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Vissers-Bodmer Syndrome, an autosomal dominant disease, is a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, hypotonia and autistic features with a highly variable phenotype. It is caused by variants in the CCR4-NOT transcription complex, subunit 1 gene (CNOT1). However, the pathophysiologic mechanism of the Vissers-Bodmer Syndrome remains unclear. Notably, this syndrome has not been previously reported in the Chinese. In this study, we utilized whole exome sequencing to identify three novel variants in the CNOT1 gene, encompassing one frameshift variant and two missense variants, in three Chinese patients mainly presenting with developmental delay, intellectual disability and/or autism. Interestingly, three patients exhibited novel manifestations including spina bifida occulta, horse-shoe kidney and café-au-lait spot. The frameshift variant, p.Gly172Alafs*5, occurring de novo, leading to a premature stop codon in the protein, was classified into pathogenic. Two missense variants c.3451A > G (p.Asn1151Asp) and c.557C > T (p.Ser186Phe) were predicted to be deleterious by multiple prediction algorithms with high conservation among a variety of species. Additionally, three-dimensional structure modeling and predicting indicated the substitution of the mutated amino acids would decrease the stability of CNOT1 protein. Given that CNOT1 is a relatively novel disease gene, we evaluated the gene-disease validity following ClinGen Standard Operating Procedure. The existing evidence substantiates a “Definitive” level of gene-disease relationship. The genetic findings provide a reliable basis for the genetic counseling of the family reproduction. Moreover, our results expand the genetic and phenotypic spectrum of CNOT1-related Vissers-Bodmer Syndrome.

Abstract Background Lysine acetyltransferase 6B (KAT6B) encodes a highly conserved histone acetyltransferase that regulates the expression of multiple genes and is essential for human growth and development. Methods We identified a novel frameshift variant c.3185del (p.leu1062Argfs*52) in a 5‐year‐old Chinese boy and further analyzed KAT6B expression and its interacting complexes and downstream products using real‐time quantitative polymerase chain reaction (qPCR). Furthermore, we assessed its three‐dimensional protein structure and compared the variant with other reported KAT6B variants. Results The deletion changed the leucine at position 1062 into an arginine, resulting in translation termination after base 3340, which may have affected protein stability and protein–protein interactions. KAT6B mRNA expression levels in this case were substantially different from those of the parents and controls in the same age range. There were also significant differences in mRNA expression levels among affected children's parents. RUNX2 and NR5A1, downstream products of the gene, affect the corresponding clinical symptoms. The mRNA expression levels of the two in children were lower than those of their parents and controls in the same age range. Conclusion This deletion in KAT6B may affect protein function and cause corresponding clinical symptoms through interactions with key complexes and downstream products.

Abstract Background Research on myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated disease (MOGAD) among Chinese children is relatively rare. Therefore, this study aimed to explore and analyze the clinical characteristics and prognoses of Chinese children with acquired demyelinating syndromes (ADSs) who tested positive or negative for MOG-Ab. Methods The clinical data of children with MOGAD who were treated in the Department of Neurology at Shanghai Children's Hospital from January 2017 to October 2021 were retrospectively collected. Results Among 90 children with ADSs, 30 were MOG-Ab-positive, and 60 were MOG-Ab-negative. MOG-Ab-positive children experienced more prodromal infections than did MOG-Ab-negative children (P

Dopa-responsive dystonia (DRD), also known as Segawa syndrome, is a rare neurotransmitter disease. The decrease in dopamine caused by tyrosine hydroxylase (TH) gene mutation may lead to dystonia, tremor and severe encephalopathy in children. Although the disease caused by recessive genetic mutation of the tyrosine hydroxylase (TH) gene is rare, we found that the clinical manifestations of seven children with tyrosine hydroxylase gene mutations are similar to dopa-responsive dystonia. To explore the clinical manifestations and possible pathogenesis of the disease, we analyzed the clinical data of seven patients. Next-generation sequencing showed that the TH gene mutation in three children was a reported homozygous mutation (c.698G>A). At the same time, two new mutations of the TH gene were found in other children: c.316_317insCGT, and c.832G>A (p.Ala278Thr). We collected venous blood from four patients with Segawa syndrome and their parents for real-time quantitative polymerase chain reaction analysis of TH gene expression. We predicted the structure and function of proteins on the missense mutation iterative thread assembly refinement (I-TASSER) server and studied the conservation of protein mutation sites. Combined with molecular biology experiments and related literature analysis, the qPCR results of two patients showed that the expression of the TH gene was lower than that in 10 normal controls, and the expression of the TH gene of one mother was lower than the average expression level. We speculated that mutation in the TH gene may clinically manifest by affecting the production of dopamine and catecholamine downstream, which enriches the gene pool of Segawa syndrome. At the same time, the application of levodopa is helpful to the study, diagnosis and treatment of Segawa syndrome.

