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1.
Artigo em Inglês | MEDLINE | ID: mdl-32580277

RESUMO

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare, inherited disorder characterized by a congenital absence of conjugate horizontal eye movements with progressive scoliosis developing in childhood and adolescence. Mutations in the Roundabout (ROBO3) gene located on chromosome 11q23-25 are responsible for the development of horizontal gaze palsy and progressive scoliosis. However, some studies redefined the locus responsible for this pathology to a 9-cM region. This study carried out a systematic review in which 25 documents were analyzed, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. The search was made in the following electronic databases from January 1995 to October 2019: PubMed, Scopus, Web of Science, PEDRO, SPORT Discus, and CINAHL. HGPPS requires a multidisciplinary diagnostic approach, in which magnetic resonance imaging might be the first technique to suggest the diagnosis, which should be verified by an analysis of the ROBO3 gene. This is important to allow for adequate ocular follow up, apply supportive therapies to prevent the rapid progression of scoliosis, and lead to appropriate genetic counseling.


Assuntos
Transtornos da Motilidade Ocular , Oftalmoplegia Externa Progressiva Crônica , Receptores de Superfície Celular , Escoliose , Adolescente , Criança , Feminino , Humanos , Masculino , Mutação , Oftalmoplegia Externa Progressiva Crônica/genética , Receptores de Superfície Celular/genética , Receptores Imunológicos , Escoliose/genética
2.
Radiology ; 295(3): 736-740, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32421468

RESUMO

HistoryA 13-year-old girl was born to consanguineous parents. She presented with mild intellectual impairment, convergent strabismus, horizontal gaze palsy, and bilateral abducens palsy. Vertical gaze was preserved, and no abnormalities suggesting facial paralysis were noted. In addition, she reported progressive back pain since she was 5 years old. Other symptoms were denied. No medications or related drugs had been administered thus far. The patient underwent brain MRI for further evaluation. Current and previous spine radiographs were also reviewed.


Assuntos
Análise Mutacional de DNA , Oftalmoplegia Externa Progressiva Crônica/genética , Receptores de Superfície Celular/genética , Escoliose/genética , Adolescente , Consanguinidade , Feminino , Humanos , Imagem por Ressonância Magnética , Oftalmoplegia Externa Progressiva Crônica/diagnóstico por imagem , Doenças Raras , Escoliose/diagnóstico por imagem
3.
BMC Med Genet ; 21(1): 21, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005172

RESUMO

BACKGROUND: More than 95% of individuals with RTT have mutations in methyl-CpG-binding protein 2 (MECP2), whose protein product modulates gene transcription. The disorder is caused by mutations in a single gene and the disease severity in affected individuals can be quite variable. Specific MECP2 mutations may lead phenotypic variability and different degrees of disease severity. It is known that low bone mass is a frequent and early complication of subjects with Rett syndrome. As a consequence of the low bone mass Rett girls are at an increased risk of fragility fractures. This study aimed to investigate if specific MECP2 mutations may affects the degree of involvement of the bone status in Rett subjects. METHODS: In 232 women with Rett syndrome (mean age 13.8 ± 8.3 yrs) we measured bone mineral density at whole body and at femur (BMD-FN and BMD-TH) by using a DXA machine (Hologic QDR 4500). QUS parameters were assessed at phalanxes by Bone Profiler-IGEA (amplitude dependent speed of sound: AD-SoS and bone transmission time: BTT). Moreover, ambulation capacity (independent or assisted), fracture history and presence of scoliosis were assessed. We divided the subjects with the most common point mutations in two group based on genotype-phenotype severity; in particular, there has been consensus in recognising that the mutations R106T, R168X, R255X, R270X are considered more severe. RESULTS: As aspect, BMD-WB, BMD-FN and BMD-TH were lower in subjects with Rett syndrome that present the most severe mutations with respect to subjects with Rett syndrome with less severe mutations, but the difference was statistically significant only for BMD-FN and BMD-TH (p < 0.05). Also both AD-SoS and BTT values were lower in subjects that present the most severe mutations with respect to less severe mutations but the difference was not statistically significant. Moreover, subjects with Rett syndrome with more severe mutations present a higher prevalence of scoliosis (p < 0.05) and of inability to walk (p < 0.05). CONCLUSION: This study confirms that MECP2 mutation type is a strong predictor of disease severity in subjects with Rett syndrome. In particular, the subjects with more severe mutation present a greater deterioration of bone status, and a higher prevalence of scoliosis and inability to walk.


