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1.
Clin Exp Rheumatol ; 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33427614

RESUMO

OBJECTIVES: The aim of this study is to investigate the relationship between spinal MRI findings with disease activity and other clinical and serological parameters, and to determine the importance of MRI scoring system in evaluating disease activity of SAPHO syndrome. METHODS: Thirty patients with SAPHO syndrome underwent clinical, laboratory and MRI evaluation at baseline, 3 months, 6 months and 1 year. Magnetic resonance images were analysed using modified Spondyloarthritis Research Consortium of Canada (SPARCC) scoring system. Correlations between MRI score and clinical and laboratory parameters were analysed using Spearman's rank correlation test. RESULTS: Persistent improvement was observed after 12 months in terms of total modified SPARCC scores (37(12,59) vs. 23(5,45) at baseline and 12 months, p<0.05). Total modified SPARCC scores showed Spearman correlations with hypersensitive C-reaction protein (hs-CRP), ankylosing spondylitis disease activity score (ASDAS) and bath ankylosing spondylitis metroloty index (BASMI) at baseline, 3 months, 6 months and 12 months (p varied from <0.001 to <0.05, and r varied from 0.418 to 0.601). Modified SPARCC scores of spine joint, as the largest contribution to the total scores with the mean score of 12(5,30) after 12 months vs. 26 (12,40) at baseline. CONCLUSIONS: The modified SPARCC score proposed in this study exhibits promising potential in the evaluation of extensive radiographic damage in SAPHO and the reflection the disease activity. Our study suggests that MRI could be used together with other parameters of disease activity in the assessment of symptomatic SAPHO patients with spine involvement.

4.
J Med Genet ; 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381727

RESUMO

BACKGROUND: Early-onset scoliosis (EOS), defined by an onset age of scoliosis less than 10 years, conveys significant health risk to affected children. Identification of the molecular aetiology underlying patients with EOS could provide valuable information for both clinical management and prenatal screening. METHODS: In this study, we consecutively recruited a cohort of 447 Chinese patients with operative EOS. We performed exome sequencing (ES) screening on these individuals and their available family members (totaling 670 subjects). Another cohort of 13 patients with idiopathic early-onset scoliosis (IEOS) from the USA who underwent ES was also recruited. RESULTS: After ES data processing and variant interpretation, we detected molecular diagnostic variants in 92 out of 447 (20.6%) Chinese patients with EOS, including 8 patients with molecular confirmation of their clinical diagnosis and 84 patients with molecular diagnoses of previously unrecognised diseases underlying scoliosis. One out of 13 patients with IEOS from the US cohort was molecularly diagnosed. The age at presentation, the number of organ systems involved and the Cobb angle were the three top features predictive of a molecular diagnosis. CONCLUSION: ES enabled the molecular diagnosis/classification of patients with EOS. Specific clinical features/feature pairs are able to indicate the likelihood of gaining a molecular diagnosis through ES.

5.
Kidney Int ; 98(4): 1020-1030, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32450157

RESUMO

Congenital anomalies of the kidney and urinary tract (CAKUTs) are the most common cause of chronic kidney disease in children. Human 16p11.2 deletions have been associated with CAKUT, but the responsible molecular mechanism remains to be illuminated. To explore this, we investigated 102 carriers of 16p11.2 deletion from multi-center cohorts, among which we retrospectively ascertained kidney morphologic and functional data from 37 individuals (12 Chinese and 25 Caucasian/Hispanic). Significantly higher CAKUT rates were observed in 16p11.2 deletion carriers (about 25% in Chinese and 16% in Caucasian/Hispanic) than those found in the non-clinically ascertained general populations (about 1/1000 found at autopsy). Furthermore, we identified seven additional individuals with heterozygous loss-of-function variants in TBX6, a gene that maps to the 16p11.2 region. Four of these seven cases showed obvious CAKUT. To further investigate the role of TBX6 in kidney development, we engineered mice with mutated Tbx6 alleles. The Tbx6 heterozygous null (i.e., loss-of-function) mutant (Tbx6+/‒) resulted in 13% solitary kidneys. Remarkably, this incidence increased to 29% in a compound heterozygous model (Tbx6mh/‒) that reduced Tbx6 gene dosage to below haploinsufficiency, by combining the null allele with a novel mild hypomorphic allele (mh). Renal hypoplasia was also frequently observed in these Tbx6-mutated mouse models. Thus, our findings in patients and mice establish TBX6 as a novel gene involved in CAKUT and its gene dosage insufficiency as a potential driver for kidney defects observed in the 16p11.2 microdeletion syndrome.

