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1.
Medicine (Baltimore) ; 98(28): e16389, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305444

RESUMO

INTRODUCTION: Various phenotypes have been identified for MYH7 gene mutation-related myopathy. Here, we describe a patient with severe muscular weakness and skeletal deformity with de novo heterozygous MYH7 gene mutation. PATIENT CONCERNS: A 33-year-old woman presented with early onset of muscular weakness, with delayed motor development during infancy. At age 8 years, she was unable to walk, with signs of skeletal deformity, including the progression of kyphoscoliosis. At age 31 years, she developed dyspnea. DIAGNOSIS: She diagnosed with esophageal hiatal hernia with abdominal CT. In electromyography, short duration, small amplitude motor unit action potential (MUAP), and early recruitment patterns were observed in the involved proximal muscles, suggesting myopathy. Muscle histopathology showed fiber-type disproportion. INTERVENTIONS: Next-generation sequencing study revealed a heterozygous in-frame deletion variation in the exon 14 of the MYH7 gene (c.1498_1500del/p.Glu500del), which is a novel variation confirmed by conventional Sanger sequencing. Compared with the parental test, this variant was concluded as de novo. OUTCOMES: She received laparoscopic hiatal hernia repair and Nissen fundoplication for esophageal hiatal hernia. After surgery, her postural dyspnea improved. As there is no fundamental treatment for MYH7-related myopathies, she continued conservative treatment for her symptoms. CONCLUSION: Here, we presented a rare case of de novo mutation of the myosin head domain in the MYH7 gene. This report broadens both the phenotypic and genotypic spectra of MYH7-related myopathies.


Assuntos
Miosinas Cardíacas/genética , Cifose/genética , Debilidade Muscular/genética , Mutação , Cadeias Pesadas de Miosina/genética , Escoliose/genética , Adulto , Idade de Início , Dispneia/etiologia , Dispneia/genética , Dispneia/cirurgia , Feminino , Humanos , Cifose/fisiopatologia , Debilidade Muscular/patologia , Debilidade Muscular/fisiopatologia , Fenótipo , Escoliose/fisiopatologia
2.
Medicine (Baltimore) ; 98(27): e16314, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277174

RESUMO

The Ladybird Homeobox 1 (LBX1) gene has been implicated in the etiology of adolescent idiopathic scoliosis (AIS). The association between LBX1 gene polymorphisms and AIS has been investigated in several studies. However, these findings have yield contradictory results rather than conclusive evidence.This study is to provide a meta-analysis of the published case-control studies on the association between LBX1 gene polymorphisms and AIS in Asian and Caucasian populations.This meta-analysis conformed to the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines. We conducted a literature research on PubMed, Embase, Web of Science, and Cochrane Library until February 10, 2018. We included all case-control or cohort studies about association between LBX1 gene polymorphisms and AIS. The Risk Of Bias In Non-randomised Studies-of Interventions and Critical Appraisal Skills Programme were used to evaluate the risk of bias and study quality. We assessed the strength of association by pooled odds ratios (ORs) and 95% confidence intervals (CIs) in all genetic models under a fixed-effect model or random-effect model. We further performed subgroup analysis by ethnicity and sex. Sensitivity analysis and publication bias were also undertaken.A total of 10 studies (11,411 cases and 26,609 controls) were included in this meta-analysis. The pooled results showed a statistically significant association between LBX1 gene polymorphisms and AIS (for rs11190870, T vs C, OR = 1.54, 95% CI = 1.48-1.61, P < .00001; for rs625039, G vs A, OR = 1.50, 95% CI: 1.38-1.62; P < .00001; for rs678741, G vs A, OR = 0.74, 95% CI: 0.63-0.86; P < .0001; for rs11598564, G vs A, OR = 1.41, 95% CI: 1.31-1.51; P < .0001). For stratified analyses by ethnicity and sex, robust significant associations were detected in Asian and Caucasian populations, and in women and men under all genetic models.T allele of rs11190870 and G alleles of rs625039 and rs11598564 represent risk factors for AIS, but G allele of rs678741 may play a protective role in the occurrence of AIS. Further research is needed to confirm this finding and to understand its implications.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Proteínas de Homeodomínio/genética , Polimorfismo Genético/genética , Escoliose/genética , Fatores de Transcrição/genética , Adolescente , Feminino , Humanos , Masculino , Estudos Observacionais como Assunto , Razão de Chances , Escoliose/etnologia
3.
Cell Mol Biol Lett ; 24: 2, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30936926