BackgroundProline-rich transmembrane protein 2 (PRRT2) plays an important role in the central nervous system and mutations in the gene are implicated in a variety of neurological disorders. This study aimed to summarize the clinical characteristics and gene expression analysis of neurological diseases related to the PRRT2 gene and explore the clinical characteristics, therapeutic effects, and possible pathogenic mechanisms of related diseases.MethodsWe enrolled 10 children with PRRT2 mutation-related neurological diseases who visited the Children's Hospital affiliated with the Shanghai Jiaotong University School of Medicine/Shanghai Children's Hospital between May 2017 and February 2022. Video electroencephalography (VEEG), cranial imaging, treatment regimens, gene results, and gene expression were analyzed. Genetic testing involved targeted sequencing or whole-exome genome sequencing (WES). We further analyzed the expression and mutation conservation of PRRT2 and synaptosome-associated protein 25 (SNAP25) in blood samples using quantitative polymerase chain reaction (qPCR) and predicted the protein structure. Summary analysis of the reported gene maps and domains was also performed.ResultsTen children with PRRT2 gene mutations were analyzed, and 4 mutations were identified, consisting of 2 new (c.518A > C, p.Glu173 Ala; c.879 + 112G > A, p.?) and two known (c. 649 dup, p. Arg217Profs * 8; c. 649 del, p. Arg217Glufs * 12) mutations. Among these mutations, one was de novo(P6), and three could not be determined because one parent refused genetic testing. The clinical phenotypes were paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), epilepsy, infantile spasms, and intellectual disability. The qPCR results showed that PRRT2 gene expression levels were significantly lower in children and parent carriers than the control group. The SNAP25 gene expression level of affected children was significantly lower (P ≤ 0.001) than that of the control group. The mutation sites reported in this study are highly conserved in different species. Among the various drugs used, oxcarbazepine and sodium valproate were the most effective. All 10 children had a good disease prognosis, and 8 were completely controlled with no recurrence, whereas 2 had less severe and fewer seizures.ConclusionMutation of PRRT2 led to a significant decrease in its protein expression level and that of SNAP25, suggesting that the mutant protein may lead to the loss of its function and that of related proteins. This mutation site is highly conserved in most species, and there was no significant correlation between specific PRRT2 genotypes and clinical phenotypes. Asymptomatic carriers also have decreased gene expression levels, suggesting that more factors are involved.

Aberrant sialylation is frequently observed in tumor development, but which sialyltransferases are involved in this event are not well known. Herein, we performed comprehensive analyses on six ST3GAL family members, the α-2,3 sialyltransferases, in clear cell renal cell carcinoma (ccRCC) from public datasets. Only ST3GAL5 was consistently and significantly overexpressed in ccRCC (n = 791 in total), compared with normal kidney tissues. Its overexpression was positively correlated with tumor stage, grade, and the poor prognosis in ccRCC patients. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses indicated the involvement of ST3GAL5 in tumor immunoregulation. Then we revealed that ST3GAL5 expression showed a positive correlation with CD8+ T cell infiltration, using multiple tools on TIMER2.0 web server. Notably, ST3GAL5 overexpression was further identified to be associated with expression signature of CD8+ T cell exhaustion in ccRCC samples from three datasets (n = 867 in total; r > 0.3, p < 0.001). In our own ccRCC cohort (n = 45), immunohistochemistry and immunofluorescence staining confirmed that ST3GAL5 overexpression was accompanied by high CD8+ T cell infiltration with the increased exhaustion markers. Altogether, ST3GAL5 as a promising prognostic biomarker with CD8+ T cell exhaustion in ccRCC is indicated.