6.
Hum Mutat ; 41(1): 182-195, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31471994

RESUMO

Congenital scoliosis (CS) is a birth defect with variable clinical and anatomical manifestations due to spinal malformation. The genetic etiology underlying about 10% of CS cases in the Chinese population is compound inheritance by which the gene dosage is reduced below that of haploinsufficiency. In this genetic model, the trait manifests as a result of the combined effect of a rare variant and common pathogenic variant allele at a locus. From exome sequencing (ES) data of 523 patients in Asia and two patients in Texas, we identified six TBX6 gene-disruptive variants from 11 unrelated CS patients via ES and in vitro functional testing. The in trans mild hypomorphic allele was identified in 10 of the 11 subjects; as anticipated these 10 shared a similar spinal deformity of hemivertebrae. The remaining case has a homozygous variant in TBX6 (c.418C>T) and presents a more severe spinal deformity phenotype. We found decreased transcriptional activity and abnormal cellular localization as the molecular mechanisms for TBX6 missense loss-of-function alleles. Expanding the mutational spectrum of TBX6 pathogenic alleles enabled an increased molecular diagnostic detection rate, provided further evidence for the gene dosage-dependent genetic model underlying CS, and refined clinical classification.

7.
Clin Exp Rheumatol ; 38(1): 35-41, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31025928

RESUMO

OBJECTIVES: SAPHO syndrome is a rare inflammatory disorder with multiple phenotypes, including synovitis, acne, pustulosis, hyperostosis, and osteitis. IgG4 is a subclass of immunoglobulin G, and the elevation of IgG4 has been found in different autoimmune diseases. In the present study, we explored the clinical significance of serum IgG4 levels in patients with SAPHO syndrome. METHODS: Fifty-two patients who met the classification criteria of SAPHO syndrome were included in this study. Clinical data and disease activity markers were collected including erythrocyte sedimentation rate (ESR), high sensitivity C-reactive protein (hsCRP), pain visual analogue scale (VAS), Bath Ankylosing Spondylitis Metrology Index (BASMI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and Ankylosing Spondylitis Disease Activity Score (ASDAS). Serum immunoglobin (IgA, IgM, and IgG) and IgG subclass (IgG1, IgG2, IgG3, and IgG4) levels were determined using the immunonephelometric assay. RESULTS: Raised serum IgG4 levels (>1400 mg/dL) were detected in 23% (12/52) of patients. Patients with elevated sIgG4 levels had significantly higher pain VAS (5.42±2.76 vs. 3.08±1.78, p=0.02), BASMI (1.80±1.64 vs. 0.38±0.94, p=0.03) and ASDAS (3.20±0.65 vs. 1.74±0.58, p<0.001) levels compared with patients with normal sIgG4 levels. This difference was also observed for ESR (38.2 vs. 22.2 mm/h, p=0.01) and serum CRP (21.0 vs. 2.2 mg/L, p=0.04) levels, which also positively correlated with sIgG4 levels. We also included 4 patients whose IgG4 levels decreased and correlated with the decrease in hsCRP and ESR levels after treatment. CONCLUSIONS: Elevated sIgG4 levels are common in patients with SAPHO syndrome and are associated with high disease activity. Further investigations are needed for this phenomenon.