RESUMO

Background: MicroRNA (miRNA) plays a vital role in the pathogenesis of intervertebral disc degeneration (IDD). The expression and potential mechanism of miR-573 in human nucleus pulposus (NP) remains to be elucidated. In this study, we aimed to investigate the role of miR-573 in IDD. Methods: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis was applied to examine the expression of miR-573 and Bax in idiopathic scoliosis tissues and IDD tissues. Human NP cells were employed for analysis. Moreover, the proliferation and apoptosis of NP cells were detected using MTT and flow cytometry assay respectively. The expression levels of Bcl-2, cleaved caspase-3, cleaved caspase-9, caspase-3 and caspase-9 in degenerative NP cells were measured by Western blotting assay. Furthermore, a luciferase reporter assay was used to verify the relationship between miR-573 and Bax. Results: The results revealed that the mRNA expression level of miR-573 was down-regulated whereas Bax was up-regulated notably in degenerative NP cells. In addition, overexpression of miR-573 increased cell viability remarkably, coupled with inhibition of cell apoptosis. The expression level of Bcl-2 was increased while cleaved caspase-3 and cleaved caspase-9 expression levels were decreased in miR-573 overexpression NP cells. Additionally, the bioinformatics analysis underscored that Bax was a direct target gene of miR-573. Conclusion: These results suggest that overexpression of miR-573 inhibited NP cell apoptosis by down-regulating Bax, which proved to be a novel effective strategy for IDD therapies.


Assuntos
Apoptose/genética , Regulação da Expressão Gênica , MicroRNAs/metabolismo , Núcleo Pulposo/metabolismo , Proteína X Associada a bcl-2/metabolismo , Sequência de Bases , Caspase 3/metabolismo , Caspase 9/metabolismo , Proliferação de Células/genética , Sobrevivência Celular/genética , Células Cultivadas , Humanos , Degeneração do Disco Intervertebral/genética , MicroRNAs/genética , Núcleo Pulposo/patologia , Escoliose/genética , Proteína X Associada a bcl-2/genética
4.
Biomed Res Int ; 2019: 4678969, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30886859

RESUMO

Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity disease in adolescents but its etiology and pathogenesis are still unclear. The current study aims to identify the relationship between single nucleotide polymorphisms (SNPs) of G protein-coupled receptor 126 (GPR126) gene and AIS predisposition. GPR126 contains 26 exons and alternative splicing of exon 6 and exon 25 produces 4 protein-coding transcripts. We genotyped SNPs of GPR126 gene around exon 6 and exon 25 in 131 Chinese AIS patients and 132 healthy controls and provided evidence that SNP rs41289839 G>A is strongly associated with AIS susceptibility. Linkage disequilibrium analysis suggests that rs41289839 and other AIS-related SNPs were in strong LD. Next, we demonstrated that rs41289839 G>A inhibits the inclusion of exon 6 during alternative splicing, resulting in a decreased expression level of exon 6-included transcript (GPR126-exon6in) relative to the exon 6 excluded transcript (GPR126-exon6ex) by minigene assay. Chondrogenic differentiation experiment showed that GPR126-exon6in has a high expression level relative to GPR126-exon6ex during chondrogenic differentiation of hMSCs. Our findings indicate that newly discovered SNP is related to cartilage development and may provide valuable insights into the etiology and pathogenesis of adolescent idiopathic scoliosis.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Receptores Acoplados a Proteínas-G/genética , Escoliose/genética , Adolescente , Adulto , Idoso , Alelos , Cartilagem/metabolismo , Cartilagem/patologia , Diferenciação Celular/genética , Criança , Condrogênese/genética , Éxons/genética , Feminino , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Escoliose/fisiopatologia , Adulto Jovem
5.
J Hum Genet ; 64(5): 493-498, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30787423

RESUMO

Adolescent idiopathic scoliosis (AIS) is the most common type of scoliosis. Controlling its curve progression is the most important clinical task. Although recent genome-wide association studies (GWASs) identified several susceptibility loci associated with the development of AIS, the etiology of curve progression has been still unknown. Our previous GWAS has identified that rs12946942 showed significant association with severe AIS. To confirm the association, we conducted an international meta-analysis using four cohorts with different ethnicity. We analyzed 2272 severe AIS cases and 13,859 controls in total, and found the replication of significant association of rs12946942 (combined P = 7.23×10-13; odds ratio = 1.36, 95% confidence interval = 1.25-1.49). In silico analyses suggested that SOX9 is the most likely susceptibility gene for AIS curve progression in the locus.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo Genético , Fatores de Transcrição SOX9/genética , Escoliose/etnologia , Escoliose/genética , Adolescente , Feminino , Humanos , Masculino
6.
J Mol Neurosci ; 68(1): 11-18, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30778836

