OBJECTIVE: To explore the clinical characteristics and genetic etiology for two children with Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (MEDHSIL). METHODS: Two children who had visited the Ningbo Women and Children's Hospital on October 15, 2021 were selected as the study subjects. Whole exome sequencing (WES) was carried out for both patients. Candidate variants were verified by Sanger sequencing of their family members. RESULTS: The two children were respectively found to harbor a heterozygous c.138delC (p.Ile47Serfs*42) variant and a c.833del (p.L278*) variant of the MEF2C gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be pathogenic (PVS1+PS2+PM2_Supporting). CONCLUSION The c.138delC and c.833del variants of the MEF2C gene probably underlay the pathogenesis of MEDHSIL in the two children. Above findings have enriched the mutational spectrum of the MEF2C gene and enabled genetic counseling for their families.
Child ; Humans ; Family ; Genetic Counseling ; Language ; MEF2 Transcription Factors/genetics* ; Muscle Hypotonia/genetics* ; Neurodevelopmental Disorders

OBJECTIVE: To explore the genetic basis for a child with febrile seizures. METHODS: Peripheral venous blood samples were taken from the child and his parents for the analysis of chromosomal karyotype and dynamic variant of the FMR1 gene. The family trio was also subjected to target capture and next generation sequencing (NGS) with a gene panel related to developmental retardation, mental retardation, language retardation, epilepsy and special facial features. RESULTS: The child was found to have a normal karyotype by conventional cytogenetic analysis (400 bands). No abnormal expansion was found with the CGG repeats of the FMR1 gene. NGS revealed that the child has carried a heterozygous c.864+1 delG variant of the MEF2C gene, which may lead to abnormal splicing and affect its protein function. The same variant was found in neither parent, suggesting that it has a de novo origin. Based on the American College of Medical Genetics and Genomics standards and guidelines, c.864+1delG variant of MEF2C gene was predicted to be pathogenic (PVS1+PS2+PM2). CONCLUSION MEF2C, as the key gene for chromosome 5q14.3 deletion syndrome which was speculated as a cause for febrile seizures, has an autosomal dominant effect. The c.864+1delG variant of the MEF2C gene may account for the febrile seizures in this patient.
Child ; Chromosome Deletion ; Chromosome Disorders ; Epilepsy ; Fragile X Mental Retardation Protein ; Humans ; Intellectual Disability/genetics* ; Karyotyping ; MEF2 Transcription Factors/genetics*

OBJECTIVE: To investigate the effect of Xiaozhong Zhitong Ointment(XZZTO) on remodeling and repair of skeletal muscle injury in rats based on the expression mechanism of microRNA. METHODS: The rat gastrocnemius injury model was established by blunt contusion model. The expression of MEF2 gene and protein in gastrocnemius muscle was detected by quantitative PCR at 4, 7, 14 and 21 days after injury with XZZTO. The mechanism of the effect of XZZTO on the muscle remodeling and repair of rat gastrocnemius contusion model was discussed. RESULTS: The expression level of MEF2 in the treatment group was significantly higher than that of the control group and model group, which further confirmed the important role of MEF2 in inducing skeletal muscle remodeling and repair process in the topical drugs. The expression of MEF2 increased at 7 days after injury and remained at a high level until 21 days after injury. Compared with the model group, the peak expression period was about 14 days, and then returned to the general state. CONCLUSIONS The expression level of MEF2 shows an upward trend. Even 21 days after injury, the expression of MEF2 dose not show a significant downward trend. It can be seen that XZZTO can promote the expression of MEF2. At the same time, XZZTO can regulate the regeneration and repair of skeletal muscle. Therefore, XZZTO can play a regeneration and repair role after skeletal muscle injury through gene regulation.
Animals ; Contusions ; Gastrointestinal Tract ; Gene Expression Regulation ; MEF2 Transcription Factors ; genetics ; Muscle, Skeletal ; Ointments ; Proteins ; RNA, Messenger ; Rats