Assuntos
Síndrome de Hiperostose Adquirida , Imunoglobulina G , Espondilite Anquilosante , Síndrome de Hiperostose Adquirida/sangue , Síndrome de Hiperostose Adquirida/diagnóstico , Síndrome de Hiperostose Adquirida/imunologia , Biomarcadores/sangue , Sedimentação Sanguínea , Proteína C-Reativa , Humanos , Imunoglobulina G/sangue , Índice de Gravidade de Doença
8.
Mol Genet Genomic Med ; 8(1): e1023, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31774634

RESUMO

BACKGROUND: The molecular and genetic mechanisms by which different single nucleotide variant alleles in specific genes, or at the same genetic locus, cause distinct disease phenotypes often remain unclear. Allelic truncating mutations of FBN1 could cause either classical Marfan syndrome (MFS) or a more complicated phenotype associated with Marfanoid-progeroid-lipodystrophy syndrome (MPLS). METHODS: We investigated a small cohort, encompassing two classical MFS and one MPLS subjects from China, whose clinical presentation included scoliosis potentially requiring surgical intervention. Targeted next generation sequencing was performed on all the participants. We analyzed the molecular diagnosis, clinical features, and the potential molecular mechanism involved in the MPLS subject in our cohort. RESULTS: We report a novel de novo FBN1 mutation for the first Chinese subject with MPLS, a more complicated fibrillinopathy, and two subjects with more classical MFS. We further predict that the MPLS truncating mutation, and others previously reported, is prone to escape the nonsense-mediated decay (NMD), while MFS mutations are predicted to be subjected to NMD. Also, the MPLS mutation occurs within the glucogenic hormone asprosin domain of FBN1. In vitro experiments showed that the single MPLS mutation p.Glu2759Cysfs*9 appears to perturb proper FBN1 protein aggregation as compared with the classical MFS mutation p.Tyr2596Thrfs*86. Both mutations appear to upregulate SMAD2 phosphorylation in vitro. CONCLUSION: We provide direct evidence that a dominant-negative interaction of FBN1 potentially explains the complex MPLS phenotypes through genetic and functional analysis. Our study expands the mutation spectrum of FBN1 and highlights the potential molecular mechanism for MPLS.

9.
J Hum Genet ; 65(3): 221-230, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31827250

RESUMO

Congenital scoliosis (CS) is a form of scoliosis caused by congenital vertebral malformations. Genetic predisposition has been demonstrated in CS. We previously reported that TBX6 loss-of-function causes CS in a compound heterozygous model; however, this model can explain only 10% of CS. Many monogenic and polygenic CS genes remain to be elucidated. In this study, we analyzed exome sequencing (ES) data of 615 Chinese CS from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) project. Cosegregation studies for 103 familial CS identified a novel heterozygous nonsense variant, c.2649G>A (p.Trp883Ter) in FBN1. The association between FBN1 and CS was then analyzed by extracting FBN1 variants from ES data of 574 sporadic CS and 828 controls; 30 novel variants were identified and prioritized for further analyses. A mutational burden test showed that the deleterious FBN1 variants were significantly enriched in CS subjects (OR = 3.9, P = 0.03 by Fisher's exact test). One missense variant, c.2613A>C (p.Leu871Phe) was recurrent in two unrelated CS subjects, and in vitro functional experiments for the variant suggest that FBN1 may contribute to CS by upregulating the transforming growth factor beta (TGF-ß) signaling. Our study expanded the phenotypic spectrum of FBN1, and provided nove insights into the genetic etiology of CS.