Sialylation aberration has been implicated in lung cancer development by altering signaling pathways. Hence, it is urgent to identify key sialyltransferases in the development of lung adenocarcinoma (LUAD), which is a common malignant subtype of non-small cell lung cancer. Herein, by systematically investigating the expression levels of ST3GAL family members in several public databases, we consistently found the frequent downregulation of ST3GAL6 in LUAD samples. Its downregulation is significantly negatively associated with stage, and significantly reduced in proximal-proliferative molecular subtype and predicts poor clinical outcomes. By protein–protein interaction network analysis and validation, we found that ST3GAL6 deficiency promotes LUAD cell invasiveness with the activated EGFR/MAPK signaling, accompanied by the elevated expression levels of matrix metalloproteinases 2 and 9, which can be partially reversed by EGFR inhibitor, gefitinib. Additionally, the ST3GAL6 level was positively regulated by ST3GAL6-AS1, an antisense long non-coding RNA to its host gene. The downregulation of ST3GAL6-AS1 also heralds a worse prognosis in LUAD patients and promotes LUAD cell invasiveness, recapitulating the function of its host gene, ST3GAL6. Altogether, ST3GAL6-AS1-regulated ST3GAL6 is a frequently downregulated sialyltransferase in LUAD patients and negatively regulates EGFR signaling, which can serve as a promising independent prognostic marker in LUAD patients.

Epilepsy of infancy with migrating focal seizures (EIMFS) is a kind of epileptic encephalopathy with high genetic heterogeneity. The most common pathogenic gene for EIMFS is potassium sodium-activated channel subfamily T member 1 (KCNT1). Using Sendai virus-mediated reprogramming, we established an induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells (PBMCs) of a five-month-old Chinese girl with heterozygous missense mutation (c.2800 G>A) in the KCNT1 gene. The iPSCs were stable during amplification, expressed pluripotent genes, maintained a normal karyotype, and showed characteristics of the three germs layers in an in vitro differentiation assay.

ObjectiveTo explore the correlation between serum 25-hydroxyvitamin D levels and tic disorders (TDs) in Chinese children.MethodsWe selected 2960 children with TD and 2665 healthy controls, aged 5–14 years, from the Department of Neurology of the Shanghai Children’s Hospital. Serum 25-hydroxyvitamin D levels and degrees of vitamin D deficiency were compared between patients with TD and healthy children.ResultsThe mean serum 25-hydroxyvitamin D level in the TD group was significantly lower than that in the control group (P < 0.001). The proportion of patients with 25-hydroxyvitamin D deficiency in the TD group was significantly higher than that in the control group. However, there was no correlation between 25-hydroxyvitamin D deficiency and the severity of TD. In addition, for age-wise comparison, mean levels of 25-hydroxyvitamin D and its deficiency in the TD group were the most significant in children over 9 years of age.ConclusionThere is a correlation between 25-hydroxyvitamin D deficiency and TD in Chinese children, but not between 25-hydroxyvitamin D deficiency and the severity of TD. There was a correlation between age and deficiency of 25-hydroxyvitamin D; this deficiency was most pronounced among those over the age of 9 years.

Aristaless-related homeobox (ARX)-related disorders are recessive X-linked intellectual disability disorders. We encountered a patient with a hemizygous mutation (c.1507_1508del) showing intellectual disability, early-onset epileptic encephalopathy and Ohtahara syndrome. The patient had female genitals, but an XY karyotype. We established an induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells (PBMCs) of a six-month Chinese child with a hemizygous mutation (c.1507_1508del) in ARX. The PBMCs were reprogrammed with Sendai viral vectors. The iPSCs showed stable amplification, pluripotency-related gene expression, and trilineage differentiation potential. Karyotype analysis of the iPSCs showed 23 pairs of chromosomes with normal structure and sex chromosome is XY.

