A novel hemizygous CD40L mutation of X-linked hyper IgM syndromes and compound heterozygous DOCK8 mutations of hyper IgE syndromes in two Chinese families.

X-linked hyper-immunoglobulin M (X-HIGM) syndrome and autosomal recessive hyper-immunoglobulin E syndrome (HIES) are rare inborn errors of immunity characterized by recurrent infections due to immune system impairment. In this study, we identified a novel hemizygous CD40 ligand (CD40L) mutation and compound heterozygous dedicator of cytokinesis-8 (DOCK8) mutations in two Han Chinese families with X-HIGM and HIES, respectively. We aimed to investigate the association between their genotypes and phenotypes. Genomic DNA was extracted from peripheral blood samples obtained from the families. Whole exome sequencing and Sanger sequencing were performed to identify and verify pathogenic variants in the two families. Clinical analyses of the probands were also performed. A novel hemizygous mutation of CD40L in exon 2 (c.257delA) was identified in the first proband, resulting in the substitution of glycine with glutamic acid at codon 86 of the protein. This leads to premature termination of translation at downstream codon 9 (p.E86Gfs*9). Sanger sequencing confirmed that the variant was inherited from the mother. The second proband carried two novel compound heterozygous mutations in DOCK8: one at exon 14 (c.1546C > G) inherited from the father, and the other at intron 41 (c.5355 + 6C > T; splicing) inherited from the mother. This study enhances our understanding of the pathogenetic mutation spectrum of CD40L and DOCK8 genes, facilitating the prenatal diagnosis of X-HIGM and HIES and enabling timely treatment of patients.

Abnormal H3K4 enzyme catalytic activity and neuronal morphology caused by ASH1L mutations in individuals with Tourette syndrome.

ASH1L potentially contributes to Tourette syndrome (TS) and other neuropsychiatric disorders, as our previous studies have shown. It regulates essential developmental genes by counteracting polycomb-mediated transcriptional repression, which restricts chromatin accessibility at target genes. ASH1L is highly expressed in the adult brain, playing a crucial role in the early stage. However, it remains unclear how ASH1L mutations carried by patients with TS participate in regulating neuronal growth processes leading to TS traits. Five TS families recruited in our study underwent comprehensive physical examinations and questionnaires to record clinical phenotypes and environmental impact factors. We validated the variants via Sanger sequencing and constructed two mutants near the catalytic domain of ASH1L. We conducted molecular modeling, in vitro assays, and primary neuron cultures to find the role of ASH1L in neuronal development and its correlation with TS. In this study, we validated five pathogenic ASH1L rare variants and observed symptoms in patients with simple tics and behavioral comorbidities. Mutations near the catalytic domain of TS patients cause mental state abnormalities and disrupt ASH1L function by destabilizing its spatial conformation, leading to decreased activity of catalytic H3K4, thereby affecting the neurite growth. We need to conduct larger-scale studies on TS patients and perform additional neurological evaluations on mature neurons. We first reported the effects of ASH1L mutations in TS patients, including phenotypic heterogeneity, protein function, and neurological growth. This information contributes to understanding the neurodevelopmental pathogenesis of TS in patients with ASH1L mutations.

[Genetic analysis of a child with Multiple congenital anomalies-hypotonia-seizures syndrome 1 due to variant of PIGN gene].

OBJECTIVE: To analyze the clinical phenotype and genetic etiology of a child with Multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1). METHODS: Clinical data of a 2-year-old boy who had presented at the Affiliated Hospital of Qingdao University in March 2023 for "intermittent limb twitching for 2 years" was collected. Peripheral blood samples were collected from the child and his parents for whole-exome sequencing (WES). Candidate variants were verified by Sanger sequencing and bioinformatic analysis based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). RESULTS: The child had manifested with distinctive facial features, limb deformities, hypotonia, motor and intellectual delays, and epileptic seizures. WES revealed that he has harbored compound heterozygous variants of the PIGN gene, namely c.963G>A (p.Q321=) and c.994A>T (p.I332F), which were inherited from his phenotypically normal mother and father, respectively. Based on the ACMG guidelines, the c.963G>A was classified as a pathogenic variant (PVS1+PM2_Supporting+PM3), whilst the c.994A>T was classified as a variant of uncertain significance (PM2_Supporting+PP3). CONCLUSION: Above discovery has expanded the mutational spectrum of the PIGN gene variants associated with MCAHS1, which may facilitate delineation of its genotype-phenotype correlation.