Assuntos
Doenças Ósseas/genética , Proteína 2 de Ligação a Metil-CpG/genética , Osteoporose/genética , Síndrome de Rett/genética , Adolescente , Adulto , Densidade Óssea/genética , Doenças Ósseas/diagnóstico por imagem , Doenças Ósseas/fisiopatologia , Criança , Pré-Escolar , Feminino , Fraturas Ósseas/diagnóstico por imagem , Fraturas Ósseas/genética , Fraturas Ósseas/fisiopatologia , Humanos , Masculino , Mutação , Osteoporose/diagnóstico por imagem , Osteoporose/fisiopatologia , Síndrome de Rett/diagnóstico por imagem , Síndrome de Rett/fisiopatologia , Escoliose/diagnóstico por imagem , Escoliose/genética , Escoliose/fisiopatologia , Índice de Gravidade de Doença , Adulto Jovem
4.
Nat Commun ; 11(1): 479, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980602

RESUMO

Congenital scoliosis (CS) is a complex genetic disorder characterized by vertebral malformations. The precise etiology of CS is not fully defined. Here, we identify that mutation in dual serine/threonine and tyrosine protein kinase (dstyk) lead to CS-like vertebral malformations in zebrafish. We demonstrate that the scoliosis in dstyk mutants is related to the wavy and malformed notochord sheath formation and abnormal axial skeleton segmentation due to dysregulated biogenesis of notochord vacuoles and notochord function. Further studies show that DSTYK is located in late endosomal/lysosomal compartments and is involved in the lysosome biogenesis in mammalian cells. Dstyk knockdown inhibits notochord vacuole and lysosome biogenesis through mTORC1-dependent repression of TFEB nuclear translocation. Inhibition of mTORC1 activity can rescue the defect in notochord vacuole biogenesis and scoliosis in dstyk mutants. Together, our findings reveal a key role of DSTYK in notochord vacuole biogenesis, notochord morphogenesis and spine development through mTORC1/TFEB pathway.


Assuntos
Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Escoliose/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/anormalidades , Peixe-Zebra/genética , Transporte Ativo do Núcleo Celular , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Humanos , Modelos Biológicos , Mutação , Notocorda/anormalidades , Notocorda/metabolismo , Notocorda/ultraestrutura , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Escoliose/congênito , Escoliose/metabolismo , Transdução de Sinais , Coluna Vertebral/anormalidades , Coluna Vertebral/metabolismo , Fatores de Transcrição/metabolismo , Vacúolos/metabolismo , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/antagonistas & inibidores , Proteínas de Peixe-Zebra/metabolismo
5.
Cell Prolif ; 53(2): e12736, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31828859

RESUMO

Scoliosis, a complex three-dimensional deformity of the spine with the Cobb angle (a measure of the spinal lateral curvature) >10 degree, encompasses a spectrum of pathologies, including congenital, idiopathic, syndromic and neuromuscular aetiologies. The pathogenesis is multifactorial involving both environmental and genetic factors but the exact cellular and molecular mechanisms of disease development remain largely unknown. Emerging evidence showed that non-coding RNAs (ncRNAs), namely microRNAs, long ncRNAs and circular RNAs, are deregulated in many orthopaedic diseases, including scoliosis. Importantly, these deregulated ncRNAs functionally participate in the initiation and progression of scoliosis. Here, we review recent progress in ncRNA research on scoliosis.