Background: The chromodomain helicase DNA-binding protein 2 (CHD2) gene, is an ATPase and part of the CHD family of chromatin remodelers. Mutations in the CHD2 gene are inherited in an autosomal-dominant manner and can lead to intellectual disability, epilepsy, and autism. We investigated the clinical characteristics of CHD2-related conditions and their possible pathogenesis.Methods: We collected and analysed the clinical data of patients that were identified as having CHD2 mutations. Genetic testing was performed using targeted sequencing or whole-exome sequencing. We analysed the expression of CHD2 and repressor element 1-silencing transcription factor (REST) in blood samples using quantitative PCR and the conservation of the mutations. The CHD2 mutations we identified were compared with the known mutations reported in the CHD2-related literature.Results: Eight patients with CHD2 gene mutations were analysed. Six mutations were identified; four were unreported previously (c.670C>T; c.4012A>C; c.2416dup; c.1727–1728insAT), and two were known mutations: c.5035C>T (two cases) and c.4173dup (two cases). Among these mutations, seven were de novo mutations, and one could not be determined because the parents refused genetic testing. The clinical manifestations included mild or severe intellectual disability, epilepsy, and behavioural abnormalities. Quantitative PCR showed that the CHD2 gene expression levels among the patients, parents, and the controls were not significantly different. The levels of REST gene expression in the patients were significantly higher than those of the controls; thus, mutation of the CHD2 gene led to an increase in the expression level of the REST gene. The mutations reported were all located in conserved positions in different species. Among the various medications administered for treatment, valproate showed the best results for the treatment of epilepsy caused by CHD2 gene mutation.Conclusion: Mutation in CHD2 did not lead to a significant decrease in its expression level, indicating that the clinical phenotype was unrelated to its expression level, and the mutant protein may retain some function. Most of the mutations relatively stable. In addition, the clinical manifestations from the same mutation in the CHD2 gene were different among the known cases; this may be related to the regulation of REST or other regulatory factors.

The gene encoding collagen like tail subunit of asymmetric acetylcholinesterase (COLQ) is responsible for the transcription of three strands of collagen of acetylcholinesterase, which is attached to the endplate of neuromuscular junctions. Mutations in the COLQ gene are inherited in an autosomal-recessive manner and can lead to type V congenital myasthenia syndrome (CMS), which manifests as decreased muscle strength at birth or shortly after birth, respiratory failure, restricted eye movements, drooping of eyelids, and difficulty swallowing. Here we reported three variants within COLQ in two unrelated children with CMS. An intronic variant (c.393+1G>A) and a novel missense variant (p.Q381P) were identified as compound heterozygous in a 13-month-old boy, with the parents being carriers of each. An intragenic deletion including exons 14 and 15 was found in a homozygous state in a 12-year-old boy. We studied the relative expression of the COLQ and AChE gene in the probands' families, performed three-dimensional protein structural analysis, and analyzed the conservation of the missense mutation c.1142A>C (p.Q381P). The splicing mutation c.393+1G>A was found to affect the normal splicing of COLQ exon 5, resulting in a 27-bp deletion. The missense mutation c.1142A>C (p.Q381P) was located in a conserved position in different species. We found that homozygous deletion of COLQ exons 14–15 resulted in a 241-bp deletion, which decreased the number of amino acids and caused a frameshift translation. COLQ expression was significantly lower in the probands than in the probands' parents and siblings, while AChE expression was significantly higher. Moreover, the mutations were found to cause significant differences in the predicted three-dimensional structure of the protein. The splicing mutation c.393+1G>A, missense mutation c.1A>C (p.Q381P), and COLQ exon 14–15 deletion could cause CMS.

Mental retardation, X-linked 21/34 (MRX21/34), is a rare intellectual disability disease caused by mutations in the IL1RAPL1 (Interleukin-1 Receptor Accessory Protein-Like 1) gene. Using Sendai virus-mediated reprogramming, we established an induced pluripotent stem cell (iPSC) line from PBMCs collected from a ten-year-old boy with MRX21/34. The iPSCs showed stable amplification, expressed pluripotent genes, displayed a normal karyotype, and had characteristics of trilineage differentiation potential in an in vitro differentiation assay.

Allan–Herndon–Dudley syndrome (AHDS) is a rare, X-chromosome-linked inherited disorder that affects brain development and is caused by a mutation in SLC16A2. Herein, we generated an induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells of a one-year-old male infant with AHDS using Sendai-virus-mediated reprogramming. These iPSCs exhibited stable amplification, expressed pluripotent markers, and differentiated spontaneously into three germ layers in vitro. Additionally, this iPSC line was found to maintain a normal karyotype and retain the pathogenic mutation in SLC16A2, facilitating the study of disease mechanisms and development of new therapies of AHDS.