RESUMO

Scoliosis is a common manifestation of neurofibromatosis type 1, causing significant morbidity. The etiology of dystrophic scoliosis in neurofibromatosis type 1 is not fully understood and therapies are lacking. Somatic mutations in NF1 have been shown in tibial pseudarthrosis providing rationale for similar processes in neurofibromatosis type 1-associated dystrophic scoliosis. Spinal samples from surgical procedures with matched peripheral blood of two individuals with neurofibromatosis type 1 and dystrophic scoliosis were obtained and DNA extracted. Next generation sequencing of various spinal sections as well as the germline/blood sample were performed using a RASopathy gene panel (includes the NF1 gene). Variants were compared between the spinal tissue samples and the germline data. In addition, the next generation sequencing allele frequency data were used to detect somatic loss of heterozygosity. All samples had a detected potentially inactivating NF1 germline mutation. Both individuals demonstrated an allelic imbalance inclusive of NF1 in the next generation sequencing data. In addition, for the same two individuals, there was an increase in the % variant reads for the germline mutation in some of the surgical spinal samples corresponding to the allelic imbalance. Contra analysis did not show any deletion in Chromosome 17 next generation sequencing data. Microarray analysis verified somatic copy neutral loss of heterozygosity for these two individuals for the majority of the chromosome 17 q-arm, inclusive of the NF1 gene. These results suggest that the cause of dystrophic scoliosis is multifactorial and that a somatic NF1 mutation contributes to the etiology.


Assuntos
Neurofibromatose 1/genética , Neurofibromina 1/genética , Escoliose/genética , Criança , Feminino , Frequência do Gene , Humanos , Perda de Heterozigosidade , Masculino , Mutação , Neurofibromatose 1/complicações , Neurofibromatose 1/patologia , Escoliose/etiologia , Escoliose/patologia , Coluna Vertebral/metabolismo , Coluna Vertebral/patologia
7.
Int J Med Sci ; 16(2): 221-230, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30745802

RESUMO

Background: In a previous report, we demonstrated the presence of cells with a neural/glial phenotype on the concave side of the vertebral body growth plate in Idiopathic Scoliosis (IS) and proposed this phenotype alteration as the main etiological factor of IS. In the present study, we utilized the same specimens of vertebral body growth plates removed during surgery for Grade III-IV IS to analyse gene expression. We suggested that phenotype changes observed on the concave side of the vertebral body growth plate can be associated with altered expression of particular genes, which in turn compromise mechanical properties of the concave side. Methods: We used a Real-Time SYBR Green PCR assay to investigate gene expression in vertebral body growth plates removed during surgery for Grade III-IV IS; cartilage tissues from human fetal spine were used as a surrogate control. Special attention was given to genes responsible for growth regulation, chondrocyte differentiation, matrix synthesis, sulfation and transmembrane transport of sulfates. We performed morphological, histochemical, biochemical, and ultrastructural analysis of vertebral body growth plates. Results: Expression of genes that control chondroitin sulfate sulfation and corresponding protein synthesis was significantly lower in scoliotic specimens compared to controls. Biochemical analysis showed 1) a decrease in diffused proteoglycans in the total pool of proteoglycans; 2) a reduced level of their sulfation; 3) a reduction in the amount of chondroitin sulfate coinciding with raising the amount of keratan sulfate; and 4) reduced levels of sulfation on the concave side of the scoliotic deformity. Conclusion: The results suggested that altered expression of genes that control chondroitin sulfate sulfation and corresponding changes in protein synthesis on the concave side of vertebral body growth plates could be causal agents of the scoliotic deformity.


Assuntos
Condrócitos/fisiologia , Lâmina de Crescimento/metabolismo , Escoliose/metabolismo , Coluna Vertebral/metabolismo , Adolescente , Diferenciação Celular , Criança , Condrócitos/ultraestrutura , Sulfatos de Condroitina/metabolismo , Lâmina de Crescimento/patologia , Humanos , Biossíntese de Proteínas , Escoliose/genética , Escoliose/patologia
8.
J Hum Genet ; 64(5): 467-471, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30796325

RESUMO

Spondylocarpotarsal synostosis syndrome, a rare syndromic skeletal disorder characterized by disrupted vertebral segmentation with vertebral fusion, scoliosis, short stature, and carpal/tarsal synostosis, has been associated with biallelic truncating mutations in the filamin B gene or monoallelic mutations in the myosin heavy chain 3 gene. We herein report the case of a patient with a typical phenotype of spondylocarpotarsal synostosis syndrome who had a homozygous frameshift mutation in the refilin A gene (RFLNA) [c.241delC, p.(Leu81Cysfs*111)], which encodes one of the filamin-binding proteins. Refilins, filamins, and myosins play critical roles in forming perinuclear actin caps, which change the nuclear morphology during cell migration and differentiation. The present study implies that RFLNA is an additional causative gene for spondylocarpotarsal synostosis syndrome in humans and a defect in forming actin bundles and perinuclear actin caps may be a critical mechanism for the development of spondylocarpotarsal synostosis syndrome.