Assuntos
RNA não Traduzido/genética , Escoliose/genética , Animais , Humanos
7.
Dis Model Mech ; 12(12)2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848143

RESUMO

Idiopathic scoliosis (IS) is the most common type of musculoskeletal defect affecting children worldwide, and is classified by age of onset, location and degree of spine curvature. Although rare, IS with onset during infancy is the more severe and rapidly progressive form of the disease, associated with increased mortality due to significant respiratory compromise. The pathophysiology of IS, in particular for infantile IS, remains elusive. Here, we demonstrate the role of PRMT5 in the infantile IS phenotype in mouse. Conditional genetic ablation of PRMT5 in osteochondral progenitors results in impaired terminal hypertrophic chondrocyte differentiation and asymmetric defects of endochondral bone formation in the perinatal spine. Analysis of these several markers of endochondral ossification revealed increased type X collagen (COLX) and Ihh expression, coupled with a dramatic reduction in Mmp13 and RUNX2 expression, in the vertebral growth plate and in regions of the intervertebral disc in the Prmt5 conditional mutant mice. We also demonstrate that PRMT5 has a continuous role in the intervertebral disc and vertebral growth plate in adult mice. Altogether, our results establish PRMT5 as a critical promoter of terminal hypertrophic chondrocyte differentiation and endochondral bone formation during spine development and homeostasis.This article has an associated First Person interview with the first author of the paper.


Assuntos
Proteína Morfogenética Óssea 4/genética , Condrócitos/citologia , Regulação da Expressão Gênica no Desenvolvimento , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Escoliose/genética , Alelos , Animais , Proteína Morfogenética Óssea 4/metabolismo , Cartilagem/metabolismo , Diferenciação Celular , Proliferação de Células , Condrogênese , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Cruzamentos Genéticos , Deleção de Genes , Proteínas Hedgehog/metabolismo , Homeostase , Metaloproteinase 13 da Matriz/metabolismo , Camundongos , Mutação , Osteogênese/genética , Fenótipo , Regiões Promotoras Genéticas , Células-Tronco/citologia
8.
Medicine (Baltimore) ; 98(48): e17828, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770198

RESUMO

RATIONALE: Multicentric carpotarsal osteolysis (MCTO) is a rare hereditary disease caused by mutations in MafB, a negative regulator of osteoclastogenesis. PATIENT CONCERNS: A 20-year-old, Japanese woman with scoliosis visited our institute for treatment. Scoliosis was apparent since she was 12 years old, but she had not sought treatment until the age of 19. Medical examination showed a typical facial appearance associated with a small forehead and hypotelorism; shortening of the fingers of both hands and both upper limbs was observed, in addition to clubfoot. No café au lait spots or mental retardation were observed. On the other hand, the trunk showed evidence of an irregular waistline and a rib hump that obviously suggested scoliosis. Neurological deficit was not observed. Spirometry showed decreased forced vital capacity (FVC). Although proteinuria was observed, renal dysfunction and hypertension were not seen. The major curve of scoliosis was 82° (MC, Th7-L2; Th11 apical vertebra), and the upper curve was 77° (UC, Th1-6; Th3 apical vertebra). In a recumbent-traction position, the major curve was 54° and the upper curve was 56°. The pelvic incidence minus lumbar lordosis (PI-LL) angle was <10° and no mismatch was observed; thoracic kyphosis was decreased to 16°. DIAGNOSIS: The patient was diagnosed with symptomatic scoliosis secondary to MCTO. INTERVENTIONS: We decided to perform a correction and fusion from Th2 to L3 using a posterior spinal instrumentation. OUTCOMES: Postoperative x-ray demonstrated scoliosis angle correction from 77° to 38° at Th1-6 and 82° to 39° at Th7-L2. Postoperative x-ray demonstrated thoracic kyphosis angle correction from 16° to 21°. The patient's height increased from 155 to 161 cm. LESSONS: It has been 24 months since the operation, and no exacerbation has been observed. To the best of our knowledge, this is the first report of surgical treatment of scoliosis secondary to MCTO.