Assuntos
Anormalidades Congênitas/genética , Fibrilina-1/genética , Predisposição Genética para Doença , Escoliose/genética , Criança , Pré-Escolar , Códon sem Sentido/genética , Anormalidades Congênitas/diagnóstico por imagem , Anormalidades Congênitas/fisiopatologia , Exoma/genética , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Mutação , Mutação de Sentido Incorreto/genética , Linhagem , Escoliose/diagnóstico por imagem , Escoliose/fisiopatologia , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/fisiopatologia , Fator de Crescimento Transformador beta/genética
10.
J Food Biochem ; 43(2): e12708, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31353662

RESUMO

This study investigated the effect of a hawthorn polyphenol extract (HPE) on ultraviolet B (UVB)-induced damage in HaCaT cells and mice. High-performance liquid chromatography/electrospray ionization tandem mass spectrometry was used to analyze the phenolic composition of HPE. The protective effects of HPE and its main components were compared in HaCaT cells. An enzyme-linked immunosorbent assay was used to detect DNA damage (8-hydroxydeoxyguanosine levels). Flow cytometry and western blotting were used to measure the extent of apoptosis and the levels of apoptosis-related proteins, respectively. Treatment with HPE or its polyphenol components inhibited the UVB-induced damage by removing an excess of reactive oxygen species (ROS), reducing DNA damage and p53 activation, regulating the protein expression of B-cell lymphoma 2 family members toward antiapoptotic ratios, and reducing caspase activation. Similar effects were observed in a UVB-irradiated mouse skin, as detected using terminal deoxynucleotidyl transferase dUTP nick-end labeling, immunohistochemistry, and western blotting assays. These results suggest that HPE can be used as a natural dietary supplement for the prevention and treatment of UVB radiation-induced skin damage. PRACTICAL APPLICATIONS: Hawthorn (Crataegus pinnatifida) shows antioxidant, anti-inflammatory, and lipid-lowering effects. As natural, healthy, and effective additives, HPEs have been widely used in food and health products. The results of this study reveal the molecular mechanisms underlying HPE effects, showing that HPE reverses the effects of UVB irradiation via removal of an excess of ROS and reduction of DNA damage and p53 expression in vitro and in vivo. Consequently, HPE upregulates the expression of antiapoptotic BCL-2 and downregulates that of proapoptotic BAX, thereby reducing the activation of caspase-3/9 and inhibiting apoptosis. These findings suggest that HPE can be used as the base ingredient for antiphotoaging food products. This study provides both theoretical and experimental background for hawthorn deep processing and utilization.


Assuntos
Crataegus/química , Mitocôndrias/metabolismo , Extratos Vegetais/administração & dosagem , Polifenóis/administração & dosagem , Envelhecimento da Pele/efeitos da radiação , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Feminino , Frutas/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/efeitos da radiação , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Envelhecimento da Pele/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Raios Ultravioleta/efeitos adversos
11.
J Agric Food Chem ; 67(25): 7157-7166, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31146527

RESUMO

Lonicera caerulea berry polyphenols (LCBP) are known to reduce cholesterol accumulation. Currently, it is unknown whether LCBP can activate Sirtuin 1 (SIRT1) to regulate the formation of RAW264.7 macrophage foam cells. In this study, the effect of LCBP on lipid accumulation in macrophages was evaluated. Fluorescently labeled ox-LDL and 25-NBD cholesterol were used to detect the ox-LDL uptake and cholesterol outflow rate from macrophages. Gene silencing was performed using siRNA to detect changes in the expression of the ATP-binding cassette transporter A1 (ABCA1), sterol regulatory element-binding protein 2 (SREBP2), and SIRT1 proteins using Western blotting, and changes in the expression of miR-33 were detected by real-time polymerase chain reaction. The results showed that treatment with 80 µg/mL LCBP significantly inhibited the accumulation of lipids in RAW264.7 macrophages induced by ox-LDL and reduced intracellular cholesterol levels by activating SIRT1 to enhance the expression of ABCA1, a cholesterol efflux gene, but not independent effect. Of the three key LCBP components investigated, chlorogenic acid was found to activate SIRT1 and regulate the expression of the cholesterol-related factors ABCA1, SREBP2, and miR-33; cyanidin-3-glucoside and catechins were effective to a lesser extent. Our results suggest a novel hypolipidemic mechanism of LCBP.