Assuntos
Anormalidades Múltiplas/genética , Biomarcadores Tumorais/genética , Mutação da Fase de Leitura , Homozigoto , Vértebras Lombares/anormalidades , Doenças Musculoesqueléticas/genética , Escoliose/congênito , Sinostose/genética , Vértebras Torácicas/anormalidades , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Biomarcadores Tumorais/metabolismo , Humanos , Lactente , Vértebras Lombares/metabolismo , Vértebras Lombares/patologia , Masculino , Doenças Musculoesqueléticas/metabolismo , Doenças Musculoesqueléticas/patologia , Escoliose/genética , Escoliose/metabolismo , Escoliose/patologia , Sinostose/metabolismo , Sinostose/patologia , Vértebras Torácicas/metabolismo , Vértebras Torácicas/patologia
9.
Spine Deform ; 7(2): 262-266, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30660220

RESUMO

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: To investigate a possible linkage between idiopathic scoliosis (IS) and schizophrenia in an adolescent population. SUMMARY OF BACKGROUND DATA: There is an interesting link between schizophrenia and idiopathic scoliosis: schizophrenia is a disturbance of mental equilibrium, and scoliosis of physical equilibrium, both are multifactorial, genetically determined, start at a young age, and brain development is thought to play a role. Furthermore, both may be presenting symptoms of the genetic disorder 22q11 deletion syndrome. This study poses the question whether these two poorly understood disorders are related. METHODS: A retrospective cohort study was conducted and consisted of 3,702 Swedish adolescents, collected from the National Patient Register, that underwent inpatient care for IS during 1997-2015. These were matched by age, sex, and date of diagnosis to 370,200 controls, collected from Swedish population data, and then followed up in the National Patient Register to identify in- and outpatient care for schizophrenia diagnosis. Follow-up time was calculated from first IS diagnosis date until date of schizophrenia diagnosis or end of follow-up. Cox proportional regression analysis was performed to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for being diagnosed with schizophrenia. RESULTS: Over a median follow-up time of 9.5 years, 0.7% of patients with IS developed schizophrenia versus 0.5% of controls (p = .04). The risk of schizophrenia was significantly higher in patients with IS (HR, 1.52; 95% CI, 1.03-2.23). Using only hospitalized schizophrenia as event, the prevalence for schizophrenia was 0.5% versus 0.3% (p ≤.01; HR, 1.83; 95% CI, 1.17-2.84). CONCLUSION: This study suggests that patients with IS have increased risk of schizophrenia. Dissatisfaction with one's physical appearance might lead to psychological distress and provoke mental illness in predisposed persons. Alternatively, these two disorders may share a common genetic background. LEVEL OF EVIDENCE: Level 2B.


Assuntos
Esquizofrenia/etiologia , Escoliose/complicações , Adolescente , Cromossomos Humanos Par 22/genética , Estudos de Coortes , Feminino , Seguimentos , Deleção de Genes , Humanos , Masculino , Aparência Física , Prevalência , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Psicologia do Esquizofrênico , Escoliose/genética , Escoliose/psicologia , Síndrome , Fatores de Tempo
10.
BMC Musculoskelet Disord ; 20(1): 24, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30646882

RESUMO

BACKGROUND: Rare variants of HSPG2 have recently been reported to function as a potential contributor to the susceptibility of adolescent idiopathic scoliosis (AIS) in the Caucasians. A replication study in the different population is warranted to validate the role of HSPG2 in AIS. The aim of this study was to determine the association between HSPG2 and AIS in the Chinese patients and to further investigate its influence on the phenotype of the patients. METHODS: SNVs p.Asn786Ser of HSPG2 was genotyped in 1752 patients and 1584 normal controls using multiple ligase detection reactions. The mRNA expression of HSPG2 in the paraspinal muscles was quantified for 90 patients and 26 controls. The The Student's t test was used to analyze the inter-group comparison of the HSPG2 expression. The relationship between the HSPG2 expression and the curve magnitude of the patients was analyzed by the Pearson correlation analysis. RESULTS: No case of mutation in the reported SNV p.Asn786Ser of HSPG2 was found in our cohort. The mRNA expression of HSPG2 in patients was comparable with that in the controls (0.0016 ± 0.0013 vs. 0.0019 ± 0.0012, p = 0.29). 42 patients with curve magnitude > 60 degrees were assigned to the severe curve group. The other 58 patients were assigned to the moderate curve group. These two groups were found to have comparable HSPG2 expression (0.0015 ± 0.0011 vs. 0.0017 ± 0.0014, p = 0.57). And there was no remarkable correlation between the expression level of HSPG2 and the curve severity (r = 0.131, p = 0.71). CONCLUSIONS: HSPG2 gene was not associated with the susceptibility or the phenotypes of AIS in the Chinese population. The whole HSPG2 gene can be sequenced in more AIS patients to identify potentially causative mutations.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença , Proteoglicanas de Heparan Sulfato/genética , Escoliose/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Glicosídeos/genética , Humanos , Polimorfismo de Nucleotídeo Único , Esteróis , Adulto Jovem
11.
BMC Med Genet ; 20(1): 13, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642275