Assuntos
Osteólise/complicações , Escoliose/genética , Feminino , Humanos , Fator de Transcrição MafB/metabolismo , Osteólise/genética , Escoliose/cirurgia , Fusão Vertebral/métodos , Adulto Jovem
9.
BMC Neurol ; 19(1): 253, 2019 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-31656175

RESUMO

BACKGROUND: We encountered two unrelated individuals suffering from neurological disorders, including epilepsy and scoliosis. CASE PRESENTATION: Whole-exome sequencing identified the same recurrent, de novo, pathogenic variant in NUS1 [NM_138459.4:c.691 + 1C > A] in both individuals. This variant is located in the conserved cis-prenyltransferase domain of the nuclear undecaprenyl pyrophosphate synthase 1 gene (NUS1), which encodes the Nogo-B receptor, an essential catalyst for protein glycosylation. This variant was confirmed to create a new splice donor site, resulting in aberrant RNA splicing resulting in a 91-bp deletion in exon 3 in both individuals. The mutant mRNA was partially degraded by nonsense mediated mRNA decay. To date, only four de novo variants and one homozygous variant have been reported in NUS1, which cause developmental and epileptic encephalopathy, early onset Parkinson's disease, and a congenital disorder of glycosylation. Seven patients, including our two patients, have presented with epileptic seizures and intellectual disabilities. CONCLUSIONS: Our study strongly supports the finding that this recurrent, de novo, variant in NUS1 causes developmental and epileptic encephalopathy with involuntary movement, ataxia and scoliosis.


Assuntos
Ataxia/genética , Epilepsia/genética , Mioclonia/genética , Receptores de Superfície Celular/genética , Escoliose/genética , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Mutação , Linhagem , Sítios de Splice de RNA
10.
BMC Musculoskelet Disord ; 20(1): 479, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31653238

RESUMO

BACKGROUND: Adolescent idiopathic scoliosis (AIS) which characterized by complex three-dimensional deformity of spine has been difficult to cure because of the unknown etiopathology and uncertainty of progression. Nowadays, circulating cell-free (ccf) DNA was found to be a potential biomarker for several benign and malignant diseases. However, whether ccf DNA can be a biomarker for AIS has not been reported yet. In this study, we investigate the circulating cell-free nuclear DNA (ccf n-DNA) and mitochondrial DNA (ccf mt-DNA) concentrations in the plasma of patients with AIS and controls (CT), and the changed plasma ccf n-DNA and ccf mt-DNA levels and their association with clinical parameters were assessed. METHODS: The plasma of peripheral blood from 69 AIS patients and 21 age-matched CT was collected for ccf DNA analysis. Quantitative PCR was used to detect ccf n-DNA and ccf mt-DNA levels, and correlation analyses between the ccf n-DNA and ccf mt-DNA levels and clinical characteristics were conducted. Receiver operator curves (ROC) were used to analyze the sensitivity and specificity of ccf n-DNA and ccf mt-DNA levels to different characteristics. RESULTS: The plasma ccf n-DNA levels of both GAPDH and ACTB were significantly decreased in AIS patients compared with those in controls, while the plasma ccf mt-DNA levels did not changed. According to sex-related analyses, the ccf n-DNA levels in male CT-M was higher than that in female CT and male AIS, but the ccf n-DNA levels in female AIS was not significantly changed when compared with male AIS or female CT. However, the concentration of ccf mt-DNA in female AIS increased significantly when compared with male AIS. Surprisingly, Lenke type-related analyses suggested that Lenke type 1 patients had lower ccf n-DNA levels, whereas Lenke type 5 patients had higher ccf mt-DNA levels compared with those of controls. However, a lower sensitivity and specificity of AIS predicted by ccf n-DNA or ccf mt-DNA levels was observed, whether in total, by sex, or by Lenke type. CONCLUSION: Although with no/little predictive accuracy of AIS/progressed AIS by ccf DNA levels, significantly changed plasma ccf DNA levels were observed in AIS patients compared with those in controls.