Myostatin (Mstn) is a member of the transforming growth factor-beta superfamily that functions as a negative regulator of skeletal muscle growth and differentiation in mammals. The transcriptional regulation of Mstn is controlled by multiple genes including MEF2, which raise the importance of identifying the binding sites of MEF2 on myostatin promoter region and mechanisms underlying. In this study, we investigated the transcriptional regulation of MEF2 on porcine Mstn promoter activity in C2C12 cells. Sequence analysis of the 1 969 bp porcine Mstn promoter region revealed that it contained three potential MEF2 motifs. Using a serial deletion strategy, we tested the activity of several promoter fragments by luciferase assay. Overexpression of MEF2C, but not MEF2A increased Mstn promoter activity in all the promoter fragments with MEF2 motifs by two to six folds, in both C2C12 myoblasts and myotubes. When we transfected exogenous MEF2C, Mstn mRNA level was also upregulated in C2C12 cells, but the protein level was only significantly increased in myotubes. Thus, we propose that MEF2C could modulate and restrain myogenesis by Mstn activation and Mstn-dependent gene processing in porcine. Our research also provided potential targets and an effective molecule to regulate Mstn expression and gave a new way to explore the functional performance of Mstn.
Animals ; Cells, Cultured ; Gene Expression Regulation ; MEF2 Transcription Factors ; Mice ; Muscle, Skeletal ; metabolism ; Myoblasts ; cytology ; Myogenic Regulatory Factors ; genetics ; physiology ; Myostatin ; genetics ; physiology ; Promoter Regions, Genetic ; Swine

OBJECTIVETo observe the temporal modification of transcription factor Mef2c by histone acetylases (HATs) P300, PCAF, and SRC1 during cardiogenesis and to provide a basis for investigating the pathogenesis of congenital heart disease.

METHODSThe normal heart tissues from embryonic mice (embryonic days 14.5 and 16.5) and neonatal mice (postnatal days 0.5 and 7) were collected. The binding of P300, PCAF, and SRC1 to Mef2c gene and level of histone H3 acetylation in the promoter region of Mef2c were evaluated by chromatin immunoprecipitation assays. Meanwhile, real-time PCR was used to measure the mRNA expression of Mef2c.

RESULTSP300, PCAF, SRC1 were involved in histone acetylation in the promoter region of Mef2c during cardiogenesis in mice, and binding of P300, PCAF, and SRC1 to the promoter of Mef2c varied significantly in different stages of cardiogenesis (P<0.01). The level of histone H3 acetylation and mRNA expression of Mef2c in the promoter region of Mef2c also varied significantly in different stages of cardiac development (P<0.01). The levels of acetylated H3, Mef2c mRNA, and HATs (P300, PCAF, SRC1) changed over time. They were highest on embryonic day 14.5 (P<0.01), decreased gradually with cardiac development, and were maintained at low levels after birth.

CONCLUSIONSThe mRNA expression of Mef2c varies during cardiogenesis in mice, which indicates that Mef2c plays an important role in the process of cardiac development. Meanwhile, histone acetylation in the promoter region of Mef2c is regulated temporally by HATs P300, PCAF, and SRC1.

Animals ; Female ; Gene Expression Regulation, Developmental ; Heart ; embryology ; Histone Acetyltransferases ; physiology ; MEF2 Transcription Factors ; genetics ; physiology ; Male ; Mice ; Promoter Regions, Genetic ; RNA, Messenger ; analysis

OBJECTIVE: To explore MEF2A gene and susceptibility to coronary artery disease in the Chinese. METHODS: One hundred seventy-five coronary artery disease (CAD) patients and 228 normal subjects were recruited and their blood samples were amplified to detect sequences of all 11 exons of MEF2A gene by PCR. Single-strand conformational polymorphism (SSCP) analysis was used to detect the mutation. The amplified products were purified and sequenced. RESULTS: The tri-nucleotide (CAG) length polymorphism in the last coding exon of MEF2A in the Chinese was revealed and 4 of the 175 (2.3%) CAD samples containing 4 prolines were due to one proline deletion in MEF2A gene. But all the 228 normal subjects contained 5 prolines. The mutation in both 175 CAD samples and 228 normal subjects was not found in other exons. CONCLUSION The deletion mutation in exon 11 in MEF2A gene may be related to CAD susceptibility in the Chinese population.
Base Sequence ; China ; Coronary Artery Disease ; genetics ; Exons ; genetics ; Female ; Gene Deletion ; Genetic Predisposition to Disease ; genetics ; Humans ; MEF2 Transcription Factors ; Male ; Middle Aged ; Molecular Sequence Data ; Mutation ; Myogenic Regulatory Factors ; genetics ; Polymerase Chain Reaction ; Polymorphism, Single-Stranded Conformational ; Trinucleotide Repeats

BACKGROUNDPremature ventricular contractions (PVCs) are common in the general population, and frequent PVCs may result in the poor quality of life or even the damage of cardiac function. We examined the efficacy and safety of a traditional Chinese medicine Wenxin Keli for the treatment of frequent PVCs among a relatively large Chinese cohort.

