenylbutyric acid. The drug rescues cell death by modulating UPR activation thanks to both its chaperone and histone deacetylase inhibitor abilities. As chaperone it increases general cellular protein secretion in all patients' cells as well as collagen secretion in cells with the most C-terminal mutation. As histone deacetylase inhibitor it enhances the expression of the autophagic gene Atg5 with a consequent stimulation of autophagy. These results demonstrate that the cellular response to ER stress can be a relevant target to ameliorate OI cell homeostasis.


Assuntos
Autofagia/efeitos dos fármacos , Fibroblastos/metabolismo , Homeostase/efeitos dos fármacos , Osteogênese Imperfeita/tratamento farmacológico , Fenilbutiratos/farmacologia , Autofagia/genética , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Células Cultivadas , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Fibroblastos/patologia , Homeostase/genética , Humanos , Mutação , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/metabolismo , Osteogênese Imperfeita/patologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Resposta a Proteínas não Dobradas/genética , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo
20.
Mol Med Rep ; 17(3): 4433-4439, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29344653

RESUMO

Osteogenesis imperfecta (OI) is a rare congenital disorder characterized by bone fragility and fractures, and associated with bone deformity, short stature, dentin, ligament and blue­gray eye sclera. OI is caused by a heterozygous mutation in collagen α­1(I) chain (COL1A1) or collagen α­2(I) chain (COL1A2) genes that encode α chains of type I collagen. Collagen α chain peptide contains an N­propeptide, which has a role in assembly and processing of collagen. Point mutations in the N­propeptide domain appear to trigger OI. In the present study, a novel heterozygous missense mutation, c.281T>A (p.Val94Asp), was identified in the von Willebrand C domain of N­terminal of type I collagen in an individual with type IV OI. The majority of N­terminal mutations are associated with OI/Ehlers­Danlos syndrome (EDS); however, in the present study, the affected individual did not suffer from EDS and the level of serum phosphorus of the patient was low (0.67 mmol/l). A number of clinical phenotypes were observed at the same variation site or in the same region on the polypeptide chain of COL1A, which suggests that additional genetic and environmental factors may influence the severity of OI. The present study may provide insight into the phenotype­genotype association in collagen-associated diseases and improve clinical diagnosis of OI.


Assuntos
Colágeno Tipo I/genética , Osteogênese Imperfeita/diagnóstico , Fósforo/sangue , Sequência de Bases , Criança , Colágeno Tipo I/química , Análise Mutacional de DNA , Estudos de Associação Genética , Humanos , Masculino , Mutação de Sentido Incorreto , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/genética , Linhagem , Estrutura Terciária de Proteína
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