Assuntos
Ácidos Nucleicos Livres/sangue , DNA Mitocondrial/sangue , Escoliose/diagnóstico , Actinas/genética , Adolescente , Biomarcadores/sangue , Núcleo Celular/genética , Ácidos Nucleicos Livres/isolamento & purificação , Criança , DNA Mitocondrial/isolamento & purificação , Progressão da Doença , Feminino , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/genética , Humanos , Masculino , Valor Preditivo dos Testes , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Escoliose/sangue , Escoliose/genética , Sensibilidade e Especificidade , Fatores Sexuais
11.
Nat Commun ; 10(1): 3685, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31417091

RESUMO

Adolescent idiopathic scoliosis (AIS) is the most common pediatric spinal deformity. Several AIS susceptibility loci have been identified; however, they could explain only a small proportion of AIS heritability. To identify additional AIS susceptibility loci, we conduct a meta-analysis of the three genome-wide association studies consisting of 79,211 Japanese individuals. We identify 20 loci significantly associated with AIS, including 14 previously not reported loci. These loci explain 4.6% of the phenotypic variance of AIS. We find 21 cis-expression quantitative trait loci-associated genes in seven of the fourteen loci. By a female meta-analysis, we identify additional three significant loci. We also find significant genetic correlations of AIS with body mass index and uric acid. The cell-type specificity analyses show the significant heritability enrichment for AIS in multiple cell-type groups, suggesting the heterogeneity of etiology and pathogenesis of AIS. Our findings provide insights into etiology and pathogenesis of AIS.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Escoliose/genética , Adolescente , Índice de Massa Corporal , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Japão , Masculino , Locos de Características Quantitativas/genética , Fatores Sexuais , Ácido Úrico/metabolismo
12.
Spine (Phila Pa 1976) ; 44(23): 1623-1629, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31365516

RESUMO

STUDY DESIGN: Genetic case-control study of single nucleotide polymorphisms (SNPs). OBJECTIVE: To examine the association of previously reported susceptibility genes for adolescent idiopathic scoliosis (AIS) and intervertebral disc (IVD) degeneration with adult spinal deformity (ASD). SUMMARY OF BACKGROUND DATA: ASD is a spinal deformity that develops and progresses with age. Its etiology is unclear. Several ASD susceptibility genes were recently reported using a candidate gene approach; however, the sample sizes were small and associations with ASD development were not determined. METHODS: ASD was defined as structural scoliosis with a Cobb angle more than 15° on standing radiographs, taken of patients at age 40 to 75 years in this study. Subjects in whom scoliosis was diagnosed before age 20 were excluded. We recruited 356 Japanese ASD subjects and 3341 healthy controls for case-control association studies of previously reported SNPs. We genotyped four known AIS-associated SNPs (rs11190870 in LBX1, rs6570507 in GPR126, rs10738445 in BNC2, and rs6137473 in PAX1) and three IVD degeneration-associated SNPs (rs1245582 in CHST3, rs2073711 in CILP, and rs1676486 in COL11A1) by the Invader assay. RESULTS: Among the AIS-associated SNPs, rs11190870 and rs6137473 showed strong and nominal associations with ASD (P = 1.44 × 10, 1.00 × 10, respectively). Of the IVD degeneration-associated SNPs, rs1245582 and rs2073711 showed no association with ASD, while rs1676486 showed a nominal association (P = 1.10 × 10). In a subgroup analysis, rs11190870 was significantly associated with a Cobb angle more than 20° in the minor thoracic curve (P = 1.44 × 10) and with a left convex lumbar curve (P = 6.70 × 10), and nominally associated with an apical vertebra higher than L1 (P = 1.80 × 10). CONCLUSION: rs11190870 in LBX1, a strong susceptibility SNP for AIS, may also be a susceptibility SNP for ASD. Thus, ASD and AIS may share a common genetic background. LEVEL OF EVIDENCE: 4.


