OBJECTIVETo investigate a genetic association for schizophrenia within chromosome 22q11 in a Chinese Han population.

METHODSThe PCR-based restriction fragment length polymorphism (PCR-RFLP) analysis was used to detect three single nucleotide polymorphisms (SNPs), rs165655 (A/G base change) and rs165815 (C/T base change) present in the ARVCF (armadillo repeat gene deletion in velocardiofacial syndrome) locus, and rs756656 (A/C base change) in the LOC128979 (expressed sequence tags, EST) locus, among 100 Chinese family trios consisting of fathers, mothers and affected offspring with schizophrenia. Genotype data were analyzed by using linkage disequilibrium (LD) methods including haplotype relative risk (HRR) analysis, transmission disequilibrium test (TDT) and haplotype transmission analysis.

RESULTSThe genotype frequency distributions of three SNPs were all in Hardy-Weinberg equilibrium (P>0.05). Both the HRR and the TDT analysis showed that rs165815 was associated with schizophrenia (chi2=6.447, df=1, P=0.011 and chi2=6.313, df=1, P=0.012, respectively), whereas the other two SNPs did not show any allelic association. The haplotype transmission analysis showed a biased transmission for the rs165655-rs165815 haplotype system (chi2=17.224, df=3, P=0.0006) and for the rs756656-rs165655-rs165815 hapoltype system (chi2=20.965, df=7, P=0.0038).

CONCLUSIONEither the ARVCF gene itself or a nearby locus may confer susceptibility to schizophrenia in a Chinese Han population.

Adult ; Armadillo Domain Proteins ; Catechol O-Methyltransferase ; genetics ; Cell Adhesion Molecules ; genetics ; China ; Chromosomes, Human, Pair 22 ; genetics ; Female ; Genetic Predisposition to Disease ; Haplotypes ; Humans ; Male ; Phosphoproteins ; genetics ; Polymorphism, Single Nucleotide ; Schizophrenia ; genetics

BACKGROUNDArrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable cardiac disease predominantly caused by mutations in desmosomal protein genes. Previous genetic analyses of the Chinese ARVC population are limited to small size and restriction to a single gene. This study was aimed to investigate the genotype in a large series of Chinese patients with ARVC through comprehensively screening nine ARVC-causing genes.

METHODSA total of 100 unrelated ARVC patients and 300 age, gender and ethnicity matched healthy controls were genetically tested with multiplexing targeted resequencing for nine previously reported ARVC-causing genes, including plakophilin-2, desmoplakin, desmoglein-2, desmocollin-2, plakoglobin, transforming growth factor beta-3, transmembrane protein 43, desmin and Lamin A/C.

RESULTSFifty-nine mutations were identified in 64% of the patients, among which, 93% were located in desmosomal protein genes. Plakophilin-2 mutations accounted for 54% of the total and 58% of the desmosomal mutations, with a truncating mutation type making up about 2/3 of the plakophilin-2 mutations. Only four mutations were found in non-desmosomal genes; two in transmembrane protein 43 and two in transforming growth factor beta-3. Two of them (one of each gene) appeared as single missense mutations. No mutation was identified in desmin or Lamin A/C. Multiple mutations were found in 23% of the patients, with plakophilin-2 being found in 57% of the multi-mutation carriers.

CONCLUSIONSPlakophilin-2 was the most common gene mutation that was identified in Chinese ARVC patients. Non-desmosomal genes should be added to desmosomal protein genes when performing molecular genetic screening in patients with suspected ARVC.

Adult ; Arrhythmogenic Right Ventricular Dysplasia ; genetics ; metabolism ; Asian Continental Ancestry Group ; Desmin ; genetics ; Desmoglein 2 ; genetics ; Female ; Humans ; Male ; Middle Aged ; Mutation ; Plakophilins ; genetics ; Young Adult ; gamma Catenin ; genetics

