Clinical characteristics and gene analysis of SMC1A gene related disorders / 中华神经科杂志

Objective:To analyze the clinical characteristics and genetic features of SMC1A gene related disorders. Methods:The data of 5 children with SMC1A gene variants were collected from Children′s Hospital of Fudan University from February 2018 to January 2022. The clinical features, electroencephalogram (EEG), brain imaging and gene testing results were summarized. Results:Among the 5 patients, 4 are females and 1 is male. Two female cases are siblings. One boy had dysmorphic features, consisting of bilateral ptosis, synophrys, a short nose and upturned nasal tip. He also had patent foramen ovale plus atrial septal defect, unilateral cryptorchidism and microcephaly. Three cases had microcephaly. Two girls had patent foramen ovale, and 2 girls had microcephaly. Four cases had epilepsy, and age at seizure onset ranged from 2 to 52 months. Multiple seizure types were observed, including bilateral tonic clonic seizures in 2 patients, and focal seizures in 3 patients. The seizures in 3 cases were in cluster. All patients had developmental delay, including 1 patient with mild and 4 patients with moderate to severe developmental delay. Three patients had slow background activity in EEG. Interictal EEG showed abnormal discharges in 4 patients, including focal discharges in 3 cases and generalized discharges in 1 case. Brain magnetic resonance imaging was normal in 3 patients and showed mild cortical thickening in 1 case. All cases harbored 4 SMC1A gene variants, including 2 missense variants and 2 frameshift variants (c.580_587del, c.2699delG, c.3362G>A, c.1486C>T). Three cases harbored heterozygous SMC1A variants and 2 cases carried somatic mosaic SMC1A variants with 17.5% and 88.1% mosaicism in peripheral blood. The follow-up lasted for 3 months to 4 years. The epilepsy was refractory in 2 cases. During the follow-up, all cases had very slow developmental progress or developmental retardation. All cases had different levels of growth retardation. The scores of Cornelia de Lange syndrome (CdLS) phenotypes in 5 cases were 2-6. One case had the combined phenotypes of atypical CdLS and developmental epileptic encephalopathy (DEE). The phenotype was atypical CdLS in 1 case and DEE in 1 case. The phenotypes of 2 cases with SMC1A missense variants were mild, manifesting as non-refractory epilepsy and moderate to severe developmental delay. Conclusions:All of cases with SMC1A gene variants have developmental delay. Most of the patients have clusters of seizures and some dysmorphisms. The phenotypes of SMC1A gene related disorders are diverse. Except CdLS and DEE, there are some patients with mild phenotype due to missense variants of SMC1A gene.

Cornelia de Lange syndrome with recurrent seizures and SMC1A gene c. 2923C > T mutation: a case report and literature review / 中华实用儿科临床杂志

Objective:To explore the characteristics, clinical manifestations and gene mutation types of Cornelia de Lange syndrome (CdLs), and to improve the understanding of the disease.Methods:Clinical data and gene test results of a pediatric case of CdLs diagnosed in the First Affiliated Hospital of Xinxiang Medical University in August 2019 were analyzed retrospectively.Results:A female patient with 2 years and 8 months old presented a special appearance with a low and flat nose, a wide eye distance, audition ears, a downward inclination of the mouth corner, a high arch of the jaw and a small jaw deformity, who had recurrent seizures, speech and mental retardation.The result of gene test showed the mutation of SMC1A gene c. 2923C > T, and thus the patient was diagnosed as type 2 CdLs. Conclusions:CdLs is a rare genetic metabolic disease with special facial features and physical signs.There is only one case of CdLs with gene mutation of SMC1A in China through literature review.The mutation of SMC1A gene c. 2923C>T in CdLs cases has not been reported at home and abroad, which expands the variation spectrum of the SMC1A gene.

