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The mutations of TTN gene that encodes titin are the most common mutation type among the genetic causes of dilated cardiomyopathy (DCM). This article reviews the worldwide studies on potential molecular pathogenesis (transcription, post-translational modification, etc.), clinical phenotypes, and gene therapies of pediatric DCM caused by TTN mutations, with the hope of providing a reference for the precision treatment of pediatric DCM caused by TTN mutations.
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Humans , Cardiomyopathy, Dilated/therapy , Connectin/genetics , Genetic Therapy , Mutation , PhenotypeABSTRACT
Las encefalitis autoinmunes son una condición emergente, caracterizada por la aparición repentina de síntomas psicóticos o depresivos "de novo", crisis convulsivas o estatus epiléptico refractario, o demencia rápidamente progresiva. Las encefalitis autoinmunes están asociadas a diversos fenómenos desencadenantes, como infecciones virales previas entre las más comunes, y se asocian con la presencia de anticuerpos antineuronales y/o onconeuronales, que deben estudiarse ante la sospecha de esta entidad. Es muy importante desarrollar un diagnóstico presuntivo y precoz, ya que la terapia con inmunosupresores como los corticoides -iniciados en el momento oportuno-, puede cambiar su evolución hacia la mejoría clínica. Presentamos un paciente con encefalitis autoinmunes y anticuerpos anti-Titina positivos (habitualmente presentes en timoma y miastenia gravis), no asociados a neoplasia conocida y con buena respuesta a esteroides.
Autoimmune Encephalitis, are an emerging condition, characterized by the sudden onset of psychotic or depressive symptoms "de novo", refractory seizures or epilepsy, or rapidly progressive dementias. The autoimmune encephalitis are associated to various triggered phenomena as a previous viral infections among others; it's related to the presence of antineuronal and/or onconeuronal antibodies, and there must be studied when autoimmune encephalitis is suspected. It is very important to develop a presumptive and early diagnosis, since steroid therapy -on opportunity time- can change its evolution towards clinical improvement. We present a patient with autoimmune encephalitis, and positive anti-Titin antibodies (usually presents in thymoma and myasthenia gravis) not associated with known neoplasia, and with a good response to steroids.
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The objective of this study was to investigate the expression profile of the myozenin2 (MYOZ2) gene and elucidate its effect on adipogenic differentiation of C3H10T1 / 2 cells and its possible mechanism∙ The longissimus dorsi‚ subcutaneous fat and liver tissue was collected from 180-day-old Mashen pigs‚ 60-day-old ICR mice‚ 35-day-old Ross broiler and 12-month-old Small tail han sheep‚ and the expression profile of the MYOZ2 gene mRNA was detected∙ The results showed that the MYOZ2 gene has similar patterns of tissue expression in examined species‚ with the highest expression level in longissimus dorsi‚ and a small amount of expression in the subcutaneous fat and liver tissue∙ After the MYOZ2 gene was silenced in C3H10T1 / 2 cells‚ qRT-PCR results showed that the expression levels of key adipogenic genes PPARγ and FABP4 were significantly down-regulated compared with the control group (P < 0∙ 01) ; Western Blotting results showed that the PPARγ protein content was significantly decreased (P < 0∙ 05) ; Oil red O staining showed that the number of lipid droplets and the content of triglyceride were significantly decreased after silencing MYOZ2 (P < 0∙ 05) ∙ The expression of fatty acid metabolism related genes SCD‚ FASN‚ SREBP1‚ NR1H3‚ DGAT1‚ PNPLA2‚ HSL‚ CES1‚ CPT1 after MYOZ2 silencing were detected by qRT-PCR∙ The results showed that SCD‚ FASN‚ SREBP1‚ PNPLA2 and HSL were significantly down-regulated (P < 0∙ 01) ‚ NR1H3 was significantly reduced (P < 0∙ 05) ‚ DGAT1 expression was down-regulated but the difference was not significant‚ CES1 and CPT1 were significantly up-regulated (P < 0∙ 