Identification of a pathogenic SMCHD1 variant in a Chinese patient with bosma arhinia microphthalmia syndrome: a case report.

BACKGROUND: Bosma arhinia microphthalmia syndrome (BAMS; MIM603457) is a rare genetic disorder, predominantly autosomal dominant. It is a multi-system developmental disorder characterized by severe hypoplasia of the nose and eyes, and reproductive system defects. BAMS is extremely rare in the world and no cases have been reported in Chinese population so far. Pathogenic variants in the SMCHD1 gene (MIM614982) cause BAMS, while the underlying molecular mechanisms requires further investigation. CASE PRESENTATION: In this study, a Chinese girl who has suffered from congenital absence of nose and microphthalmia was enrolled and subsequently submitted to a comprehensive clinical and genetic evaluation. Whole-exome sequencing (WES) was employed to identify the genetic entity of thisgirl. A heterozygous pathogenic variant, NM_015295, c.1025G > C; p. (Trp342Ser) of SMCHD1 was identified. By performing very detailed physical and genetic examinations, the patient was diagnosed as BAMS. CONCLUSION: This report is the first description of a variant in SMCHD1 in a Chinese patient affected with BAMS.Our study not only furnished valuable genetic data for counseling of BAMS, but also confirmed the diagnosis of BAMS, which may help the management and prognosis for this patient.

Effect of hospital-community online management on medication management of elderly patients with peritoneal dialysis during COVID-19.

INTRODUCTION: The study aimed to explore feasibility and effect of hospital-community online management on the medication management of elderly peritoneal dialysis (PD) patients with end-stage renal disease (ESRD) during COVID-19. METHODS: A total of 160 patients receiving PD were randomly divided into the control (n = 80, outpatient follow-up management mode) and observation (n = 80, hospital-community online management mode) groups. The self-efficacy (General Self-Efficacy Scale [GSES]), medication adherence (8-item Morisky medication adherence scale [MMAS-8]), quality of life (kidney disease quality of life short form [KDQOL-SF]), and degree of depression (beck depression inventory [BDI]) before and after the intervention were compared. RESULTS: After the intervention, the scores of GSES (4.20 ± 0.46 vs. 3.09 ± 0.33), MMAS-8 (5.82 ± 0.92 vs. 5.13 ± 1.25), and KDQOL-SF were significantly higher, whereas the BDI score (9.50 ± 2.86 vs. 12.08 ± 2.95) was significantly lower in the observation group than in the control group (p < 0.05). CONCLUSION: Hospital-community online management presents good effects in the medication management of PD patients with ESRD.

Abnormal hemispheric specialization and inter-hemispheric functional cooperation in generalized anxiety disorder.

Abnormal hemispheric specialization and inter-hemispheric interactions may contribute to the pathogenesis of general anxiety disorder (GAD). The current study investigated these abnormalities in GAD patients based on the two analytic approaches and examined whether such abnormalities are correlated with anxiety symptom severity. Seventy-three patients with GAD and 60 matched healthy controls were recruited. All participants completed anxiety symptoms assessment and resting-state functional magnetic resonance imaging (rs-fMRI). The autonomy index (AI) and Connectivity between Functionally Homotopic voxels (CFH) were applied to measure and compared between groups. Compared to controls, patients showed stronger AI in the right middle temporal gyrus (MTG). Seed-based analysis revealed stronger functional connectivity (FC) of the right MTG with both right precuneus and right dorsolateral prefrontal cortex (dlPFC) in patients. Patients also exhibited greater CFH in right anterior cingulate cortex (ACC) but decreased CFH in bilateral postcentral gyrus (PCG) and superior occipital gyrus (SOG). Further there were significant correlations between these regional CFH and anxiety symptoms severity. GAD patients demonstrate right hemispheric specialization and aberrant inter-hemispheric functional cooperation, and abnormal inter-hemispheric coordination is associated with anxiety symptom severity. These findings provide a clue to understanding the neuropathological mechanisms of GAD.

Upregulation of miR-181a-5p and miR-125b-2-3p in the Maternal Circulation of Fetuses with Rh-Negative Hemolytic Disease of the Fetus and Newborn Could Be Related to Dysfunction of Placental Function.

The transplacental transfer of maternal antibodies to the fetus is a critical mechanism for infant protection and perinatal disease. Hemolytic disease of the fetus and newborn (HDFN) is a representative fetal disease caused by transplacental transfer of maternal IgG antibodies. However, it is unclear whether placental-related miRNAs are expressed in Rh-HDFN. Through the investigation of the miR-181a-5p and miR-125b-2-3p levels in maternal plasma using qPCR, we found that both miR-181a-5p and miR-125b-2-3p were highly expressed in maternal plasma of newborns with Rh-HDFN compared with healthy controls, indicating the potential roles of these two miRNAs in Rh-HDFN. To demonstrate whether dysregulation of miR-125b-2-3p and miR-181a-5p contributes to Rh-HDFN development, we analyze the placental miRNA-/mRNA sequencing data (GSE73714) using weighted gene coexpression network analysis (WGCNA), miRNA target predictive databases, and DAVID (Database for Annotation, Visualization, and Integrated Discovery). The results showed that miR-125b-2-3p and miR-181a-5p could regulate several biological processes including cytoplasmic microtubule organization and angiogenesis. Moreover, core promoter sequence-specific DNA binding and protein binding were highly enriched molecular functions, indicating the potential roles of transcriptional regulation. Further pathway enrichment showed that miR-181a-5p and miR-125b-2-3p could regulate several biological pathways that were closely related to placental function, including the FoxO signaling pathway, focal adhesion, mTOR signaling pathway, and central carbon metabolism in cancer. In conclusion, the present results first revealed miRNA expression in the maternal circulation of newborns with Rh-HDFN, which could be caused by dysfunction of the placenta.