Assuntos
Colesterol/metabolismo , Células Espumosas/efeitos dos fármacos , Lonicera/química , Macrófagos/efeitos dos fármacos , Polifenóis/farmacologia , Sirtuína 1/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Células Espumosas/metabolismo , Frutas/química , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Camundongos , Células RAW 264.7 , Sirtuína 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
12.
Clin Exp Rheumatol ; 37(4): 663-669, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30767869

RESUMO

OBJECTIVES: To evaluate the clinical efficacy of bisphosphonates treatment for spinal bone marrow oedema (BME) in patients with synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. METHODS: SAPHO syndrome patients presenting to Peking Union Medical College Hospital from 2015 to 2016 were recruited. Patients were administered pamidronate disodium 1 mg/kg/d intravenously, for 3 days, at baseline and 3 months later. The symptoms were evaluated using the Visual Analog Score (VAS) for pain, and other clinical measures including, spinal BME scores, ß-crosslaps, osteocalcin, and inflammatory factors, were collected. RESULTS: A total of 30 patients (20 women and 10 men) with a median age of 47.2 (interquartile range 8.8) years were recruited. In a short time, the patients showed a significant decrease in VAS (before vs. after; first treatment: 5.70±1.62 vs. 2.30±1.29 cm, second treatment: 4.03±1.88 vs. 2.17±1.23 cm) and ß-crosslaps (first treatment: 0.4441±0.1923 vs. 0.0859±0.0374 pg/ml, second treatment: 0.2891±0.1983 vs. 0.0962±0.0324 pg/ml) (all p<0.05). At 12-month follow-up, compared with the baseline, we noticed a significant drop in the VAS (5.70±1.62 vs. 2.43±1.25 cm), erythrocyte sedimentation rate (28.87±25.26 vs. 18.00±18.65 mm/h), high-sensitivity C-reactive protein level (11.76±10.19 vs. 5.84±5.88 mg/L), osteocalcin (2.30±1.27 vs. 1.65±0.80 ng/ml), and BME (30.50±24.09 vs. 22.13±27.79) (all p<0.05). No one had serious adverse events. CONCLUSIONS: Bisphosphonates can significantly and rapidly relieve symptoms in patients with SAPHO syndrome and have a long-term effect on inflammation and spinal BME. We suggest that bisphosphonates could be used as the first-line therapeutic drug for SAPHO syndrome, especially in patients with spinal BME.


Assuntos
Síndrome de Hiperostose Adquirida , Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Acne Vulgar , Síndrome de Hiperostose Adquirida/tratamento farmacológico , Feminino , Humanos , Hiperostose , Masculino , Pessoa de Meia-Idade , Osteíte , Estudos Prospectivos , Sinovite , Resultado do Tratamento
13.
Rheumatology (Oxford) ; 58(6): 1047-1055, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30624750

RESUMO

OBJECTIVES: To explore the patterns of osteoarticular involvement in SAPHO syndrome. METHODS: Baseline clinical characteristics and imaging data of 99mTc-MDP whole-body bone scintigraphy (WBBS) were collected from 157 out of 164 patients diagnosed with SAPHO syndrome. The twelve most frequently involved osteoarticular sites were analysed by hierarchical cluster analysis with the Ward minimum-variance method. RESULTS: Three distinctive patterns of osteoarticular involvement were identified: the spinal type (70 patients, 44.6%), with predominantly thoracic, lumbar or sacral vertebral lesions; the costal type (52 patients, 33.1%), with lesions of anterior ribs, particularly the first ribs; and the sternoclavicular type (35 patients, 22.3%), with predominantly sternal and bilateral sternoclavicular lesions, characterized by the typical bullhead sign. Notably, a total of 77 (49%) patients exhibited lesions of ribs on WBBS, of which 61.3% involved the first ribs. Interestingly, patients of spinal type were older at onset of cutaneous manifestations than those of sternoclavicular type (P = 0.036) and costal type (P = 0.035). The disease course was remarkably longer in sternoclavicular type than costal type (P = 0.001) and spinal type (P < 0.001). CONCLUSION: The osteoarticular involvement in SAPHO syndrome can be categorized as three distinct patterns with different corresponding clinical features. The costal involvement in SAPHO syndrome, which was under-recognized previously, may define a distinct sub-type of the disease.