PURPOSE: The significance of abnormal E-cadherin/ catenin complex expression and the correlation of each of its components in cancer remain unclear. This study aimed to characterize the clinical significance of the abnormal membrane expression of the E-cadherin/ catenin complex and the localization patterns of the beta- catenin and p120CTN in early gastric cancer. MATERIALS AND METHODS: Immunohistochemical staining for E-cadherin, alpha-, beta- and gamma-catenin and p120CTN were performed on 47 early gastric cancer specimens. The patterns of membrange expression of the E-cadherin/catenin complex, and the localization patterns of the beta-catenin and p120CTN, were semi quantitatively graded as loss, reduced, preserved or negative and positive. RESULTS: An abnormal immunoreactivity of at least one of E-cadherin/catenin complex proteins was noted in 46 (97.8%) of the 47 early gastric cancer cases. There were no significant correlations of the membrane E-cadherin/catenin expression with, either, sex, age, location, size, macroscopic type, depth of invasion or lymphovascular invasion. Abnormal expressions of membrane E-cadherin, beta-catenin and gamma-catenin were more frequent in the diffuse-type than in the intestinal type. No linear correlation was shown for the beta-catenin between the membrane and cytoplasmic expressions. Nuclear staining of the beta-catenin was observed in 5 (10.6%) cases, but nuclear staining of the p120CTN, a promotor of Kaiso transcriptional factor, was not seen. CONCLUSION: These results suggest that alterations of the E-cadherin/catenin complex may be involved in the early stages of gastric cancer. Although beta-catenin functions as a transcriptional factor, the inactivation of membrane E-cadherin does not appear to result in significant increases in the level of cytoplasmic beta-catenin. Kaiso transcriptional factor may not be involved in the early carcinogenesis of gastric cancer.
beta Catenin ; Cadherins ; Carcinogenesis ; Cell Adhesion ; Cytoplasm ; gamma Catenin* ; Membranes ; Stomach Neoplasms*

OBJECTIVE: To explore the clinical and genetic characteristics of a child with Arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS: A 6-year-old boy with ARVC who had visited Fujian Provincial Children's Hospital on August 23, 2022 was selected as the study subject. Relevant clinical data were collected, and peripheral venous blood samples were collected from the child and his parents for genetic testing through whole exome sequencing (WES). Sanger sequencing was carried out for family verification, and pathogenicity analysis was conducted for the candidate variants. RESULTS: The child had exhibited clinical symptoms including systemic edema, generalized heart enlargement, universal reduction of interventricular septum and ventricular wall movement, reduced left ventricular diastolic and systolic function, and reduced right ventricular systolic function. WES revealed that the child has harbored compound heterozygous variants of the PKP2 gene, namely c.119_122del (p.Leu40ArgfsTer71) and c.1978G>A (p.Gly660Arg), which were verified by Sanger sequencing to be respectively inherited from his father and mother. The c.119_122del variant has not been recorded in the 1000 Genomes, gnomAD and ExAC databases, and was predicted to lead to truncation of the PKP2 protein by SWISS-MODEL and PyMOL online software and classified as likely pathogenic based on the guidelines jointly developed by the American College of Medical Genetics and Genomics (ACMG) and ClinGen. The c.1978G>A variant has also not been recorded in the 1000 Genomes, gnomAD and ExAC databases, and was predicted to be deleterious by online software including REVEL, SIFT, CADD, Mutation Taster, and PolyPhen-2. The amino acid encoded by the variant site was highly conserved among various species by analysis using T-coffee and ESPript v3.0 online servers. The variant may affect the protein function by SWISS-MODEL and PyMOL online server analysis, and was classified as likely pathogenic based on the guidelines jointly developed by the ACMG and ClinGen. CONCLUSION The compound heterozygous variants of c.119_122del (p.Leu40ArgfsTer71) and c.1978G>A (p.Gly660Arg) of the PKP2 gene probably underlay the ARVC in this child. Above finding has broadened the spectrum of PKP2 gene variants and provided a reference for the diagnosis and genetic counseling.
Male ; Child ; Humans ; Arrhythmogenic Right Ventricular Dysplasia/genetics* ; Diastole ; Ethnicity ; Genetic Counseling ; Genetic Testing ; Plakophilins/genetics*

BACKGROUND AND OBJECTIVES: E-cadherin and catenins (alpha, beta, gamma, p120cat) are important epithelial adhesion molecules in normal epithelial cells. Loss of E-cadherin-catenin adhesion is an important step in the progression of epithelial cancers such as tongue cancer. E-cadherin and catenins expression in carcinoma of human tongue was evaluated in relation to their clinicopathological features and prognostic values. SUBJECTS AND METHOD: Thirty-nine specimens of tongue squamous cell carcinoma were examined in this study. These patients were all treated by primary surgery without prior radiotherapy or chemotherapy. The specimens of formalin-fixed and paraffin-embedded tumor tissues were investigated by immunohistochemical analysis using E-cadherin and catenin (alpha, beta, gamma, p120cat) monoclonal antibodies. RESULTS: The expressions of E-cadherin, alpha-catenin, beta-catenin, gamma-catenin and p120cat in cell membranes were reduced or absent in 71.8%, 74.4%, 76.9%, 59.0% and 82.1% of the tumors examined, respectively. The reduced expressions of alpha-catenin and gamma-catenin in the cell membranes was cor-related with tumore differentiation (p=0.018, p=0.004, respectively). There were significant correlations between E-cadherin and expressions of the four cantenins in the cell membranes of tongue cancer. There were no correlations between beta-catenin and p120cat expression in the cytoplasm, cell nucleus and clinicopathological features. There was significant correlation between E-cadherin expression and Kaplan-Meier survival curves. CONCLUSION: These results suggest that E-cadherin and catenins (alpha, beta, gamma, p120cat) can be used as prognostic markers of human tongue squamous cell carninoma. The result of beta-catenin and p120cat absence in the nucleus suggests that Wnt/Wingless signaling or Kaiso transcription did not occur in the human tongue squamous cell carcinoma.
alpha Catenin ; Antibodies, Monoclonal ; beta Catenin ; Cadherins* ; Carcinoma, Squamous Cell ; Catenins ; Cell Membrane ; Cell Nucleus ; Cytoplasm ; Drug Therapy ; Epithelial Cells ; gamma Catenin ; Humans ; Kaplan-Meier Estimate ; Prognosis ; Radiotherapy ; Tongue Neoplasms* ; Tongue*