Mediator complex subunit 12 (MED12)-related disorders are recessive-X-linked intellectual disabilities present primarily in male patients. We came across a female patient with a heterozygous mutation (c.1249-1G > C) related to MED12-related syndrome. MED12 expression was significantly lower than that in her parents, and another X chromosome was inactive. We established an induced pluripotent stem cell (iPSC) line from peripheral blood mononuclear cells (PBMCs) of a 1-year old Chinese girl with a heterozygous mutation (c.1249-1G > C) in MED12. PBMCs were reprogrammed using nonintegrative Sendai viral vectors. The iPSCs showed stable amplification, pluripotency-related gene expression, trilineage differentiation potential, and a normal karyotype.

Mitochondrial DNA depletion syndrome-13 (MTDPS13) is a rare autosomal recessive mitochondrial disease caused by mutations in the FBXL4 (F-box and leucine-rich repeat protein 4) gene. Using Sendai virus-mediated reprogramming, we established an induced pluripotent stem cell (iPSC) line from PBMCs collected from a one-year-old female patient with MTDPS13. The iPSCs were stable during amplification, expressed pluripotent genes, maintained a normal karyotype, and showed characteristics of the three germs layers in an in vitro differentiation assay.

This article explores the idea of women's empowerment as a key element in such a philosophy. It outlines the four pillars of empowerment--economic, political, knowledge, and psychological--on the basis of empirical study. The most successful cases of emancipation via education have taken place in informal education programmes that aim to encourage critical thinking on gendered social norms and the encouragement of corrective measures. So, the paper says, both macro- and micro-level interventions are necessary to establish a changed gender division of labour, with the former focusing on the private sphere, which severely restricts women's availability and opportunities for transformational action. Women's empowerment relies heavily on the development of agency, both on an individual and collective scale. For this to work, non-governmental organizations (NGOs) led by women must be involved. Policy challenges are discussed in the last section of the article. This paper concluded that when compared to their male counterparts, female Chinese school leaders were more pessimistic about the progress towards gender parity in contemporary China. Despite this, many of our participants painted an optimistic picture of gender relations in Chinese schools, with many assuming they were working towards achieving gender parity for all of their pupils. Women's empowerment remains a promising theoretical premise that has not received concomitant operationalization and support to reach its full range of possibilities, so there is a need to challenge its normative meaning and demand that it be taken seriously as a theory of change in gender relations. [ABSTRACT FROM AUTHOR]

As Chinese women become more educated and participate in the labor force, they earn more money independently. At the same time, thanks to China's one-child policy, women have gained more intergenerational wealth. The economic foundation allowed Chinese women to play bigger power in the consumer market, and a phenomenon called "Her Economy" since 2007. The improvement of discourse power and economic empowerment of Chinese women in the consumer market rendered them better achieve self-empowerment. However, female behavior is also shaped by society, and female consumption is more likely to be influenced by consumer culture and become the background board of consumer society, and women find it difficult to achieve real empowerment through consumption. Although the existing literature has explored this issue, the research field has not been extended to Chinese female consumers, and the theoretical perspective of empowerment is lacking. Thus, this paper reviews women's consumption and empowerment in China from a critical perspective. [ABSTRACT FROM AUTHOR]

Aberrant sialylation is frequently observed in tumor development, but which sialyltransferases are involved in this event are not well known. Herein, we performed comprehensive analyses on six ST3GAL family members, the α-2,3 sialyltransferases, in clear cell renal cell carcinoma (ccRCC) from public datasets. Only ST3GAL5 was consistently and significantly overexpressed in ccRCC (n = 791 in total), compared with normal kidney tissues. Its overexpression was positively correlated with tumor stage, grade, and the poor prognosis in ccRCC patients. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses indicated the involvement of ST3GAL5 in tumor immunoregulation. Then we revealed that ST3GAL5 expression showed a positive correlation with CD8+ T cell infiltration, using multiple tools on TIMER2.0 web server. Notably, ST3GAL5 overexpression was further identified to be associated with expression signature of CD8+ T cell exhaustion in ccRCC samples from three datasets (n = 867 in total; r > 0.3, p < 0.001). In our own ccRCC cohort (n = 45), immunohistochemistry and immunofluorescence staining confirmed that ST3GAL5 overexpression was accompanied by high CD8+ T cell infiltration with the increased exhaustion markers. Altogether, ST3GAL5 as a promising prognostic biomarker with CD8+ T cell exhaustion in ccRCC is indicated. [ABSTRACT FROM AUTHOR]