05) ∙ The STRING database was used to construct a MYOZ2-related protein interaction network map‚ and it was found that MYOZ2 may affect the adipogenic differentiation through the interaction of titin-cap (TCAP) and PPARγ∙ After silencing TCAP‚ qRT-PCR results showed that compared with the control group‚ the expression of key adipogenic genes PPARγ and FABP4 were significantly up-regulated (P < 0∙ 01) ; Western Blotting results showed that PPARγ protein was significantly increased (P< 0∙ 05) ; Oil red O staining showed that the number of lipid droplets and the content of triglyceride were significantly increased after TCAP silencing (P < 0∙ 05) ∙ qRT-PCR was used to detect the expression of TCAP after silencing MYOZ2‚ and the results showed that the expression of TCAP was significantly increased (P<0∙ 01) ∙ In summary‚ MYOZ2 was highly expressed in longissimus dorsi and lower expressed in subcutaneous fat and liver tissues∙ In addition‚ MYOZ2 may regulate the expression of key adipogenic genes PPARγ and FABP4 through the interaction of MYOZ2-TCAP -PPARγ‚ and to further regulate the expression of fatty acid metabolism related genes SCD‚ FASN‚ SREBP1‚ NR1H3‚ DGAT1‚ PNPLA2‚ HSL‚ CES1 and CPT1‚ thus playing an important role in the process of adipogenic differentiation∙
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@#[Abstract] Objective：To study the expression of long non-coding RNA(lncRNA) titin antisense RNA1 (TTN-AS1) in lung adenocarcinoma (LUAD) tissues, and explore its relationship with clinicopathologic characteristics and prognosis of LUAD patients. Methods: The TTN-AS1 expression in LUAD data set was analyzed using TCGAdatabase. 52 pairs of tumor tissues and matched para-carcinoma tissues from LUAD patients, who underwent surgical resection and were later pathologically conformed in Fourth Hospital of Hebei Medical University between Jan. 2014 and Jan. 2015, were used in this study. qPCR was performed to detect TTN-AS1 expression in the specimens. Then, the correlations between TTN-AS1 expression and clinicopathologic characteristics were analyzed. Survival analysis was used to determine the significance of TTN-AS1 expression for predicting the prognosis of LUAD patients. Results: TCGAdatabase analysis and qPCR results showed that TTN-AS1 expression in LUAD tissues was significantly higher than that in normal lung and para-carcinoma tissues (both P<0.01). TTN-AS1 expression in LUAD tissues was significantly correlated with the TNM stage and lymph node metastasis (P<0.05), but not correlated with gender, age, tumor invasion range (P>0.05). Kaplan-Meier univariate analysis result demonstrated that the patients with high TTN-AS1 expression had shorter post-operative disease-free survival (DFS) and overall survival (OS) than those patients with low TTN-AS1 expression (all P<0.01). Cox proportional hazard regression model result demonstrated that wider tumor invasion range, positive lymph node metastasis and high TTN-AS1 expression were significantly correlated with shorter postoperative DFS and OS (P<0.05). Conclusion: TTN-AS1 was highly expressed in LUAD tissues, and closely correlated with TNM stage and lymph node metastasis of LUAD patients (all P<0.05). High expression of TTN-AS1 is significantly correlated with shorter DFS and OS, indicating that TTN-AS1 may be a biomarker for predicting poor prognosis of LUAD patients.
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Cardiomyopathy is a heterogeneous heart disease characterized by abnormalities in myocardial structure and function, which ultimately leads to heart failure even death. RNA-binding motif protein 20 (RBM 20) is a family of serine/arginine-rich proteins, highly expressed in heart. It plays an important role in the assembly and alternative splicing of RNA spliceosome, and participates in the development of cardiomyopathy. RBM 20 regulates the alternative splicing of Titin, RyR 2, LDB 3, CaMKIIô, CACNA1C involved in diastolic function, sarcomere assembly and ion transport. In this review, the role of RBM 20 in cardiomyopathy and the regulatory mechanisms of RBM 20 is summarized.