Assuntos
Estudos de Associação Genética/métodos , Predisposição Genética para Doença/genética , Proteínas de Homeodomínio/genética , Degeneração do Disco Intervertebral/genética , Polimorfismo de Nucleotídeo Único/genética , Escoliose/genética , Fatores de Transcrição/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/epidemiologia , Genótipo , Humanos , Degeneração do Disco Intervertebral/diagnóstico por imagem , Degeneração do Disco Intervertebral/epidemiologia , Masculino , Pessoa de Meia-Idade , Escoliose/diagnóstico por imagem , Escoliose/epidemiologia
13.
Behav Sci Law ; 37(5): 512-521, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31389076

RESUMO

Trisomy 20 is a genetic abnormality in which individuals have an extra copy of chromosome 20. Complete trisomy 20 is rare and believed to be incompatible with life. A mosaic form of trisomy 20, in which only some cells or tissues contain the extra chromosome, is a relatively commonly encountered chromosomal abnormality found during prenatal testing, and c. 90% result in a normal phenotype. However, despite the absence of a consistent phenotype, certain findings have been reported across multiple cases of mosaic trisomy 20. These include an array of morphological findings, developmental delays, and learning disabilities. Beyond physical manifestations, a wide range of developmental and learning delays have also been reported. In this work, we provide an overview of the trisomy 20 literature and a case report of a young adult male with mosaic trisomy 20 who committed homicide. His developmental and life history, eventual diagnosis of mosaic trisomy 20, similarities and differences in his condition compared with prior research findings, and potentially new phenotypic findings associated with trisomy 20 that he manifested (childhood visual hallucinations, self-injury, polydactyly) are presented. Additionally, the potential role of this genetic diagnosis in his neuropsychiatric history and its successful application as a mitigating factor at his capital sentencing trial are described. We did not identify other similar cases during our search of major scientific and legal databases. As a backdrop, the use of genetics in criminal trials is on the rise, and courts are increasingly likely to accept behavioral genetics evidence; therefore, it is crucial that the legal system is well acquainted with the opportunities and limitations of these approaches.


Assuntos
Direito Penal , Homicídio/psicologia , Transtornos Mentais/psicologia , Mosaicismo , Trissomia/fisiopatologia , Sobreviventes Adultos de Maus-Tratos Infantis , Cromossomos Humanos Par 20/genética , Criptorquidismo/genética , Criptorquidismo/fisiopatologia , Exposição à Violência , Psiquiatria Legal , Genética Comportamental , Alucinações/genética , Alucinações/fisiopatologia , Alucinações/psicologia , Humanos , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/psicologia , Masculino , Transtornos Mentais/genética , Transtornos Mentais/fisiopatologia , Fenótipo , Polidactilia/genética , Polidactilia/fisiopatologia , Escoliose/genética , Escoliose/fisiopatologia , Trissomia/genética , Adulto Jovem
14.
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
15.
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
16.
J Orthop Res ; 37(10): 2217-2225, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31119800

RESUMO

Idiopathic scoliosis (IS) etiology remains unclear, but strong genetic background is suggested. Previously reported TIMP2 study indicates an association of genic rs8179090 with IS progression in a Han Chinese population. However, there has been a lack of investigation into intragenic TIMP2 polymorphisms in IS patients. We recruited 100 Caucasian females with IS and 100 controls. Patients were subdivided accordingly to: progression rate, curve severity, joint mobility, and curve pattern. Allele-specific-polymerase chain reaction based on fluorescence resonance energy transfer was applied to evaluate nine TIMP2 polymorphisms. Distribution of genotype and allele frequency in only one polymorphism (rs11658743) differed in case-control study. Four of the polymorphisms (rs2277700, rs11077401, rs2376999, and rs4789934) showed non-equal distributions either in genotype or/and allele distributions in the patients of different progression rates. The rs11077401 was related to curve severity patients distinction and the rs8179090 distinguished patients with different joint mobility level. Two polymorphisms either differed statistically in case of curve patterns subgrouping (rs8068674 and rs8179090) or showed a slight tendency toward significance in the recessive model of allele distributions (rs9916809 and rs8179090). The remaining two polymorphisms (rs2377005, rs11658743) showed no association with either clinical or radiographic IS characteristics. The influence of the G allele of the rs8179090 on the clinical course of IS has not yet been confirmed. We identified four TIMP2 polymorphisms (rs11077401, rs2376999, rs2277700, and rs4789934) that were associated with a higher risk of the progressive IS form. Further genetic association studies based on suggested clinical criteria would be necessary to validate TIMP2 polymorphisms associated with the curve progression. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2217-2225, 2019.