RESUMO

BACKGROUND: Muscular dystrophies are a clinically and genetically heterogeneous group of disorders characterized by variable degrees of progressive muscle degeneration and weakness. There is a wide variability in the age of onset, symptoms and rate of progression in subtypes of these disorders. Herein, we present the results of our study conducted to identify the pathogenic genetic variation involved in our patient affected by rigid spine muscular dystrophy. CASE PRESENTATION: A 14-year-old boy, product of a first-cousin marriage, was enrolled in our study with failure to thrive, fatigue, muscular dystrophy, generalized muscular atrophy, kyphoscoliosis, and flexion contracture of the knees and elbows. Whole-exome sequencing (WES) was carried out on the DNA of the patient to investigate all coding regions and uncovered a novel, homozygous missense mutation in SEPN1 gene (c. 1379 C > T, p.Ser460Phe). This mutation has not been reported before in different public variant databases and also our database (BayanGene), so it is classified as a variation of unknown significance (VUS). Subsequently, it was confirmed that the novel variation was homozygous in our patient and heterozygous in his parents. Different bioinformatics tools showed the damaging effects of the variant on protein. Multiple sequence alignment using BLASTP on ExPASy and WebLogo, revealed the conservation of the mutated residue. CONCLUSION: We reported a novel homozygous mutation in SEPN1 gene that expands our understanding of rigid spine muscular dystrophy. Although bioinformatics analyses of results were in favor of the pathogenicity of the mutation, functional studies are needed to establish the pathogenicity of the variant.


Assuntos
Predisposição Genética para Doença , Corpos de Mallory/patologia , Proteínas Musculares/genética , Distrofias Musculares/genética , Mutação , Escoliose/genética , Selenoproteínas/genética , Adolescente , Sequência de Aminoácidos , Análise Mutacional de DNA , Testes Genéticos , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Irã (Geográfico) , Masculino , Corpos de Mallory/genética , Atrofia Muscular , Distrofias Musculares/fisiopatologia , Mutação de Sentido Incorreto , Linhagem , Escoliose/fisiopatologia , Alinhamento de Sequência
12.
Gene ; 688: 215-220, 2019 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-30572100

RESUMO

INTRODUCTION: PAX1 has been identified to be associated with adolescent idiopathic scoliosis (AIS). However, data are unavailable for northern Chinese populations, and it is important to determine the exact clinical phenotypes of the associated genetic polymorphisms. METHODS: Five PAX1 single nucleotide polymorphism (SNP) loci were genotyped in 480 northern Chinese Han AIS patients and 841 controls. A stratified genotype-phenotype correlation analysis was conducted based on positive SNP loci and the Peking Union Medical College (PUMC) classification system. Luciferase assays were performed to determine the regulation of PAX1 transcriptional activity. RESULTS: The A allele of rs17861031 and the G allele of rs6137473 were significantly associated with AIS [p = 0.05 and 3.12 × 10-3, odds ratio (OR) = 0.78 and 1.30, respectively]. Moreover, rs17861031 may regulate the PAX1 gene. The A allele of rs17861031 was identified as a risk allele for PUMC type I AIS (p = 0.03), and the G allele of rs6137473 was identified as a risk allele for PUMC type II AIS (p = 1.90 × 10-3). CONCLUSIONS: Both rs17861031 and rs6137473 were significantly associated with AIS and different PUMC classifications of AIS in a northern Chinese Han population.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença/genética , Fatores de Transcrição Box Pareados/genética , Polimorfismo de Nucleotídeo Único/genética , Escoliose/genética , Adolescente , Alelos , Estudos de Casos e Controles , Criança , Feminino , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Genótipo , Humanos , Masculino , Fenótipo
13.
Cell Physiol Biochem ; 48(5): 2134-2146, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30110682