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Dilated cardiomyopathy (DCM) is the most common type of childhood myocardial disease in the clinic.It is mainly characterized by left ventricular or biventricular enlargement and myocardial contractile dysfunction,often accompanied by various arrhythmias.DCM is insidious and has a high rate of sudden death.At present,there is no alternative option to heart transplantation,thus DCM seriously threatens the life and health of children.With the rapid development of bioinformatics,second-generation sequencing and data mining are widely used in DCM diagnosis and treatment.Many sarcomere gene mutations such as MYH7,TNNT2,TTN,have attracted wide attention during the development of DCM.In this paper,the research results of sarcomere gene mutation and DCM in recent years are summarized,and the function of the corresponding gene and its effect on the heart are discussed.This review describes the specific mechanism of DCM gene mutation leading to DCM,which provides a reference for future DCM precision medicine.
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Aim To observe the changes of diaphragm contractility and cytoskeletal proteins titin,nebulin and sarcoplasmic reticulum Ca~(2+)-ATPase gene expressions in adriamycin-induced cytotoxicity in rats.Methods The animal models of diaphragm damage were duplicated by injecting adriamycin into abdominal cavity one time.Forty male sprague-dawley rats were randomly divided into four groups(n=10):Three groups received adriamycin in low,middle and high dosage(10,20 and 40 mg·kg~(-1))respectively.Meanwhile,the normal saline was given to rats in control groups.Three days later,these rats were killed,and the diaphragm was removed by thoracotomy.The diaphragm contractility was assessed in isolated diaphragm strips perfusion by these paramemters including peak twitch tension(Pt),maximum tetanic tension(Po),time to peak contraction(CT),half relaxaion time(1/2RT),maximal rates of contraction(+dt/dt_(max))and maximal rates of relaxation(-dt/dt_(max)).The expressions of titin,nebulin and sarcoplasmic reticulum Ca~(2+)-ATPase(SERCA)at mRNA level were detected by RT-PCR analysis.Results In contrast to those in control group,Po,Pt,±dt/dt_(max) in the adriamycin group were lower(P<0.01);CT,1/2RT in the adriamycin group increased significantly(P<0.01).The levels of titin,nebulin and SERCA gene expressions in middle-dose group were lower than those in control group(P<0.01).Conclusions The mRNA levels of titin,nebulin and SERCA of diaphragm are down-regulated in adriamycin-induced cytotoxicity in rats.It may be associated with the decline of diaphragm contractility.
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Objective To investigate the removal effect of immunoadsorption (IA) on associated antibodies and the efficacy in late-onset myasthenia gravis (MG). Methods A total of 25 late-onset MG patients were randomly selected to enroll in this study. IA therapy was given to 10 patients (IA group), while immunoglobin (0.4 g·kg-1·d-1) was administrated to the other 15 patients for 5 days(Ig group). The titers of Titin antibody (Titin-ab), acetylcholine receptor antibody (AchR-ab) and presynaptic membrane antibody (PrsmR-ab) were detected before and after the treatment. Quantitive MG (QMG) score was assessed before and immediately after the entire course of treatment. The clinical efficacy, the duration of respiratory support and in-hospital were compared between two groups. The correlation between three antibodies and QMG score was also analyzed. Results Compared with that before treatment, the Titin-ab PIN values, the AchR-ab PIN values, and the PrsmR-ab P/N values of IA group were all decreased significantly after treatment (P<0.05, respectively). The P/N value of Titin-ab in IA group was decreased by 54.7%～3.5%, which was significantly higher than that in Ig group(19.9%±3.1%) (P<0.01). QMG score reduced by 42.4%± 4.2% and 23.8%±3.7% in IA group and Ig group respectively (P<0.01, respectively). Symptoms were effectively ameliorated by both treatments, but the effective power of IA group was higher than that of Ig group (70% vs 40%, P<0.05). Remission time of IA group was significantly shorter than that of Ig group [(5.38±0.42) d vs (8.4±1.54) d, P=0.008), so was the duration of in-hospital [(13.50±0.50) d vs (16.50±0.50) d, P<0.05). The number of respiratory support in IA group was less than that in Ig group (1/10 vs 6/15, P<0.05). By the Pearson correlation analysis, the decrease of Titin-ab showed a better longitudinal correlation with the decrease of QMG score than the other two antibodies (r=0.6315, P<0.01). Conclusion IA can rapidly and effectively clear the pathogenic antibodies of late-onset MG patients and its short-term clinical efficacy is better than immunoglobin.
