Somatic GATA4 mutation contributes to tetralogy of Fallot.

Tetralogy of Fallot (TOF) is the most prevalent cyanotic congenital heart pathology and causes infant morbidity and mortality worldwide. GATA-binding protein 4 (GATA4) serves as a pivotal transcriptional factor for embryonic cardiogenesis and germline GATA4 mutations are causally linked to TOF. However, the effects of somatic GATA4 mutations on the pathogenesis of TOF remain to be ascertained. In the present study, sequencing assay of GATA4 was performed utilizing genomic DNA derived from resected heart tissue specimens as well as matched peripheral blood specimens of 62 patients with non-familial TOF who underwent surgical treatment for TOF. Sequencing of GATA4 was also performed using the heart tissue specimens as well as matched peripheral venous blood samples of 68 sporadic cases who underwent heart valve displacement because of rheumatic heart disorder and the peripheral venous whole blood samples of 216 healthy subjects. The function of the mutant was explored by dual-luciferase activity analysis. Consequently, a new GATA4 mutation, NM_002052.5:c.708T>G;p.(Tyr236*), was found in the heart tissue of one patient with TOF. No mutation was detected in the heart tissue of the 68 cases suffering from rheumatic heart disorder or in the venous blood samples of all 346 individuals. GATA4 mutant failed to transactivate its target gene, myosin heavy chain 6. Additionally, this mutation nullified the synergistic transactivation between GATA4 and T-box transcription factor 5 or NK2 homeobox 5, two genes causative for TOF. Somatic GATA4 mutation predisposes TOF, highlighting the significant contribution of somatic variations to the molecular pathogenesis underpinning TOF.

A novel KLF13 mutation underlying congenital patent ductus arteriosus and ventricular septal defect, as well as bicuspid aortic valve.

Recently, mutations in the Kruppel-like factor 13 (KLF13) gene encoding a Kruppel-like transcription factor have been reported to cause congenital heart disease (CHD). However, due to pronounced genetic heterogeneity, the mutational spectrum of KLF13 in other cohorts of cases suffering from distinct types of CHD remain to be ascertained. In the present investigation, by Sanger sequencing of KLF13 in 316 unrelated cases affected by different forms of CHD, a new mutation in heterozygous status, NM_015995.3: c.430G>T; p.(Glu144*), was detected in an index patient affected with patent ductus arteriosus (PDA) and ventricular septal defect (VSD), as well as bicuspid aortic valve (BAV), with a mutation frequency of ~0.32%. Genetic investigation of the available family members of the proband demonstrated that the truncating mutation co-segregated with CHD. The nonsense mutation was not observed in 400 unrelated volunteers without CHD who were enrolled as control subjects. Quantitative biological measurements with dual luciferase reporters revealed that Glu144*-mutant KLF13 did not transactivate the downstream genes vascular endothelial growth factor A and natriuretic peptide A. In addition, the mutation abrogated the synergistic transcriptional activation between KLF13 and T-box transcription factor 5, a well-established CHD-causing gene. In conclusion, the present study indicates that genetically defective KLF13 contributes to familial PDA and VSD, as well as BAV, which expands the phenotypic spectrum linked to KLF13, and reveals a novel molecular pathogenesis of the disease, providing a new molecular target for the early prophylaxis and individualized treatment of CHD.

NR2F2 loss­of­function mutation is responsible for congenital bicuspid aortic valve.

Congenital bicuspid aortic valve (BAV) represents the most common type of cardiac birth defect affecting 0.4­2% of the general population, and accounts for a markedly increased incidence of life­threatening complications, including valvulopathy and aortopathy. Accumulating evidence has demonstrated the genetic basis of BAV. However, the genetic basis for BAV in the majority of cases remains to be elucidated. In the present study, the coding regions and splicing donors/acceptors of the nuclear receptor subfamily 2 group F member 2 (NR2F2) gene, which encodes a transcription factor essential for proper cardiovascular development, were sequenced in 176 unrelated cases of congenital BAV. The available family members of the proband carrying an identified NR2F2 mutation and 280 unrelated, sex­ and ethnicity­matched healthy individuals as controls were additionally genotyped for NR2F2. The functional effect of the mutation was characterized using a dual­luciferase reporter assay system. As a result, a novel heterozygous NR2F2 mutation, NM_021005.3: c.288C>A; p.(Cys96*), was identified in a family with BAV, which was transmitted in an autosomal dominant mode with complete penetrance. The nonsense mutation was absent from the 560 control chromosomes. Functional analysis identified that the mutant NR2F2 protein had no transcriptional activity. Furthermore, the mutation disrupted the synergistic transcriptional activation between NR2F2 and transcription factor GATA­4, another transcription factor that is associated with BAV. These findings suggested NR2F2 as a novel susceptibility gene of human BAV, which reveals a novel molecular pathogenesis underpinning BAV.