RESUMO

BACKGROUND/AIMS: Congenital scoliosis (CS) is a result of anomalous development of vertebrae and is frequently associated with somitogenesis malformation. Although noncoding RNAs (ncRNAs) have been recently determined to be involved in the pathogenesis of CS, the competing endogenous RNA (ceRNA) regulatory networks in CS remain largely unknown. METHODS: Sequencing was conducted to explore the ncRNA expression profiles in rat embryos (gestation day 9) following vitamin A deficiency (VAD) (n = 9 for the vitamin A deficiency-induced congenital scoliosis (VAD-CS) group and n = 4 for the control group). Real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted to verify the expression levels of selected mRNAs, long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs). Bioinformatics analysis was used to discover the possible relationships and functions of the ceRNAs. RESULTS: A total of 749 mRNAs, 56 miRNAs, 685 lncRNAs, and 70 circRNAs were identified to have significantly different expression levels in the two groups. Wnt, PI3K-ATK, FoxO, EGFR, and mTOR were found to be the most significant pathways involved in VAD-CS pathogenesis. The circRNA/miRNA/mRNA and lncRNA/miRNA/mRNA networks of CS were built, and the gene expression mechanisms regulated by ncRNAs were unveiled via the ceRNA regulatory networks. CONCLUSION: We comprehensively identified ceRNA regulatory networks of embryonic somite development in VAD-CS as well as revealed the contribution of different ncRNA expression profiles. Our data demonstrate the association between mRNAs and ncRNAs in the pathogenic mechanism of CS.


Assuntos
Redes Reguladoras de Genes , RNA/metabolismo , Escoliose/patologia , Animais , Biologia Computacional , Modelos Animais de Doenças , Regulação para Baixo/genética , Embrião de Mamíferos/metabolismo , Feminino , Redes Reguladoras de Genes/genética , MicroRNAs/metabolismo , RNA/química , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Escoliose/etiologia , Escoliose/genética , Regulação para Cima/genética , Deficiência de Vitamina A/complicações , Deficiência de Vitamina A/patologia
14.
Anal Cell Pathol (Amst) ; 2018: 6836092, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30079294

RESUMO

Idiopathic scoliosis (IS) is a common medical condition beginning in childhood and characterized by strong evidence for a genetic susceptibility to three-dimensional spinal deformity. The primary goal of the current case-control study is to examine the association between the TGFB1 (-509C/T) functional polymorphic variant and genetic predisposition to IS in the Bulgarian population and the genotype-phenotype correlations in distinct case-control subgroups based on age at onset, family history, and gender. A total of 127 patients with primary scoliosis and 254 gender-matched control subjects were recruited. The mean Cobb angle was 53.8 ± 21.2°. Genotyping of cases and controls was performed using the TaqMan real-time amplification technique. The results were processed statistically using Pearson's Chi-squared test and Fisher's exact test with a value of p less than 0.05 as statistically significant. The polymorphic T allele and TT genotype were associated with a greater incidence of IS and can be considered as predisposing factors with a moderate effect on deformity development. The current results suggested that there was a genetic predisposition in early and late onset IS and familial, sporadic, and female cases. Nevertheless, replication studies are needed to reveal the relationship between the TGFB1 locus and certain subtypes of IS in different populations.


Assuntos
Escoliose/genética , Fator de Crescimento Transformador beta1/genética , Adolescente , Alelos , Bulgária , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Polimorfismo de Nucleotídeo Único/genética
15.
BMJ Case Rep ; 20182018 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-29982180

RESUMO

Pathogenic variants in the lysyl-hydroxylase-1 gene (PLOD1) are responsible for the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS). The disease is classically responsible for severe hypotonia at birth, progressive kyphoscoliosis, generalised joint hypermobility and scleral fragility. Arterial fragility is an important feature of the disease, but its characterisation remains limited. We report the clinical history of a 41-year-old woman who presented repeated arterial accidents, which occurred in previously normal medium size arteries within a limited time span of 2 years. Molecular investigations revealed compound heterozygosity for two PLOD1 gene deletions of exons 11-12 and 14-15. Arterial fragility is an important characteristic of kyphoscoliotic EDS. It manifests as spontaneous arterial rupture, dissections and dissecting aneurysms which may occur even during early childhood. This fragility is particularly likely to manifest during surgical intervention. Early medical management and surveillance may be indicated, but its modalities remain to be defined.