Assuntos
Síndrome de Hiperostose Adquirida/diagnóstico por imagem , Osso e Ossos/diagnóstico por imagem , Cintilografia , Imagem Corporal Total/métodos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
Genet Med ; 21(7): 1548-1558, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30636772

RESUMO

PURPOSE: To characterize clinically measurable endophenotypes, implicating the TBX6 compound inheritance model. METHODS: Patients with congenital scoliosis (CS) from China(N = 345, cohort 1), Japan (N = 142, cohort 2), and the United States (N = 10, cohort 3) were studied. Clinically measurable endophenotypes were compared according to the TBX6 genotypes. A mouse model for Tbx6 compound inheritance (N = 52) was investigated by micro computed tomography (micro-CT). A clinical diagnostic algorithm (TACScore) was developed to assist in clinical recognition of TBX6-associated CS (TACS). RESULTS: In cohort 1, TACS patients (N = 33) were significantly younger at onset than the remaining CS patients (P = 0.02), presented with one or more hemivertebrae/butterfly vertebrae (P = 4.9 × 10‒8), and exhibited vertebral malformations involving the lower part of the spine (T8-S5, P = 4.4 × 10‒3); observations were confirmed in two replication cohorts. Simple rib anomalies were prevalent in TACS patients (P = 3.1 × 10‒7), while intraspinal anomalies were uncommon (P = 7.0 × 10‒7). A clinically usable TACScore was developed with an area under the curve (AUC) of 0.9 (P = 1.6 × 10‒15). A Tbx6-/mh (mild-hypomorphic) mouse model supported that a gene dosage effect underlies the TACS phenotype. CONCLUSION: TACS is a clinically distinguishable entity with consistent clinically measurable endophenotypes. The type and distribution of vertebral column abnormalities in TBX6/Tbx6 compound inheritance implicate subtle perturbations in gene dosage as a cause of spine developmental birth defects responsible for about 10% of CS.


Assuntos
Dosagem de Genes , Padrões de Herança , Escoliose/congênito , Escoliose/genética , Proteínas com Domínio T/genética , Animais , Estudos de Coortes , Modelos Animais de Doenças , Humanos , Camundongos , Modelos Genéticos , Escoliose/classificação , Escoliose/patologia , Coluna Vertebral/patologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-31921798

RESUMO

Background: Adolescent idiopathic scoliosis (AIS) is a complex disease affecting a large number of teenagers, especially in female. This study reveals novel epigenetic perturbation to the pathogenesis of AIS. Methods: A female monozygotic (MZ) twin pair discordant for AIS were examined for whole-exome sequencing and epigenome difference. Sets of differentially methylated regions (DMRs) were validated using MethylTarget™ method in 20 AIS female patients and 20 healthy female controls. Results: Few exome difference but several potential DMRs were found between the MZ twins. We identified 313 hypermethylated DMRs and 397 hypomethylated DMRs, respectively. Most of them were enriched in the MAPK and PI3K-Akt signaling pathway, which may contribute to the discordance of AIS. Several DMRs related to scoliosis genes were tested, and the NDN: TSS-DMR (chr15:23932133-23932304, hg19) was confirmed in additional samples. The methylation level of this DMR was significantly higher in the AIS group than in the control group (p = 0.04). Conclusions: We described the epigenome difference in an AIS female discordant MZ twin pair using Whole Genome Bisulfite Sequencing (WGBS). The NDN: TSS-DMR had higher methylation level in female AIS, which can help elucidate the potential etiology of AIS.