METHODSWe performed a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. A total of 1200 eligible participants were randomly assigned in a ratio of 1:1 to receive Wenxin Keli or the placebo for 4 weeks. The primary and secondary endpoint was the change of PVC numbers and PVC-related symptoms after a 4-week treatment compared with baseline, respectively. In addition, vital signs, laboratory values, and electrocardiographic parameters were assessed in a safety analysis.

RESULTSAt the initial evaluation, no significant differences in the baseline characteristics were observed between the Wenxin Keli group and the placebo group. A smaller number of PVCs was observed after the 4-week treatment than at baseline, in both the Wenxin Keli group (5686 ± 5940 vs. 15,138 ± 7597 beats/d, P < 0.001) and the placebo group (10,592 ± 8009 vs. 14,529 ± 5929 beats/d, P < 0.001); moreover, the Wenxin Keli group demonstrated a significantly greater reduction in the frequency of PVCs than the placebo group (P < 0.001). In a full analysis set, patients in the Wenxin Keli group exhibited significantly higher total effective responses in the reduction of PVCs compared to those in the placebo group (83.8% vs. 43.5%,P < 0.001). The per-protocol analysis yielded similar results (83.0% vs. 39.3%,P < 0.001). Treatment with Wenxin Keli also demonstrated superior performance compared to the placebo with respect to PVC-related symptoms. No severe adverse effects attributable to Wenxin Keli were reported.

CONCLUSIONSWenxin Keli treatment effectively reduced the overall number of PVCs and alleviated PVC-related symptoms in patients without structural heart diseases and had no severe side effects.

Coronary Artery Disease ; genetics ; prevention & control ; Double-Blind Method ; Drugs, Chinese Herbal ; adverse effects ; therapeutic use ; Humans ; MEF2 Transcription Factors ; genetics ; Mutation ; genetics ; Myocardial Infarction ; drug therapy ; genetics ; Randomized Controlled Trials as Topic ; Ventricular Premature Complexes ; drug therapy ; genetics

BACKGROUNDSome single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha gene have been reported to be associated with type 2 diabetes in different populations, and studies on Chinese patients yielded controversial results. The objective of this case-control study was to explore the relationship between SNPs of PGC-1alpha and type 2 diabetes in the southern Chinese population and to determine whether the common variants: Gly482Ser and Thr394Thr, in the PGC-1alpha gene have any impacts on interaction with myocyte enhancer factor (MEF) 2C.

METHODSThe SNPs in all exons of the PGC-1alpha gene was investigated in 50 type 2 diabetic patients using polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and direct sequencing. Thereafter, 263 type 2 diabetic patients and 282 healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). A bacterial two-hybrid system and site-directed mutagenesis were used to investigate whether Gly482Ser and Thr394Thr variants in the PGC-1alpha gene alter the interaction with MEF2C.

RESULTSThree frequent SNPs (Thr394Thr, Gly482Ser and Thr528Thr) were found in exons of the PGC-1alpha gene. Only the Gly482Ser variant had a different distribution between diabetic patients and healthy subjects, with the 482Ser allele more frequent in patients than in controls (40.1% vs 29.3%, P < 0.01). Even in controls, the 482Ser (A) carriers were more likely to have higher levels of total cholesterol and low-density lipoprotein cholesterol than the 482Gly (G) carriers. The 394A-482G-528A haplotype was associated with protection from diabetes, while the 394A-482A-528A was associated with the susceptibility to diabetes. The bacterial two-hybrid system and site-directed mutagenesis revealed that the 482Ser variant was less efficient than the 482Gly variant to interact with MEF2C, whereas the 394Thr (A) had a synergic effect on the interaction between 482Ser variant and MEF2C.