Assuntos
Aneurisma Dissecante/etiologia , Síndrome de Ehlers-Danlos/complicações , Cifose/complicações , Artérias da Tíbia , Adulto , Aneurisma Dissecante/genética , Artéria Celíaca/anormalidades , Artéria Celíaca/diagnóstico por imagem , Ecocardiografia , Síndrome de Ehlers-Danlos/genética , Feminino , Humanos , Cifose/genética , Ruptura Espontânea/etiologia , Ruptura Espontânea/genética , Escoliose/complicações , Escoliose/genética , Artérias da Tíbia/anormalidades , Artérias da Tíbia/diagnóstico por imagem
16.
G3 (Bethesda) ; 8(8): 2663-2672, 2018 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-29930198

RESUMO

Idiopathic scoliosis (IS) is a structural lateral spinal curvature of ≥10° that affects up to 3% of otherwise healthy children and can lead to life-long problems in severe cases. It is well-established that IS is a genetic disorder. Previous studies have identified genes that may contribute to the IS phenotype, but the overall genetic etiology of IS is not well understood. We used exome sequencing to study five multigenerational families with IS. Bioinformatic analyses identified unique and low frequency variants (minor allele frequency ≤5%) that were present in all sequenced members of the family. Across the five families, we identified a total of 270 variants with predicted functional consequences in 246 genes, and found that eight genes were shared by two families. We performed GO term enrichment analyses, with the hypothesis that certain functional annotations or pathways would be enriched in the 246 genes identified in our IS families. Using three complementary programs to complete these analyses, we identified enriched categories that include stereocilia and other actin-based cellular projections, cilia and other microtubule-based cellular projections, and the extracellular matrix (ECM). Our results suggest that there are multiple paths to IS and provide a foundation for future studies of IS pathogenesis.


Assuntos
Citoesqueleto de Actina/genética , Matriz Extracelular/genética , Microtúbulos/genética , Escoliose/genética , Adulto , Criança , Matriz Extracelular/metabolismo , Feminino , Humanos , Masculino , Microtúbulos/metabolismo , Linhagem , Polimorfismo Genético , Escoliose/etiologia , Escoliose/patologia
17.
Med Sci Monit ; 24: 2992-3001, 2018 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-29735971

RESUMO

BACKGROUND The present study aimed to evaluate the pathogenicity of 5 [i]GDF3[/i] gene variations using functional and [i]in silico[/i] assessment approaches in a Chinese congenital scoliosis population. MATERIAL AND METHODS We selected 13 patients carrying 5 variants from a congenital scoliosis cohort. The PCR products of samples were verified by Sanger sequencing. The data and sequence alignment were analyzed using Chromas and ClustalW. SIFT and PolyPhen-2 were used to predict the functional effects of each missense and amino acid substitutions. SWISS-MODEL server and Swiss-PdbViewer were used to analyze conformational changes of GDF3 structure. DUET, UCSF Chimera, and Ligplot software were used to further explore the protein stability, side chains, and hydrophobic interaction changes, respectively. Luciferase reporter gene and Western blot assays were used to perform functional assessments for every variant from the molecular level. RESULTS Of the 13 patients, the S212L variant reoccurred in 9 patients. The rest of the patients carried 1 missense mutation each. The variants of R84L and R84C were predicted as probably damaging [i]loci[/i]. S212L, N215S, A251T were predicted as benign [i]loci[/i]. In functional assays, R84L, S212L, and A251T display inhibitory effects on functional assays. N251S mutation showed a negative effect in protein expression assays but not in luciferase reporter gene assays. The variant of R84C displayed no negative effects on 2 functional assays. CONCLUSIONS Our results suggest that the 4 of the 5 variants in [i]GDF3[/i] gene contribute different pathogenicity in congenital scoliosis, which may provide molecular evidence for clinical genetic testing.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Biologia Computacional/métodos , Fator 3 de Diferenciação de Crescimento/genética , Mutação/genética , Escoliose/congênito , Escoliose/genética , Adolescente , Sequência de Aminoácidos , Animais , Sequência de Bases , Linhagem Celular , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Genes Reporter , Fator 3 de Diferenciação de Crescimento/química , Humanos , Luciferases/metabolismo , Masculino , Escoliose/diagnóstico por imagem , Homologia Estrutural de Proteína
18.
Brain Dev ; 40(7): 515-529, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29657083

RESUMO

Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder caused by mutations in MECP2, is associated with a peculiar breathing disturbance exclusively during wakefulness that is distressing, and can even prompt emergency resuscitation. Through the RTT Natural History Study, we characterized cross sectional and longitudinal characteristics of awake breathing abnormalities in RTT and identified associated clinical features. Participants were recruited from 2006 to 2015, and cumulative lifetime prevalence of breathing dysfunction was determined using the Kaplan-Meier estimator. Risk factors were assessed using logistic regression. Of 1205 participants, 1185 had sufficient data for analysis, including 922 females with classic RTT, 778 of whom were followed longitudinally for up to 9.0 years, for a total of 3944 person-years. Participants with classic or atypical severe RTT were more likely to have breathing dysfunction (nearly 100% over the lifespan) compared to those with atypical mild RTT (60-70%). Remission was common, lasting 1 year on average, with 15% ending the study in terminal remission. Factors associated with higher odds of severe breathing dysfunction included poor gross and fine motor function, frequency of stereotypical hand movements, seizure frequency, prolonged corrected QT interval on EKG, and two quality of life metrics: caregiver concern about physical health and contracting illness. Factors associated with lower prevalence of severe breathing dysfunction included higher body mass index and head circumference Z-scores, advanced age, and severe scoliosis or contractures. Awake breathing dysfunction is common in RTT, more so than seizures, and is associated with function, quality of life and risk for cardiac dysrhythmia.