A novel nonsense PKD1L1 variant cause heterotaxy syndrome with congenital asplenia in a Han Chinese patient.

Heterotaxy syndrome is a very rare congenital disease, which is caused by the disorder of left-right asymmetry during visceral development. However, pathogenic genetic lesions are found in less than 20% of HS patients. In this cohort study, whole-exome sequencing was performed for 110 patients with situs inversus or situs ambiguous. We identified a novel nonsense variant in PKD1L1(c.1387 C > T; p.463Gln*) in a Chinese patient with heterotaxy syndrome and congenital asplenia. This homozygous variant caused the domain of PKD1L1 complete absence. To our knowledge, this novel variant is the first phenotype of congenital asplenia found in patients with PKD1L1 variants, and the first PKD1L1 variant found in China. Our findings expand the spectrum of PKD1L1 variants and provide support for PKD1L1 variant and congenital asplenia, and the critical role of PKD1L1 during left-right patterning in the Han Chinese population.

Knockdown of growth factor receptor bound protein 7 suppresses angiogenesis by inhibiting the secretion of vascular endothelial growth factor A in ovarian cancer cells.

Growth factor receptor bound protein 7 (GRB7) plays an important role in regulating the growth and metastasis of ovarian cancer. Angiogenesis is the basis for the growth, invasion, and metastasis of malignant tumors. In the current study, we aimed to determine whether GRB7 plays a role in regulating angiogenesis in ovarian cancer. Immunohistochemistry on tissue microarray showed that GRB7 and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) protein expression were positively correlated in ovarian cancer tissues. GRB7 knockdown suppressed vascular endothelial growth factor A (VEGFA) expression and reduced VEGFA secretion. The effects of GRB7-silenced SKOV-3 cells on human umbilical vein endothelial cells (HUVECs) were evaluated using a transwell cell co-culture model, which showed that knockdown of GRB7 in SKOV-3 cells suppressed HUVEC proliferation, migration, invasion, and tube formation. Moreover, knockdown of GRB7 in SKOV-3 cells downregulated the expression of proteins associated with angiogenesis, including vascular endothelial growth factor receptor-2 (VEGFR2), mitogen-activated protein kinase kinase 1 (MAP2K1/MEK1), extracellular signal-regulated kinases 1 and 2 (ERK1/2), notch receptor 1 (NOTCH1), and delta-like canonical Notch ligand 4 (DLL4) in HUVECs. In conclusion, knockdown of GRB7 in ovarian cancer cells is an attractive potential therapeutic target for the suppression of angiogenesis in ovarian cancer. GRB7 may regulate angiogenesis through VEGFA/VEGFR2 signaling and its downstream pathways.

Case Report: BAF-Opathies/SSRIDDs Due to a de novo ACTL6A Variant, Previously Considered to Be Heart-Hand Syndrome.

Purpose: This study aims to identify genetic lesions in patients with congenital heart disease (CHD) with or without other phenotypes. In this study, over 400 patients were recruited and several novel variants in known causative genes were identified. A Chinese patient clinically diagnosed with HHS (patent ductus arteriosus, persistent left superior vena cava, and congenital absence of left arm radius) was included in the study cohort. Methods: Targeted, whole exome, and Sanger sequencing were performed to identify genetic lesions. The effects of the variant on ACTL6A RNA and protein were assessed using bioinformatics analysis. Results: At the start of the study, no mutations in known and candidate causative genes associated with CHD were identified. Seven years later, we noticed craniofacial deformities and identified a de novo heterozygous deletion variant in ACTL6A (NM_004301, c.478_478delT; p.F160Lfs*9). Intellectual disability and short stature were identified by a follow-up visit 10 years later. This variant leads to frameshift sequences and a premature termination codon and may affect the features of proteins. According to the nonsense-mediated mRNA decay theory, this variant may induce the decay of ACTL6A mRNA in patients. Conclusion: Our study reported the first ACTL6A variant in a Chinese individual, providing further evidence that ACTL6A is involved in heart and upper limb skeletal and intellectual development, thereby expanding the spectrum of ACTL6A variants. Thus, mutation analysis of the ACTL6A gene should be considered in patients with BAF-opathies or heart-hand syndromes due to potential misdiagnosis. Craniofacial dysmorphisms and intellectual disability are key to distinguishing these two diseases clinically, and attention to developmental delay/intellectual disability and craniofacial deformities will contribute to the diagnosis of BAF-opathies.