Safe Male Circumcision for HIV Prevention among Adolescents with Deafness in Uganda: Awareness Prevalence and Implications for Policy and Programming

Background: Safe Male Circumcision (SMC)[1] has been widely recommended by WHO as part of a comprehensive HIV prevention strategy. However, literature pertaining to SMC amongst adolescents with a disability, and the deaf community in particular, is almost non-existent. This study sought to establish SMC prevalence, knowledge, attitude and post circumcision behaviour among adolescents with deafness in Uganda.Methods: The study was cross-sectional, used a mixed-methods approach and recruited 447 participants. 363 questionnaires were administered to adolescents of age 15 - 24 years (192 males and 171 females) from three study sites. We assessed socio-demographic variables, circumcision status, post circumcision behaviour, attitude and knowledge levels towards SMC. Qualitative data was also collected from 84 participants (m=46, f=38) using focus group discussions and key informant interviews. Quantitative data were analysed using Stata software while qualitative was thematically analysed.Results: A total of 60.9% male adolescents with deafness self-reported to be circumcised. Both male and female participants reported SMC information to be highly inaccessible (84%). Only 27.8% study participants knew about the partial protective effect of SMC against HIV, 51.8% were uncertain, while 26% thought that SMC provided full protection. Both male and female respondents had a positive attitude towards SMC (68.3%) and females were more knowledgeable (50.3%) about the partial preventive effect of SMC against HIV transmission and timeframe for the resumption of sexual activity compared to males (30.2%). Linkages were noted between SMC, social networks and key sociodemographic characteristics like ethnicity, religion and education level.Conclusion: Despite a 60.9% prevalence and general positive attitude towards SMC, study findings showed limited service access and substantial knowledge gaps in SMC efficacy, also related to high-risk behaviour after circumcision. This can largely be explained by limited targeting by HIV prevention programmes among this (deaf) category of adolescents, related barriers associated with vulnerability arising from their disability (deafness) and developmental stage (adolescence). Key actors in HIV prevention efforts should demonstrate cognizance of heightened risk among vulnerable adolescent categories through more inclusive interventions to address prevailing knowledge and service gaps. [1] This study was conducted between 2015-2016 when the commonly used term was Safe Male Circumcision (SMC) and not Voluntary Medical Male Circumcision (VMMC) as its popularly being packaged now. This manuscript has stuck to the originally used SMC acronym.

Proliferation, migration and apoptosis of acute myeloid leukemia cells regulated by mir-23a-3p targeting SMC1A and the mechanism / 中华肿瘤杂志

Objective@#To investigate the effects of miR-23a-3p on proliferation, migration and apoptosis on human acute myeloid leukemia (AML) cells by targeting SMC1A.@*Methods@#Microarray analysis was used to screen differentially expressed microRNAs and mRNAs in human AML cells. Real-time fluorescence quantitative PCR (RT-qRCR) was used to detect the expressions of miR-23a-3p and SMCA in human AML cell line U937. TargetScan database was used to analyze the correlation between miR-23a-3p and SMC1A. Double luciferase reporter gene was used to detect the interaction between miR-23a-3p and SMC1A. The effect of miR-23a-3p expression on the proliferation of U937 cells was detected by clonal assay. The migration, apoptosis, cell cycle and caspase-3 activity of U937 cells regulated by miR-23a-3p were detected by cell scratch assay and flow cytometry, respectively. Western blot was used to detect the expressions of Bax and Bcl-2 in U937 cells.@*Results@#Compared with human normal monocyte SC group (1.00), the expression of miR-23a-3p in U937 cells was up-regulated (2.56±0.78) (P<0.01), while the expression of SMC1A was down-regulated (0.48±0.56, P<0.01). miR-23a-3p specifically bond to SMC1A 3′UTR and regulated the expression activity of SMC1A. Overexpression of miR-23a-3p promoted the proliferation and migration of U937 cells and inhibited the apoptosis of U937 cells, while up-regulation of SMC1A inhibited the proliferation and migration of U937 cells and promoted the apoptosis of U937 cells. The percentages of G0/G1 phase, G2/M phase and S phase cells in the negative control group were (37.48±0.21)%, (16.78±0.18)% and (45.74±0.15)% respectively, and those in the miR-23a-3p mimics group were (19.96±0.11)%, (41.69±0.24)% and (38.24±0.34)%, respectively. The difference was statistically significant (all P<0.05). The proportions of G0/G1 phase, G2/M phase and S phase cells in the group of miR-23a-3p mimics+ pcDNA3.1-SMC1A were (36.88±0.21)%, (30.44±0.33)% and (32.88±0.16)%, respectively, without significant difference when compared with those of the miR-23a-3p mimics group (P>0.05). The relative expression levels of Bax and Bcl-2 protein in the negative control group were 0.55±0.45 and 0.31±0.54, respectively. Overexpression of miR-23a-3p inhibited the expression of Bax protein in U937 cells (0.23±0.13, P<0.001), promoted the expression of Bcl-2 protein (0.50±0.23, P<0.01), while SMC1A increased the expression of Bax protein in U937 cells (0.40±0.11, P<0.01), and inhibited the expression of Bcl-2 protein (0.37±0.15). In the negative control group, caspase-3 activity was (25.82±0.89)%. Overexpression of miR-23a-3p inhibited caspase-3 activity in U937 cells (3.64±0.56)%, P<0.01, while up-regulation of SMC1A promoted caspase-3 activity in U937 cells (15.29±0.85)%, P<0.01.@*Conclusion@#miR-23a-3p can inhibit the proliferation and migration and promote apoptosis of human AML cells by targeting SMC1A.