Assuntos
Escoliose/genética , Inibidor Tecidual de Metaloproteinase-2/genética , Adolescente , Alelos , Estudos de Casos e Controles , Criança , Progressão da Doença , Grupo com Ancestrais do Continente Europeu , Feminino , Genótipo , Humanos , Instabilidade Articular/genética , Polimorfismo de Nucleotídeo Único , Escoliose/diagnóstico por imagem , Vértebras Torácicas/diagnóstico por imagem
17.
Spine J ; 19(9): 1584-1596, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31100472

RESUMO

BACKGROUND CONTEXT: Coexistence of abnormal skeletal growth and reduced bone mineral density in the context of adolescent idiopathic scoliosis (AIS) suggests disturbed bone metabolism existing in such patients. Our previous study suggested increased proliferation ability and decreased osteogenic differentiation ability of bone marrow mesenchymal stem cells (BM-MSCs) of AIS. PURPOSE: To explore the differential miRNA expression profile, Go (gene ontology) terms and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways in BM-MSCs of AIS and non-AIS controls were conducted using microarray approach and bioinformatics analyses. STUDY DESIGN: miRNA microarray approach and bioinformatics analysis. METHODS: The differentially expressed miRNAs (DEMs) of BM-MSCs from AIS patients compared with those from healthy individuals were analyzed using a microarray analysis. Comprehensive bioinformatics analyses were then used to enrich datasets for gene ontology and pathway. Based on the interaction network analysis of DEMs contained in significant pathways, 12 potential crucial miRNAs were selected for validation by RT-PCR. RESULTS: The study identified 54 previously unrecognized DEMs (12 upregulated, 42 downregulated) in BM-MSCs from AIS patients. These miRNAs are involved in multiple biological processes, including small GTPase-mediated signal transduction, DNA-dependent transcription, cytokinesis, cell adhesion, transmembrane transport, response to hypoxia, etc. Pathway analysis of these new identified miRNAs revealed dysregulated MAPK signaling pathway, PI3K-Akt signaling pathway, calcium signaling pathway, Notch signaling pathway, and ubiquitin-mediated proteolysis pathway, all of which have been reported to play important role in regulating the osteogenic or adipogenic differentiation of MSCs. Furthermore, interaction networks analysis indicated that seven most significant central miRNAs, including miR-17-5p, miR-106a-5p, miR-106b-5p, miR-16-5p, miR-93-5p, miR-15a-5p, and miR-181b-5p may play essential roles in AIS pathogenesis and accompanied osteopenia. CONCLUSION: The current study reports the differential miRNAs expression profiles of BM-MSCs from AIS patients and related pathways for the first time. The identification of these candidate miRNAs provides a deep insight into the pathogenesis of AIS and the accompanying generalized osteopenia.


Assuntos
Células da Medula Óssea/metabolismo , Redes Reguladoras de Genes , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , Escoliose/genética , Adolescente , Feminino , Humanos , Masculino , Osteogênese , Escoliose/metabolismo
18.
Med Hypotheses ; 127: 57-62, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31088649

RESUMO

Adolescent idiopathic scoliosis (AIS), defined as a lateral deviation of the spine of at least ten degrees, is a classic enigma in orthopaedics and affects 1-4% of the general population. Despite (over) a century of intensive research, the etiology is still largely unknown. One of the major problems in all existing AIS research is the fact that most patients come to medical attention after onset of the curve. Therefore, it is impossible to know whether current investigated parameters are causative, or an effect of the scoliosis. Moreover, up until now there is no known animal model that captures the core features of AIS. In order to identify causal pathways leading to AIS we propose another approach, which has been of great value in other medical disciplines: To use a subset of the population, with a higher risk for a certain disease as a "model" for the general population. Such a "model" may allow the identification of causative mechanisms that might be applicable to the general population. The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome and occurs in ∼1:3000-6000 children and 1:1000 pregnancies. Nearly half of the population of patients with 22q11.2DS develop a scoliosis that in most cases resembles AIS as far as age at onset and curve pattern. We postulate that within 22q11.2DS certain causal pathways leading to scoliosis can be identified and that these are applicable to the general population.


