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.
Humans ; Cardiomyopathy, Dilated/therapy* ; Connectin/genetics* ; Genetic Therapy ; Mutation ; Phenotype

Titin, the largest known protein in the body expressed in three isoforms (N2A, N2BA and N2B), is essential for muscle structure, force generation, conduction and regulation. Since the 1950s, muscle contraction mechanisms have been explained by the sliding filament theory involving thin and thick muscle filaments, while the contribution of cytoskeleton in force generation and conduction was ignored. With the discovery of insoluble protein residues and large molecular weight proteins in muscle fibers, the third myofilament, titin, has been identified and attracted a lot of interests. The development of single molecule mechanics and gene sequencing technology further contributed to the extensive studies on the arrangement, structure, elastic properties and components of titin in sarcomere. Therefore, this paper reviews the structure, isforms classification, elastic function and regulatory factors of titin, to provide better understanding of titin.
Connectin/genetics* ; Muscle Proteins/metabolism* ; Protein Isoforms/genetics* ; Sarcomeres/metabolism* ; Muscle Fibers, Skeletal/metabolism*

OBJECTIVETo investigate TCAP gene mutation and clinical features of a Chinese patient with limb-girdle muscular dystrophy type 2G(LGMD 2G).

METHODSClinical data of the patient was analyzed. Exons of the TCAP gene were amplified and sequenced.

RESULTSThe patient has presented clinically as LGMD and pathologically as vacuolar myopathy. Genetic analysis has identified compound heterozygous mutations of exons 1 and 2 of the TCAP gene(c.100delC, c.166insG).

CONCLUSIONLGMD is a group of neuromuscular disorders with substantial phenotypic heterogeneity. Genetic diagnosis has become indispensable for accurate diagnosis for patients suspected to have the disease.

Adult ; Base Sequence ; Connectin ; genetics ; Exons ; Female ; Humans ; Molecular Sequence Data ; Muscular Dystrophies, Limb-Girdle ; genetics ; Young Adult

OBJECTIVE: To explore the correlation between DSG2, TTN and GATA4 genes and Brugada syndrome in Henan Province of China. METHODS: From February 2017 to February 2019, 100 patients with Brugada syndrome and 100 healthy individuals were selected as the study and the control groups, respectively. Electrocardiogram and echocardiography were carried out, and peripheral blood samples was collected. Coding regions of DSG2, TTN and GATA4 genes were amplified by PCR and sequenced. The results were compared with standard sequences from GenBank. RESULTS: Electrocardiogram showed that all patients from the study group had ventricular arrhythmia, 87 cases (87%) presented ventricular tachycardia (VT), 84 cases (84%) presented T wave inversion, and 51 cases (51%) presented Epsilon wave. Echocardiography showed that the right ventricle in the study group was enlarged with the inner diameter of the right ventricle being (40.0±13.3) mm, and the right ventricle showed various degree of abnormal systolic function. The enlargement of right atrium accounted for 64%, and the involvement of the left ventricle accounted for 27%. The right ventricular diameter and left ventricular diastolic diameter of the study group were significantly greater than those of the control group (P< 0.05). DNA sequencing showed that 60 patients carried DSG2 gene variants, among which 18 had missense variant of exon 8. Fifty patients carried TTN gene variants, including 8 in the A-band domain and 3 in the I-band domain. Twenty patients carried 3 variants of the GATA4 gene. CONCLUSION Variants of the DSG2, TTN and GATA4 genes in Henan region are correlated with the onset of Brugada syndrome.
Arrhythmogenic Right Ventricular Dysplasia ; Brugada Syndrome/genetics* ; China ; Connectin ; Desmoglein 2/genetics* ; GATA4 Transcription Factor ; Humans ; Pedigree ; Sequence Analysis, DNA

OBJECTIVETitin is recently known as the largest protein which exists in the striated muscle sarcomere and is dynamic both in biomechanics properties and biochemical functions. Four possible disease-associated mutations located in three exons (3, 14, 49) of titin gene (TTN) have been identified in Japanese DCM patients in 2002. We observed the possible association of TTN mutation in Chinese patients with DCM.

METHODSThree exons of TTN (3, 14, 49) were screened in 117 DCM patients and 120 controls by polymerase chain reaction-single strand conformation polymorphisms (PCR-SSCP) and DNA sequence. SSCP was carried out following a protocol optimized for each PCR fragment after amplification. Abnormal SSCP results were subsequently confirmed by DNA sequencing.

RESULTSThe mutations reported in Japanese DCM patients were not identified in this patient cohort. A novel mutation [the G13053A (TTN cDNA sequence, X90568) change resulted in amino acid change at position 4351 (Gly4351Asp)] was found in two young DCM patients from a DCM family (1.7%). There was no similar mutation in controls.

CONCLUSIONThis novel Gly4351Asp mutation in TTN might be associated with DCM.

Aged ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; Cardiomyopathy, Dilated ; genetics ; Case-Control Studies ; Connectin ; DNA Mutational Analysis ; Female ; Genotype ; Humans ; Male ; Middle Aged ; Muscle Proteins ; genetics ; Mutation ; Polymorphism, Single-Stranded Conformational ; Protein Kinases ; genetics

To investigate whether transcription of hepatitis B virus (HBV) gene occurs in human sperm, total RNA was extracted from sperm of patients with chronic HBV infection (test-1), from donor sperm transfected with a plasmid containing the full-length HBV genome (test-2), and from nontransfected donor sperm (control), used as the template for reverse transcription-polymerase chain reaction (RT-PCR). Positive bands for HBV DNA were observed in the test groups but not in the control. Next, to identify the role of host genes in regulating viral gene transcription in sperm, total RNA was extracted from 2-cell embryos derived from hamster oocytes fertilized in vitro by HBV-transfected (test) or nontransfected (control) human sperm and successively subjected to SMART-PCR, suppression subtractive hybridization, T/A cloning, bacterial amplification, microarray hybridization, sequencing and the Basic Local Alignment Search Tool (BLAST) search to isolate differentially expressed genes. Twenty-nine sequences showing significant identity to five human gene families were identified, with chorionic somatomammotropin hormone 2 (CSH2), eukaryotic translation initiation factor 4 gamma 2 (EIF4G2), pterin-4 alpha-carbinolamine dehydratase 2 (PCBD2), pregnancy-specific beta-1-glycoprotein 4 (PSG4) and titin (TTN) selected to represent target genes. Using real-time quantitative RT-PCR (qRT-PCR), when CSH2 and PCBD2 (or EIF4G2, PSG4 and TTN) were silenced by RNA interference, transcriptional levels of HBV s and x genes significantly decreased (or increased) (P < 0.05). Silencing of a control gene in sperm did not significantly change transcription of HBV s and x genes (P > 0.05). This study provides the first experimental evidence that transcription of HBV genes occurs in human sperm and is regulated by host genes.
Animals ; Connectin/genetics* ; Cricetinae ; Eukaryotic Initiation Factor-4G/genetics* ; Gene Expression Regulation/genetics* ; Gene Silencing ; Growth Hormone/genetics* ; Hepatitis B Surface Antigens/genetics* ; Hepatitis B virus/genetics* ; Hepatitis B, Chronic/virology* ; Humans ; Hydro-Lyases/metabolism* ; Male ; Pregnancy-Specific beta 1-Glycoproteins/genetics* ; RNA, Viral/analysis* ; Spermatozoa/virology* ; Trans-Activators/genetics* ; Transcription, Genetic ; Transfection ; Viral Regulatory and Accessory Proteins