Biallelic variants in RBM42 cause a multisystem disorder with neurological, facial, cardiac, and musculoskeletal involvement

Here, we report a previously unrecognized syndromic neurodevelopmental disorder associated with biallelic loss-of-function variants in the RBM42 gene. The patient is a 2-year-old female with severe central nervous system (CNS) abnormalities, hypotonia, hearing loss, congenital heart defects, and dysmorphic facial features. Familial whole-exome sequencing (WES) reveals that the patient has two compound heterozygous variants, c.304C>T (p.R102*) and c.1312G>A (p.A438T), in the RBM42 gene which encodes an integral component of splicing complex in the RNA-binding motif protein family. The p.A438T variant is in the RRM domain which impairs RBM42 protein stability in vivo. Additionally, p.A438T disrupts the interaction of RBM42 with hnRNP K, which is the causative gene for Au-Kline syndrome with overlapping disease characteristics seen in the index patient. The human R102* or A438T mutant protein failed to fully rescue the growth defects of RBM42 ortholog knockout ΔFgRbp1 in Fusarium while it was rescued by the wild-type (WT) human RBM42. A mouse model carrying Rbm42 compound heterozygous variants, c.280C>T (p.Q94*) and c.1306_1308delinsACA (p.A436T), demonstrated gross fetal developmental defects and most of the double mutant animals died by E13.5. RNA-seq data confirmed that Rbm42 was involved in neurological and myocardial functions with an essential role in alternative splicing (AS). Overall, we present clinical, genetic, and functional data to demonstrate that defects in RBM42 constitute the underlying etiology of a new neurodevelopmental disease which links the dysregulation of global AS to abnormal embryonic development.

Establishment and evaluation of mouse models of septic myocardial injury / 中华危重病急救医学

Objective Mouse models of sepsis-induced myocardial injury by intraperitoneal injection of lipopolysaccharide (LPS) was established in order to provide a reliable method for the research of pathogenesis of sepsis-induced myocardial injury. Methods According to the method of random number table, a total of 150 male C57BL/6 mice were divided into five groups: NC group, sham group, and LPS 10, 12, 15 mg/kg groups, with 30 in each group. Septic myocardial injury was induced by intraperitoneal injection LPS in mice; sham group was injected with equal 0.9% saline; while there was no treatment in mice of NC group. Fifteen of the 30 mice in each group were used to observe the general status of mice before and after LPS or saline injection. Twenty-four hours after LPS or saline injection, the left ventricular function was assessed by echocardiography, serum level of cardiac troponin (cTnI) was determined by enzyme linked immunosorbent assays (ELISA), and the cardiac histomorphology and ultrastructure were observed; the other 15 mice were used to monitor the 7-day mortality after LPS or saline injection. Results The mice challenged to LPS displayed symptoms of sepsis, such as depression, ruffled fur, and diarrhea. Compared with NC group, left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS) were significantly decreased at 24 hours after LPS administration in LPS 10, 12, 15 mg/kg groups [LVEF: 0.459±0.044, 0.432±0.034, 0.348±0.064 vs. 0.588±0.019, LVFS: (22.36±2.60)%, (20.78±1.91)%, (16.27±3.31)% vs. (30.55±1.30)%, all P < 0.01], and cTnI levels were significantly increased (ng/L: 270.40±43.50, 281.14±41.79, 298.39±42.05 vs. 192.59±16.90, all P <0.01). Myocardium injury was observed in three LPS groups, myocardial fibrosis, interstitial edema, erythrocyte leakage and infiltrating inflammatory cells were observed under light-microscope; ultrastructural changes disorderly arranged in cardiac muscle fibers, mitochondrial swelling and even partly missing mitochondria cristae were found under transmission electron microscope (TEM), and the higher of the dose, the more sever of the damage. There was no significant difference between sham group and NC group. The 7-day mortality in LPS 10, 12, 15 mg/kg groups were 33.3%, 53.3% and 86.7%, respectively, while no death in the NC group and sham group. Conclusion For establishing the mouse model of sepsis-induced myocardial injury, intraperitoneal injection with 12 mg/kg LPS is a preferable choice in our research.

Diagnostic value of AFU, TGF-α and Fer in the AFP lowly expression primary hepatic carcinoma / 肿瘤研究与临床

Objective To study the diagnostic value of serum α-L-fueosidase (AFU), transforming growth factor alpha(TGF-α)and ferritin (Fer) in primary hepatic carcinoma (PHC). Methods AFU and Fer in the serum were studied in 36 patients with benign hepatism and 56 patients with low concentration AFP of PHC hepatic carcinoma by automatic biochemistry analyzer Roche Modular. ELISA was used to assay the degree of TGF-α The sensitivity and specificity of AFU, TGF-α and Fer for low expression AFP of PHC were evaluated by ROC curve. Results The serum AFU, Fer and TGF-α levels were all significant difference in the patients than those in controls (P <0.05). The area under ROC curve of these indexes in descending order was AFU (0.707), TGF-α (0.677) and Fer (0.592). The diagnostic sensitivity of Fer was lower than AFU and TGF-α in diagnosis of AFP lowly expression PHC. The ratio showed AFU better than TGF-α The diagnostic specificity of AFU (64 %) was higher than that of TGF-α (61%) when TGF-α and AFU was at the same diagnostic sensitivity (64 %). Conclusion AFU is more valuable than Fer and TGF-α for negative or AFP lowly expression PHC, meanwhile it has much more accuracy.