A family with X-linked Cornelia de Lange syndrome due to a novel SMC1A missense mutation identified by multi-gene panel sequencing

Cornelia de Lange syndrome (CdLS) is a rare, clinically and genetically heterogeneous, multi-system developmental disorder caused by mutations in genes that encode components of the cohesin complex. X-linked CdLS caused by an SMC1A mutation is an extremely rare disease characterized by phenotypes milder than those of classic CdLS. In the Republic of Korea, based on a literature review, one family with SMC1A-related CdLS with mild phenotypes has been genetically confirmed to date. In this study, we describe the clinical features of a Korean boy with a hemizygous novel missense mutation and his mother with a heterozygous mutation, i.e., c.2447G>A (p.Arg816His) in SMC1A, identified by multi-gene panel sequencing. The proband had a mild phenotype with typical facial features and his mother exhibited a mild, subclinical phenotype. This study expands the clinical spectrum of patients with X-linked CdLS caused by SMC1A variants. Moreover, these findings reinforce the notion that a dominant negative effect in a carrier female with a heterozygous mutation in SMC1A results in a phenotype milder than that in a male patient with the same mutation.

Effects of aralosdie C on excitation-contraction coupling of ischemia / reperfusion cardiomyocytes and role of CaMK II regulation / 中国药理学通报

Aim To investigate the effects of aralosdie C (SMC)isolated from aralosides on contractile func-tion and calcium transients in ischemia / reperfusion(I/R)-induced rat myocardial injury and the role of CaMK II. Methods The cardiomyocytes were divided into control group,I/ R group,I/ R + SMC group,KN-93+ I/ R + SMC group. The effect of SMC on the con-tractile function and calcium transient of I/ R cells was measured by cell shrinkage and ion concentration sim-ultaneous detection system. Results SMC(8 μmol· L - 1 )improved the contractile function of I/ R cardio-myocytes and the calcium transients,and SMC in-creased the rate of calcium transient and [Ca2 +]i up /down regulation significantly. While CaMK II was blocked by KN-93,the effect of SMC on contractile function and calcium transients was weakened. Con-clusions SMC can significantly improve the systolic function and calcium transients of cardiomyocytes in I/R rats,and the protective effect of SMC on cardiomyo-cytes may be related to CaMK II.

Novel Pathogenic Variant (c.3178G>A) in the SMC1A Gene in a Family With Cornelia de Lange Syndrome Identified by Exome Sequencing

Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous congenital anomaly. Mutations in the NIPBL gene account for a half of the affected individuals. We describe a family with CdLS carrying a novel pathogenic variant of the SMC1A gene identified by exome sequencing. The proband was a 3-yr-old boy presenting with a developmental delay. He had distinctive facial features without major structural anomalies and tested negative for the NIPBL gene. His younger sister, mother, and maternal grandmother presented with mild mental retardation. By exome sequencing of the proband, a novel SMC1A variant, c.3178G>A, was identified, which was expected to cause an amino acid substitution (p.Glu1060Lys) in the highly conserved coiled-coil domain of the SMC1A protein. Sanger sequencing confirmed that the three female relatives with mental retardation also carry this variant. Our results reveal that SMC1A gene defects are associated with milder phenotypes of CdLS. Furthermore, we showed that exome sequencing could be a useful tool to identify pathogenic variants in patients with CdLS.