An Updated Meta-Analysis Comparing Artificial Cervical Disc Arthroplasty (CDA) Versus Anterior Cervical Discectomy and Fusion (ACDF) for the Treatment of Cervical Degenerative Disc Disease (CDDD).

STUDY DESIGN: A meta-analysis of published randomized controlled Trials (RCTs). OBJECTIVE: The aim of this study was to compare the efficacy and safety of cervical disc arthroplasty (CDA) with anterior cervical discectomy and fusion (ACDF) for the treatment of one-level cervical degenerative disc disease (CDDD). SUMMARY OF BACKGROUND DATA: ACDF has been widely performed for the treatment of CDDD. However, the loss of motion at the operated level has been hypothesized to accelerated adjacent-level disc degeneration. CDA is designed to avoid the side effect of fusion. However, it is still uncertain whether CDA is more effective and safer than ACDF. METHODS: We performed a meta-analysis of published RCTs to examine whether there was a superior clinical effects of CDA than ACDF. A PubMed database search through October 2014 was performed for relevant studies. We included RCTs that reported relevant data in the treatment of one-level CDDD, which were suitable for detailed extraction of data. RESULTS: We identified 18 RCTs eligible for analysis. The results of the meta-analysis indicated longer operative times, more blood loss, lower neck and arm pain scores reported on a visual analog scale (VAS), better neurological success, greater motion at the operated level, fewer secondary surgical procedures in the CDA group than in the ACDF group (P < 0.05). The 2 groups had similar lengths of hospital stay, Neck Disability Index scores, and rates of adverse events (P > 0.05). CONCLUSIONS: Findings of the present meta-analysis indicated that CDA was an effective and safe surgical procedure for the treatment of one-level CDDD, and CDA was found to be more superior than ACDF in terms of VAS neck and arm pain, neurological success, range of motion at the operated level, and secondary surgical procedures. LEVEL OF EVIDENCE: 1.

Course of major paravertebral vessels and the positional relationship to the vertebral bodies in healthy Chinese subjects: a CT-based study.

BACKGROUND: Several studies, including those done in China, report that paravertebral vascular injury during posterior spinal surgery can greatly harm patients, though it is a relatively rare complication. However, few studies have examined their course and anatomic relationship to the spine. The aim of this study was to measure the course of the major paravertebral vessels and their positional relationships to the vertebral bodies in Chinese subjects using computed tomography. METHODS: We studied a total of fifty subjects who underwent thoracolumbar computed tomography from T1-S1 at our institution. We measured the theoretical distance, actual distance, theoretical angle, and actual angle of the paravertebral vessels at each thoracolumbar intervertebral disc. RESULTS: The paravertebral artery actual angle at T4-L4 ranged from -11.41 to 79.75° and the actual distance from 16.98 to 52.53 mm. The actual angle of the inferior vena cava at L1-L5 intervertebral disc ranged from -40.75 to 34.50° and the actual distance from -36.63 to 61.69 mm. There was no significant difference in the actual angle of the paravertebral vein or in the actual distance in the thoracic segments according to gender (P > 0.05). However, the actual distance in the lumbar segments were significantly different according to gender (P < 0.05). CONCLUSIONS: The major paravertebral vessels' course is closer to the mid-sagittal plane as they move posterior along the vertebrae, and the actual distance of the paravertebral artery and azygos vein increase, while the actual distance of the inferior vena cava decreases. The course of the lumbar paravertebral vessels varies, especially at L4/L5, and may be more prone to intraoperative injury in female subjects.