No abstract available.
Aspirin* ; beta Catenin*

This paper aimed to investigate the effect of total flavonoids of buckwheat flower and leaf on myocardial cell apoptosis and Wnt/β-catenin/peroxisome proliferator-activated receptor γ(PPARγ) pathway in arrhythmic rats. SD rats were randomly divided into a control group, a model group, a low-dose(20 mg·kg~(-1)) group of total flavonoids of buckwheat flower and leaf, a medium-dose(40 mg·kg~(-1)) group of total flavonoids of buckwheat flower and leaf, a high-dose(80 mg·kg~(-1)) group of total flavonoids of buckwheat flower and leaf, a propranolol hydrochloride(2 mg·kg~(-1)) group, with 12 rats in each group. Except the control group, rats in other groups were prepared as models of arrhythmia by sublingual injection of 1 mL·kg~(-1) of 0.002% aconitine. After grouping and intervention with drugs, the arrhythmia, myocardial cells apoptosis, myocardial tissue glutathione peroxidase(GSH-Px), catalase(CAT), malondialdehyde(MDA), serum interleukin-6(IL-6), prostaglandin E2(PGE2) levels, myocardial tissue apoptosis, and Wnt/β-catenin/PPARγ pathway-related protein expression of rats in each group were measured. As compared with the control group, the arrhythmia score, the number of ventricular premature beats, ventricular fibrillation duration, myocardial cell apoptosis rate, MDA levels in myocardial tissues, serum IL-6 and PGE2 levels, Bax in myocardial tissues, and Wnt1 and β-catenin protein expression levels increased significantly in the model group, whereas the GSH-Px and CAT levels, and Bcl-2 and PPARγ protein expression levels in myocardial tissues reduced significantly. As compared with the model group, the arrhythmia score, the number of ventricular premature beats, ventricular fibrillation duration, myocardial cell apoptosis rate, MDA leve in myocardial tissues, serum IL-6 and PGE2 levels, Bax in myocardial tissues, and Wnt1 and β-catenin protein expression levels reduced in the drug intervention groups, whereas the GSH-Px and CAT levels and Bcl-2 and PPARγ protein expression levels in myocardial tissues increased. The groups of total flavonoids of buckwheat flower and leaf were in a dose-dependent manner. There was no significant difference in the levels of each index in rats between the propranolol hydrochloride group and the high-dose group of total flavonoids of buckwheat flower and leaf. The total flavonoids of buckwheat flower and leaf inhibit the activation of Wnt/β-catenin pathway, up-regulate the expression of PPARγ, reduce oxidative stress and inflammatory damage in myocardial tissues of arrhythmic rats, reduce myocardial cell apoptosis, and improve the symptoms of arrhythmia in rats.
Rats ; Animals ; PPAR gamma/metabolism* ; Fagopyrum/genetics* ; Rats, Sprague-Dawley ; bcl-2-Associated X Protein ; beta Catenin/metabolism* ; Interleukin-6 ; Flavonoids/pharmacology* ; Propranolol/pharmacology* ; Ventricular Fibrillation ; Dinoprostone ; Wnt Signaling Pathway ; Plant Leaves/metabolism* ; Flowers/metabolism* ; Apoptosis ; Cardiac Complexes, Premature

BACKGROUNDArrhythmogenic right ventricular cardiomyopathy (ARVC) is one of the leading causes of sudden cardiac death. Recent studies have shown that ARVC, which is an inheritable genetic change, results from mutations in genes encoding desmosomal proteins. Plakophilin-2 is an important component of the desmosome. Because the full range of genetic variations related to ARVC is unknown and no related studies of the Chinese population have been reported, we aimed to investigate the genetic variation of plakophilin-2 in ARVC patients from the Southern Region of China.

METHODSGenomic DNA was isolated from peripheral blood samples of all 34 ARVC patients, who were screened through a clinical evaluation. They were used to detect variations in the sequences of the plakophilin-2 genes by polymerase chain reaction amplification in combination with direct sequencing.