The establishment and identification of human umbilical artery endothelial cells-smooth muscle cells co-culture model / 复旦学报（医学版）

Objective To establish a human umbilical artery EC-SMC co-culture model, and mimic the morphological and functional characteristics of human arterial wall, for further reseach of the pathological mechanism and therapy of atherosclerosis and imflammatory damage. Methods We secceeded in the primary culture of human umbilical artery endothelial cells (HUAEC) and human umbilical artery smooth muscle cells (HUASMC) by collagenase perfusion digestion and tissue planting, respectively. HUASMCs were incubated in a medium with ascorbic acid at the concentration greater than 50 μg/mL to produce collagen, which was considered as the extracellular matrix for ECs. Then HUAECs were seeded directly upon HUASMCs in a saturate density for sufficient direct physical interaction between ECs and SMCs. The morphological characteristic of EC-SMC co-culture was identified by immunofluorescence staining, and the function of EC-SMC co-culture was identified by Dil-Ac-LDL uptake test. Results The morphological identification showed that the entire surface of HUASMCs was covered by a confluent monolayer confluent monolayer, which indicated that the model had simulated the morphological characteristic of human arterial wall. The results of Dil-Ac-LDL uptake test showed that there was a fluorescent signal in HUAECs. Compared with EC monoculture, the Dil-Ac-LDL uptake of HUAECs was increased significantly in the co-culture system. All the reseach results indicated that there was an interaction between HUAECs and HUASMCs in the co-culture system. Conclusions In the present study, human umbilical artery EC-SMC co-culture model was constructed successfully, which could mimic the morphological characteristic and basic functions of human arterial wall.

A New Slip Knot with Locking Loop / 대한정형외과학회잡지

PURPOSE: To introduce a new arthroscopically tied knot with self-locking mechanism (SMC knot) and compare the knot security between the SMC knot and other arthroscopically tied knots used commonly in arthroscopic repair. MATERIALS AND METHODS: We performed tensile testing on SMC knot and four arthroscopically tied knots with No.2 Ethibond suture material. The four types of knot configurations were Tennessee knot, Duncan knot, Overhand throw knot and Revo knot. After knot creation, we measured displacement in cyclic loading, load at clinical failure, ultimate failure strength and mode of failure, using MTS Bionix test system and analyzed the data by One-way ANOVA. RESULTS: In cyclic loading, displacement of overhand throw knot was significantly higher than those of others. In clinical failure, load of SMC knot was significantly higher than those of Overhand knot and Duncan knot , but lower than that of Revo knot. In ultimate failure strength, load of SMC knot was higher than those of Overhand and Tennessee knot, but showed no difference with those of Duncan and Revo knots. As for failures, knot slippage occurred in the Overhand throw knot, Duncan knot and Tennessee knot, whereas knot breakage occurred in SMC knot and Revo knot. CONCLUSION: The results show that SMC knot is a safe arthroscopic knot that provides great knot security without slippage.

In vitro model of atherosclerosis using coculture of arterial wall cells and macrophage

In order to determine the precise mechanism of the interactions between different types of cells, which are common phenomena in tissues and organs, the importance of coculture techniques are becoming increasingly important. In the area of cardiology, artificial arteries have been developed, based on the understanding of physiological communication of the arterial smooth muscle cells (SMC), endothelial cells (EC), and the extracellular matrix (ECM). In the study of atherosclerosis, the modification of low-density lipoprotein (LDL), which result in the recruitment and accumulation of white blood cells, especially, monocytes/macrophages, and foam cell formation, are hypothesized. Although there are well known animal models, an in vitro model of atherogenesis with a precisely known atherogenesis mechanism has not yet been developed. In this paper, an arterial wall reconstruction model using rabbit primary cultivated aortic SMCs and ECs, was shown. In addition, human peripheral monocytes were used and the transmigration of monocytes was observed by scanning electron and laser confocal microscopy. Monocyte differentiation into macrophages was shown by immunohistochemistry and comprehensive gene expression analysis. With the modified form of LDL, the macrophages were observed to accumulate lipids with a foamy appearance and differentiate into the foam cells in the ECM between the ECs and SMCs in the area of our coculture model.