CONCLUSIONSThe results suggested that the 482Ser variant of PGC-1alpha conferred the susceptibility to type 2 diabetes in the southern Chinese population. The underlying mechanism may be attributable, at least in part, to the altered interaction between the different variants (Gly482Ser, Thr394Thr) in the PGC-1alpha gene and MEF2C.

Aged ; Asian Continental Ancestry Group ; genetics ; China ; Diabetes Mellitus, Type 2 ; ethnology ; genetics ; Female ; Genotype ; Heat-Shock Proteins ; genetics ; metabolism ; Humans ; MEF2 Transcription Factors ; Male ; Middle Aged ; Myogenic Regulatory Factors ; metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide ; Polymorphism, Single-Stranded Conformational ; Protein Binding ; Transcription Factors ; genetics ; metabolism

OBJECTIVETo investigate the association of the 482G/A polymorphism of the PGC-1alpha gene with type 2 diabetes by family-based study in the Han population in South China, and to analyze the quantitative and qualitative binding force changes between the PGC-1alpha domain mutant and MEF2C, as well as to evaluate the possibility of PGC-1alpha -MEF2C-GLUT4 pathway in the pathogenesis of type 2 diabetes.

METHODSBlood samples were collected from 350 patients with type 2 diabetes and their first-degree relatives. Genomic DNA was extracted and polymorphic PGC-1alpha genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism and direct DNA sequencing. The results were analyzed by family-based transmission disequilibrium test (TDT) and haplotype relative risk (HRR). The protein-protein interaction between PGC-1alpha and MEF2C was detected by means of the site-directed mutagenesis kit and bacteriomatch two-hybrid system kit.

RESULTSIn the family-based study, HRR analyses demonstrated that the 482A allele was more often transmitted to patients than predicted by chance (chi (2)= 7.2170, P= 0.0072, HRR= 1.4496). TDT-extended test(ETDT) analyses also revealed that PGC-1alpha 482A allele was significantly deviated from 0.5 from heterozygous parents to patients than expected (219 trios, P= 0.0310; 350 trios, P= 0.0292). BacterioMatch Two-Hybrid System showed that 482A variation could lead to decreased binding force between PGC-1alpha and MEF2C (62.1+/- 8.97, P< 0.05).

CONCLUSIONThe 482A polymorphism increases the risk of developing type 2 diabetic mellitus in the South China Han population, which might be mediated by the PGC-1alpha -MEF2C-GLUT4 pathway.

Asian Continental Ancestry Group ; genetics ; Diabetes Mellitus, Type 2 ; genetics ; metabolism ; Ethnic Groups ; genetics ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Glucose Transporter Type 4 ; metabolism ; Haplotypes ; Heat-Shock Proteins ; genetics ; metabolism ; Humans ; Logistic Models ; MADS Domain Proteins ; genetics ; metabolism ; MEF2 Transcription Factors ; Male ; Middle Aged ; Myogenic Regulatory Factors ; genetics ; metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Polymorphism, Single Nucleotide ; genetics ; Protein Structure, Tertiary ; genetics ; Signal Transduction ; Transcription Factors ; genetics ; metabolism ; Two-Hybrid System Techniques

OBJECTIVETo explore the mutations of MEF2A gene in Chinese patients with coronary artery disease(CAD).

METHODSWith polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and DNA direct sequencing, the mutation analysis of exon 11 of MEF2A gene was performed to 156 patients with CAD and 93 normal controls.

RESULTSBy DNA sequence analyzing the samples of abnormal mobility shift of SSCP, the MEF2A gene mutations were found in three patients with CAD. One of mutations was 147130(C>A)(P431Q), and the second one was 21 bases deletion(147108-147128) which was leading to the absence of 7 amino acids (424QQQQQQQ430), and the third was 147191(G>T). Three mutations were all found in one patient, but meanwhile 21 bases deletion was found in the other two patients.

CONCLUSIONMutations in exon 11 of MEF2A gene exist in the patients with CAD, and the mutations may be pathological.

Adult ; Aged ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; China ; Coronary Artery Disease ; ethnology ; genetics ; DNA Mutational Analysis ; Female ; Genetic Predisposition to Disease ; genetics ; Humans ; MEF2 Transcription Factors ; Male ; Middle Aged ; Molecular Sequence Data ; Mutation ; Myogenic Regulatory Factors ; genetics ; Polymerase Chain Reaction ; Polymorphism, Single-Stranded Conformational