Case Report: Mutant SCN9A Susceptible to Charcot Neuroarthropathy in a Patient With Congenital Insensitivity to Pain.

Charcot neuroarthropathy is a systemic disease with pathological changes in the musculoskeletal system, which leads to fractures, dislocations, and deformities involving multiple bones and joints, particularly those of the feet. While the common underlying cause of Charcot neuroarthropathy is diabetes mellitus, it is also associated with congenital insensitivity to pain (CIP). CIP is a rare disorder caused by loss-of-function mutations in SCN9A encoding Nav1.7. In this study, we report a patient with CIP from a consanguineous family susceptible to Charcot neuroarthropathy with a novel SCN9A mutation. This report involves the case of a middle-aged man who suffered from CIP, had repeated painless fractures, and developed bone and joint destruction. The physical and radiological examinations revealed that multiple joints were swollen and deformed, and soft-tissue trauma was evident. We identified a novel homozygous SCN9A mutation (p.Cys1339Arg) by whole-exome sequencing (WES), which was verified using Sanger sequencing. In addition, the wild-type (WT) and mutated p. Cys1339Arg were assessed in HEK293 cells expressing Nav1.7, and the results showed that p. Cys1339Arg almost abolished the Nav1.7 sodium current. In conclusion, Charcot neuroarthropathy associated with CIP demonstrated a wider spectrum of Charcot neuroarthropathy than was previously recognized or documented. In addition, this finding is conducive to understanding the critical amino acids for maintaining the function of Nav1.7, thus contributing to the development of Nav1.7-targeted analgesics.

Identification of a Novel COL17A1 Compound Heterozygous Mutation in a Chinese Girl with Non-Herlitz Junctional Epidermolysis Bullosa.

Non-Herlitz junctional epidermolysis bullosa (JEB-nH), an autosomal recessive bullous genodermatosis, is characterized by generalized skin blistering from birth onward, dental anomalies, universal alopecia and nail dystrophy. The underlying defect is mutation of the COL17A1 gene encoding the type XVII collagen, resulting in losing structure for attachment of basal epithelial cells to the matrix. In present study, we described one case of congenitally affected female child aged 10 years, with skin blistering. Dermatologic examination revealed sparse, mild blisters on the face and hand, with profound enamel pitting of the teeth. Skin biopsy from proband's bullous skin displayed subepidermal bulla formation without acantholysis. The immunofluorescence of anti-type XVII collagen antibody staining showed loss of type XVII collagen staining at the basement membrane zone. A combination of whole exome sequencing (WES) and Sanger sequencing revealed the novel heterozygous mutations (c.4324C>T;p.Q1442* and c.1834G>C;p.G612R) in COL17A1 gene, which could be associated with the observed JEB-nH. One allele had a novel nonsense mutation (c.4324C>T;p.Q1442*), resulting in nonsense-mediated mRNA decay and truncated collagen XVII; the other allele had a novel missense mutation of c.1834G>C;p.G612R in exon 22, causing a glycine-to-arginine substitution in the Gly-X-Y triple helical repeating motifs and decreasing the thermal stability of collagen XVII. Our findings indicate that the genetic test based on WES can be useful in diagnosing JEB-nH patients. The novel pathogenic mutations identified would further expand our understanding of the mutation spectrum of COL17A1 gene in association with the inherited blistering diseases.

Alternative Oxidase Promotes Biofilm Formation of Candida albicans.

This study was designed to analyze the effect of the mitochondrial respiratory pathways of Candida albicans (C. albicans) on the biofilm formation. The 2, 3-bis (2-methoxy- 4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction assay was used to measure the metabolic activities of biofilms formed by the C. albicans which were cultured in the presence of respiratory pathways inhibitors. The biofilms formed by the wide type (WT), GOA7-deleted (GOA31), GOAV-reconstituted (GOA32), AOXla-deleted (AOX1) and AOXlb-deleted (AOX2) C. albicans strains were examined by the XTT reduction assay and fluorescence microscopy. The expression of adhesion-related genes BCR1, ALS1, ALS3, ECE1 and HWP1 in the biofilms formed by the above five C. albicans strains was detected by real time polymerase chain reaction. It was found that the metabolic activity of biofilms formed by C. albicans was decreased in the presence of alternative oxidase inhibitor whereas it was increased in the presence of classical mitochondrial respiratory pathway complex HI or complex IV inhibitor. AOX1 strain produced scarce biofilms interspersed with few hyphal filaments. Moreover, no significant changes in the expression of BCR1 and ALS3 were observed in the AOX1 strain, but the expression of ALSI and ECE1 was down-regulated, and that of HWP1 was up-regulated. These results indicate that both AOX1 and AOX2 can promote the biofilm formation. However, AOXla primarily plays a regulatory role in biofilm formation in the absence of inducers where the promoting effect is mainly achieved by promoting mycelial formation.