16.
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
17.
Hum Mol Genet ; 28(4): 539-547, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30307510

RESUMO

Congenital vertebral malformations (CVMs) are associated with human TBX6 compound inheritance that combines a rare null allele and a common hypomorphic allele at the TBX6 locus. Our previous in vitro evidence suggested that this compound inheritance resulted in a TBX6 gene dosage of less than haploinsufficiency (i.e. <50%) as a potential mechanism of TBX6-associated CVMs. To further investigate this pathogenetic model, we ascertained and collected 108 Chinese CVM cases and found that 10 (9.3%) of them carried TBX6 null mutations in combination with common hypomorphic variants at the second TBX6 allele. For in vivo functional verification and genetic analysis of TBX6 compound inheritance, we generated both null and hypomorphic mutations in mouse Tbx6 using the CRISPR-Cas9 method. These Tbx6 mutants are not identical to the patient variants at the DNA sequence level, but instead functionally mimic disease-associated TBX6 variants. Intriguingly, as anticipated by the compound inheritance model, a high penetrance of CVM phenotype was only observed in the mice with combined null and hypomorphic alleles of Tbx6. These findings are consistent with our experimental observations in humans and supported the dosage effect of TBX6 in CVM etiology. In conclusion, our findings in the newly collected human CVM subjects and Tbx6 mouse models consistently support the contention that TBX6 compound inheritance causes CVMs, potentially via a gene dosage-dependent mechanism. Furthermore, mouse Tbx6 mutants mimicking human CVM-associated variants will be useful models for further mechanistic investigations of CVM pathogenesis in the cases associated with TBX6.


Assuntos
Anormalidades Congênitas/genética , Escoliose/genética , Coluna Vertebral/anormalidades , Proteínas com Domínio T/genética , Adolescente , Alelos , Animais , Sistemas CRISPR-Cas/genética , Criança , Pré-Escolar , Anormalidades Congênitas/diagnóstico por imagem , Anormalidades Congênitas/fisiopatologia , Modelos Animais de Doenças , Feminino , Haploinsuficiência , Humanos , Lactente , Masculino , Camundongos , Mutação , Fenótipo , Escoliose/diagnóstico por imagem , Escoliose/fisiopatologia , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/fisiopatologia
18.
Hum Genet ; 137(6-7): 553-567, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30019117

RESUMO

With the recent advance in genome-wide association studies (GWAS), disease-associated single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) have been extensively reported. Accordingly, the issue of incorrect identification of recombination events that can induce the distortion of multi-allelic or hemizygous variants has received more attention. However, the potential distorted calculation bias or significance of a detected association in a GWAS due to the coexistence of CNVs and SNPs in the same genomic region may remain under-recognized. Here we performed the association study within a congenital scoliosis (CS) cohort whose genetic etiology was recently elucidated as a compound inheritance model, including mostly one rare variant deletion CNV null allele and one common variant non-coding hypomorphic haplotype of the TBX6 gene. We demonstrated that the existence of a deletion in TBX6 led to an overestimation of the contribution of the SNPs on the hypomorphic allele. Furthermore, we generalized a model to explain the calculation bias, or distorted significance calculation for an association study, that can be 'induced' by CNVs at a locus. Meanwhile, overlapping between the disease-associated SNPs from published GWAS and common CNVs (overlap 10%) and pathogenic/likely pathogenic CNVs (overlap 99.69%) was significantly higher than the random distribution (p < 1 × 10-6 and p = 0.034, respectively), indicating that such co-existence of CNV and SNV alleles might generally influence data interpretation and potential outcomes of a GWAS. We also verified and assessed the influence of colocalizing CNVs to the detection sensitivity of disease-associated SNP variant alleles in another adolescent idiopathic scoliosis (AIS) genome-wide association study. We proposed that detecting co-existent CNVs when evaluating the association signals between SNPs and disease traits could improve genetic model analyses and better integrate GWAS with robust Mendelian principles.