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Objective:To investigate the effect of the titin gene and its influence on the contraction protein gene such as ?-MHC and cTnI in the procession of MSCs differentiating into cardiomyocytes in vitro.Methods:MSCs were isolated from bilateral thighbones and tibias of Wistar rats,purified、expanded and then exposed to 5-aza.we observed the morphology of MSCs with phase-contrast microscope at 1st,4th 7th,14th day after induction.Then we transfected the recombination plasmid vector(including pSITITIN and pSIACTIN)into MSCs after induction.detected the expression of titin、?-MHC and cTnI at interval times by RT-PCR.Results:1.we obtained the mild expression of titin、?-MHC and cTnI gene before 5-aza treament,but the expression of them increased after induction.2.After recombination plasmid were transfected into MSCs which have been induced by 5-aza,the expression of titin gene was decreased 3.The expression of ?-MHC gene kept invariant,while the expression of cTnI gene was weakened after the interference.Conclusion:1.titin gene probably play an important role in the procession of MSCs differentiating into cardiomyocytes in vitro.2.titin gene may regulate the expression of cTnI.
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Objective To observe whether mesenchymal stem cells(MSCs) which have been induced by 5-azacytidine(5-aza) can differentiate into cardiac like cells. To find out the role of TITIN playing during the development of cardiomycytes among structure proteins. Methods To establish a recombinant plasmid vector involving a shRNA which matching the base pair of rat TITIN N2B region mRNA perfectly,transfect it into normal neonatal cardiomyocytes and MSCs which have been induced by 5-aza respectively and investigate the expression of TITIN Z band,MHC,ACTIN as well as cTnT by immunofluorescence. Results The expression of TITIN was weakened after recombinant plasmid has been transfected into neonatal cardiomyocytes.The same thing happened upon MSCs that have been induced by 5-aza. The expression of cTnT was weakened after TITIN been silenced by small interfering RNA (siRNA). But there was obvious change in MHC and ACTIN. Conclusion Our results demonstrate that MSCs can be induced into cardiomyocyte-like cells by 5-aza in vitro,although the degree of differentiation is still lower and can not form intact contractive structure. TITIN plays an important role in the development of structure proteins.
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Objective To construct small RNAi plasmid vectors which can suppress the expression of TITIN in Wistar rat. Methods A recombinant plasmid vector involving shRNA, which matched the base pair of rat TITIN N2B region mRNA perfectly, was constructed and transfected into normal neonatal cardiomyocytes and mesenchymal stem cells (MSCs) induced by 5-aza cytidine respectively. The expression of TITIN Z band was investigated by immunofluorescence. Results The expression of TITIN was weakened after recombinant plasmid was transfected into neonatal cardiomyocytes and MSCs induced by 5-aza cytidine. Conclusion The recombinant plasmid was constructed successfully, and it actually can block the expression of TITIN.
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Objective To investigate the correlation between level of Titin antibodies (Titin-Ab) and patient's condition and different thymic pathological patterns in patients with myasthenia gravis (MG), and to assess its value in the diagnosis and prognosis of MG.Methods The levels of Titin-Ab in serum from 52 patients with MG (MG group), 18 cases with other neurologic diseases (NMG group) and 50 normal controls (NC group) were detected using enzyme-linked immunosorbentassay (ELISA). 10 cases with MG who received operation on thymus were tested again after therapy.Results The positive rate of Titin-Ab in MG group was 36.5%,but not present in MNG and NC groups.The MG group!was significantly higher than those in NMG group and NC group (all P