Assuntos
Transtornos Respiratórios/fisiopatologia , Síndrome de Rett/fisiopatologia , Adulto , Fatores Etários , Idoso , Índice de Massa Corporal , Criança , Pré-Escolar , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prevalência , Qualidade de Vida , Transtornos Respiratórios/epidemiologia , Transtornos Respiratórios/etiologia , Transtornos Respiratórios/genética , Síndrome de Rett/complicações , Síndrome de Rett/epidemiologia , Síndrome de Rett/genética , Fatores de Risco , Escoliose/complicações , Escoliose/epidemiologia , Escoliose/genética , Escoliose/fisiopatologia , Convulsões/complicações , Convulsões/epidemiologia , Convulsões/genética , Convulsões/fisiopatologia , Adulto Jovem
19.
Eur J Med Genet ; 61(7): 399-402, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29501612

RESUMO

We report a 29 week fetus with arthrogryposis multiplex congenita, multiple joint dislocations, scoliosis and dysmorphism who was detected to be double heterozygote for putatively pathogenic FBN1 (NM_000138.4:c.6004C > T; p.Pro2002Ser) and FBN2 (NM_001999.3:c.2945G > T; p.Cys982Phe) variants on exome sequencing. The de-novo status of these variants is not confirmed as parental genotypes could not be ascertained. A comparison of the post-mortem findings of the fetus with reported phenotypes of Beals and Marfan syndromes indicated overlapping clinical features suggestive of a blended phenotype.


Assuntos
Doenças do Tecido Conjuntivo/genética , Fibrilina-1/genética , Fibrilina-2/genética , Anormalidades Múltiplas/genética , Aracnodactilia/genética , Artrogripose/genética , Contratura/genética , Exoma/genética , Feto , Heterozigoto , Humanos , Luxações Articulares/genética , Fenótipo , Escoliose/genética , Análise de Sequência de DNA
20.
Int J Med Sci ; 15(5): 436-446, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29559832

RESUMO

Idiopathic scoliosis is one of the most common disabling pathologies of children and adolescents. Etiology and pathogenesis of idiopathic scoliosis remain unknown. To study the etiology of this disease we identified the cells' phenotypes in the vertebral body growth plates in patients with idiopathic scoliosis. Materials and methods: The cells were isolated from vertebral body growth plates of the convex and concave sides of the deformity harvested intraoperatively in 50 patients with scoliosis. Cells were cultured and identified by methods of common morphology, neuromorphology, electron microscopy, immunohistochemistry and PCR analysis. Results: Cultured cells of convex side of deformation were identified as chondroblasts. Cells isolated from the growth plates of the concave side of the deformation showed numerous features of neuro- and glioblasts. These cells formed synapses, contain neurofilaments, and expressed neural and glial proteins. Conclusion: For the first time we demonstrated the presence of cells with neural/glial phenotype in the concave side of the vertebral body growth plate in scoliotic deformity. We hypothesized that neural and glial cells observed in the growth plates of the vertebral bodies represent derivatives of neural crest cells deposited in somites due to alterations in their migratory pathway during embryogenesis. We also propose that ectopic localization of cells derived from neural crest in the growth plate of the vertebral bodies is the main etiological factor of the scoliotic disease.


Assuntos
Lâmina de Crescimento/patologia , Crista Neural/patologia , Neuroglia/patologia , Escoliose/patologia , Adolescente , Criança , Condrócitos/metabolismo , Condrócitos/patologia , Condrócitos/ultraestrutura , Desenvolvimento Embrionário/genética , Feminino , Regulação da Expressão Gênica/genética , Lâmina de Crescimento/metabolismo , Lâmina de Crescimento/ultraestrutura , Humanos , Masculino , Microscopia Eletrônica de Varredura , Crista Neural/metabolismo , Crista Neural/ultraestrutura , Neuroglia/metabolismo , Escoliose/etiologia , Escoliose/genética , Coluna Vertebral/metabolismo , Coluna Vertebral/patologia , Coluna Vertebral/ultraestrutura
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