Assuntos
Anormalidades Congênitas/genética , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença , Escoliose/genética , Adolescente , Anormalidades Congênitas/fisiopatologia , Feminino , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Genômica , Genótipo , Haplótipos/genética , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Escoliose/fisiopatologia
19.
J Agric Food Chem ; 66(32): 8537-8546, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30032605

RESUMO

Ultraviolet (UV) B radiation can cause skin aging by increasing matrix metalloproteinase (MMP) production and collagen degradation, leading to the formation of wrinkles. This study investigated whether hawthorn polyphenol extract (HPE) protects against UVB-induced skin photoaging using HaCaT human keratinocytes, normal human dermal fibroblasts (HDFs), and mice. Analysis of the phenol composition of HPE by high-performance liquid chromatography-mass spectrometry showed that chlorogenic acid (13.5%), procyanidin B2 (19.2%), and epicatechin (18.8%) collectively accounted for 51.4% of total phenol content and represent the active ingredients of hawthorn fruit. A cell viability assay revealed that HPE treatment promoted cell proliferation in HaCaT cells and HDFs. On the other hand, MMP-1 and type I procollagen production was decreased and increased, respectively, in UVB-exposed cells treated with HPE as compared with those without treatment, as determined by enzyme-linked immunosorbent assay. Hematoxylin and eosin and Weigert staining of dermal tissue specimens from mice demonstrated that HPE also reversed UVB-induced epidermal thickening and dermal damage. The increase in production of reactive oxygen species and decrease in antioxidant enzyme activity as well as the increase in nuclear factor-κB activation and mitogen-activated protein kinase phosphorylation induced by UVB irradiation were reversed by HPE (100 or 300 mg/kg body weight), which also suppressed MMP expression and stimulated the production of type I procollagen in the dorsal skin of UVB-irradiated mice. These results suggest that HPE is a natural product that can prevent UVB radiation-induced skin photoaging.


Assuntos
Colágeno Tipo I/metabolismo , Crataegus/química , Metaloproteinase 1 da Matriz/metabolismo , Extratos Vegetais/administração & dosagem , Polifenóis/administração & dosagem , Envelhecimento da Pele/efeitos dos fármacos , Envelhecimento da Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Animais , Colágeno Tipo I/genética , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Metaloproteinase 1 da Matriz/genética , Camundongos , Camundongos Pelados , Camundongos Endogâmicos BALB C , Pró-Colágeno/genética , Pró-Colágeno/metabolismo , Pele/efeitos dos fármacos , Pele/enzimologia , Pele/metabolismo , Pele/efeitos da radiação , Envelhecimento da Pele/genética
20.
J Cell Mol Med ; 22(1): 533-545, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28944995

RESUMO

Congenital scoliosis (CS) is a three-dimensional deformity of the spine affecting quality of life. We have demonstrated TBX6 haploinsufficiency is the most important contributor to CS. However, the pathophysiology at the protein level remains unclear. Therefore, this study was to explore the differential proteome in serum of CS patients with TBX6 haploinsufficiency. Sera from nine CS patients with TBX6 haploinsufficiency and nine age- and gender-matched healthy controls were collected and analysed by isobaric tagged relative and absolute quantification (iTRAQ) labelling coupled with mass spectrometry (MS). In total, 277 proteins were detected and 20 proteins were designated as differentially expressed proteins, which were submitted to subsequent bioinformatics analysis. Gene Ontology classification analysis showed the biological process was primarily related to 'cellular process', molecular function 'structural molecule activity' and cellular component 'extracellular region'. IPA analysis revealed 'LXR/RXR activation' was the top pathway, which is a crucial pathway in lipid metabolism. Hierarchical clustering analysis generated two clusters. In summary, this study is the first proteomic research to delineate the total and differential serum proteins in TBX6 haploinsufficiency-caused CS. The proteins discovered in this experiment may serve as potential biomarkers for CS, and lipid metabolism might play important roles in the pathogenesis of CS.


Assuntos
Haploinsuficiência/genética , Metabolismo dos Lipídeos/genética , Proteoma/metabolismo , Escoliose/sangue , Escoliose/congênito , Proteínas com Domínio T/metabolismo , Estudos de Casos e Controles , Análise por Conglomerados , Ontologia Genética , Humanos , Escoliose/genética
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