Assuntos
Síndrome da Deleção 22q11/genética , Escoliose/genética , Síndrome da Deleção 22q11/diagnóstico , Síndrome da Deleção 22q11/fisiopatologia , Idade de Início , Animais , Fenômenos Biomecânicos , Humanos , Modelos Biológicos , Pelve/fisiologia , Rotação , Escoliose/diagnóstico , Escoliose/fisiopatologia , Coluna Vertebral , Estresse Mecânico
19.
Ophthalmic Genet ; 40(2): 150-156, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30985235

RESUMO

BACKGROUND: Horizontal gaze palsy and progressive scoliosis (HGPPS) is a rare autosomal recessive disorder due to mutations in ROBO3 gene. Patients have characteristic clinical and imaging findings. We report six patients from two families with this disorder with two novel mutations. MATERIALS AND METHODS: One patient from a non-consanguineous family and five patients from extended consanguineous families were clinically and radiologically examined. Blood samples from the patients and their parents were obtained and all the coding exons and flanking intronic sequences of the ROBO3 gene were amplified and subjected to bidirectional DNA sequencing. RESULTS: All six patients had the characteristic clinical and radiological findings of HGPPS. Genetic testing showed two novel mutations including frame-shift and nonsense. CONCLUSION: Two novel mutations in the ROBO3 gene were identified in two Jordanian families with six affected individuals. To our knowledge, this is the first molecular study of HGPPS in Jordan.


Assuntos
Mutação , Oftalmoplegia Externa Progressiva Crônica/genética , Receptores de Superfície Celular/genética , Escoliose/genética , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Consanguinidade , Éxons , Feminino , Humanos , Jordânia , Imagem por Ressonância Magnética , Masculino , Oftalmoplegia Externa Progressiva Crônica/diagnóstico por imagem , Linhagem , Escoliose/diagnóstico por imagem , Análise de Sequência de DNA , Tomografia Computadorizada por Raios X
20.
Spine (Phila Pa 1976) ; 44(18): E1063-E1067, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30994600

RESUMO

STUDY DESIGN: A genetic association study. OBJECTIVE: The aim of this study was to determine whether variants of ABO, SOX6, and CDH13 are associated with the susceptibility of AIS in Chinese Han population. SUMMARY OF BACKGROUND DATA: A recent large-scale genome-wide association study reported three novel loci in CDH13, ABO, and SOX6 genes associated with adolescent idiopathic scoliosis (AIS) in Japanese population. However, the association of these three genes with AIS in other populations remains obscure. METHODS: The SNPs rs4513093, rs687621, and rs1455114 were genotyped in 1208 female patients and 2498 healthy controls. Samples for the expression analysis in paraspinal muscles were collected from 49 AIS and 33 congenital scoliosis (CS) patients during surgical interventions. Chi-square analysis was used to assess the difference regarding genotype and allele frequency between cases and controls. Tissue expressions of ABO, CDH13, and SOX6 were compared between AIS and CS patients by the Student t test. RESULTS: SNPs rs4513093 of CDH13 and rs687621 of ABO were found to be significantly associated with AIS with an odds ratio of 0.8691 and 1.203, respectively. There was no significant association of rs1455114 with AIS. Moreover, AIS patients were found to have significantly increased expression of ABO. As for expression of CDH13 and SOX6, no remarkable difference was found between the two groups. CONCLUSION: The association of CDH13 and ABO variants with AIS was successfully replicated in the Chinese Han population. More studies are warranted to explore the functional role of ABO in the development of AIS. LEVEL OF EVIDENCE: N/A.


Assuntos
Sistema ABO de Grupos Sanguíneos/genética , Fatores de Transcrição SOXD/genética , Escoliose/epidemiologia , Escoliose/genética , Adolescente , Grupo com Ancestrais do Continente Asiático/genética , Caderinas , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Vigilância da População
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