RESULTSIn exon-1 of the plakophilin-2 gene, a deletion mutation (c.145_148 del GACA) was found in one family pedigree. The mutation was also found in exon-2, 4, and 11 of the plakophilin-2 gene. The QT interval dispersion of the ECG was considerably longer in the mutation group than in the non-mutation group of ARVC patients, and this result was statistically significant (P < 0.05).

CONCLUSIONWe discovered a plakophilin-2 mutation that prolongs the QT interval dispersion in the southern Chinese ARVC population.

Adult ; Arrhythmogenic Right Ventricular Dysplasia ; genetics ; Asian Continental Ancestry Group ; genetics ; Child ; China ; DNA Mutational Analysis ; Exons ; genetics ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Mutation ; Pedigree ; Plakophilins ; genetics

OBJECTIVETo investigate the effect of irradiated human lung fibroblasts (HLFs) on the canonical Wnt/&beta;-catenin signaling pathway in human umbilical cord mesenchymal stem cells (HUMSCs).

METHODSHUMSCs were cultured alone (single group) or co-cultured with HLFs exposed to 5Gy X-rays (co-culture group). The protein levels of GSK-3&beta;, p-GSK-3&beta;, FRAT1 and &beta;-catenin in HUMSCs were examined by Western blotting 3 days after culture or co-culture. WISP-1 protein levels in conditioned medium were examined by ELISA.

RESULTSThe levels of p-GSK3&beta;/GSK3&beta; (0.15 ± 0.05), FRAT1 (0.48 ± 0.07) and &beta;-catenin (0.50 ± 0.07) in co-cultured HUMSCs significantly decreased compared to those in single group (0.55 ± 0.05, 1.16 ± 0.13 and 2.39 ± 0.15, all P<0.05). The supernatant level of WISP-1 in co-culture group was significantly decreased [(602.23 ± 161.47) ng/mL], compared to the single group [(977.77 ± 110.56) ng/mL, P<0.05].

CONCLUSIONIrradiated HLFs attenuate the activation of canonical Wnt/&beta;-catenin signaling pathway in HUMSCs in vitro.

CCN Intercellular Signaling Proteins ; metabolism ; Cells, Cultured ; Coculture Techniques ; Fibroblasts ; cytology ; radiation effects ; Gamma Rays ; Glycogen Synthase Kinase 3 ; metabolism ; Glycogen Synthase Kinase 3 beta ; Humans ; Intracellular Signaling Peptides and Proteins ; metabolism ; Mesenchymal Stromal Cells ; metabolism ; Proto-Oncogene Proteins ; metabolism ; Umbilical Cord ; cytology ; Wnt Signaling Pathway ; X-Rays ; beta Catenin ; metabolism

OBJECTIVE: To evaluate the correlation of the expression of E-cadherin, alpha-catenin, beta-catenin and the clinicopathological features in endometrial cancer (EC) and atypical complex endometrial hyperplasia (ACEH). METHODS: Immunohistochemical (IHC) staining of E-cadherin, alpha-catenin, beta-catenin was performed in tissues of 6 ACEHs, 44 endometrioid ECs. We analyzed the correlation of the expression of IHC staining with the prognostic factors according to tumor stage of ACEH and EC, histopathologic grade, and myometrial invasion. RESULTS: According to tumor stage, reduced E-cadherin expression and abnormal alpha-catenin expression were observed more frequently in advanced stage (reduced E-cadherin: ACEH 0%, stage I-II 47.2%, stage III-IV 62.5%, p=0.050; abnormal alpha-catenin: ACEH 0%, stage I-II 27.8%, stage III-IV 62.5%, p=0.035). All of the IHC staining showed no correlation with the depth of myometrial invasion but showed correlation with presence of myometrial invasion (reduced E-cadherin: invasion(-) 14.3%, invasion(+) 66.7%, p =0.001; abnormal alpha-catenin: invasion(-) 7.1%, invasion (+) 46.0%, p=0.010; abnormal beta-catenin: invasion(-) 7.1%, invasion(+) 63.0%, p=0.000). According to histological differentiation only abnormal beta-catenin expression shows relationship with histopathologic grade (grade 1:23.1%, grade 2:60%, grade 3:62.5%, p=0.039). CONCLUSION: Expression of E-cadherin and alpha-catenin showed significantly more reduced expression in EC than in ACEH, and more reduced expression in advanced stage, myometrial invasion and high histopathologic grade. And alpha-catenin showed more frequent abnormal expression in advanced stage, myometrial invasion and beta-catenin showed more frequent in myometrial invasion, high histopathologic grade significantly. These results suggests that the expression of E-cadherin and alpha-catenin, beta-catenin in EC and ACEH could be related to prognosis of the tumor.
alpha Catenin ; beta Catenin ; Cadherins* ; Endometrial Hyperplasia* ; Endometrial Neoplasms* ; Female ; Prognosis