Exploring the role of exosomal MicroRNAs as potential biomarkers in preeclampsia.

The complex pathogenesis of preeclampsia (PE), a significant contributor to maternal and neonatal mortality globally, is poorly understood despite substantial research. This review explores the involvement of exosomal microRNAs (exomiRs) in PE, focusing on their impact on the protein kinase B (AKT)/hypoxia-inducible factor 1-α (HIF1α)/vascular endothelial growth factor (VEGF) signaling pathway as well as endothelial cell proliferation and migration. Specifically, this article amalgamates existing evidence to reveal the pivotal role of exomiRs in regulating mesenchymal stem cell and trophoblast function, placental angiogenesis, the renin-angiotensin system, and nitric oxide production, which may contribute to PE etiology. This review emphasizes the limited knowledge regarding the role of exomiRs in PE while underscoring the potential of exomiRs as non-invasive biomarkers for PE diagnosis, prediction, and treatment. Further, it provides valuable insights into the mechanisms of PE, highlighting exomiRs as key players with clinical implications, warranting further exploration to enhance the current understanding and the development of novel therapeutic interventions.

JAG1 Variants Confer Genetic Susceptibility to Thyroid Dysgenesis and Thyroid Dyshormonogenesis in 813 Congenital Hypothyroidism in China.

Background and Objective: Congenital hypothyroidism (CH) is indeed a prevalent neonatal endocrine disorder, affecting approximately 1 in 2000-3000 newborns worldwide, and 1 in 2400 newborns in China. Despite its high incidence, the genetic causes of CH, particularly those related to thyroid dysgenesis (TD), are still not well understood. However, previous studies have suggested that JAG1 may be a potential susceptibility gene for congenital thyroid defects. To explore the association between JAG1 and CH, we screened JAG1 variants in a large cohort of 813 CH patients. Methods: We performed genetic analysis of JAG1 using next-generation sequencing in 813 CH cases. The pathogenicity of the variants was assessed by bioinformatics softwares, protein sequence conservation analysis, and hydrophobic analysis. Further genetic analysis was conducted targeting 20 CH-related genes in these 25 JAG1 variant carriers. Results: We identified 10 pathogenic missense mutations (p.V45L, p.V272I, p.P552L, p.G610E, p.G852D, p.A891T, p.E1030K, p.R1060W, p.A1131T, p.P1174L) carried by 25 patients, the mutation rate of JAG1 in CH was 3.08%. Among these 25 patients, 16 with 1 variant, 6 with 2 variants, and the other 3 with 3 variants. Our findings indicated that JAG1 variants confer genetic susceptibility to both TD and DH, but with different inheritance models. JAG1 variants lead to TD mainly through monogenic model, while for DH cases, both monogenic mechanisms and oligogenic mechanisms play a pivotal role. Oligogenicity may contribute to the disease severity of DH. Conclusion: JAG1 is a shared genetic factor in TD and DH, with a detection rate of 3.08% in Chinese individuals with CH. A comparison between the oligogenic and monogenic groups suggests a gene dosage effect in CH. Patients with the same JAG1 mutation exhibit diverse clinical phenotypes, indicating complex mechanisms underlying phenotypic heterogeneity.

Congenital central hypoventilation syndrome in Chinese population: Analysis of three new cases and review of the literature.

BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is a rare autosomal dominant disease that is mainly caused by PHOX2B mutations. The purpose of this study is to analyze and summarize the clinical and genetic characteristics of CCHS patients in the Chinese population from our study and previous literature. METHODS: The potential pathogenic gene mutations of CCHS were identified and verified by next generation sequencing combined with Sanger sequencing, fluorescent probe PCR and capillary electrophoresis. The clinical characteristics and gene mutations of CCHS cases in Chinese population were summarized from our study and previous literature to explore the genotype-phenotype correlations. RESULTS: We identified 48 CCHS cases including three new cases from our report in China. Overall, 77.1% of the patients had PHOX2B polyalanine repeat expansion mutations (PARMs), and the remaining 22.9% had 10 distinct PHOX2B non-polyalanine repeat expansion mutations (NPARMs). Compared to those with PARMs, patients with NPARMs were more likely to have premature birth (54.5% vs. 2.8%, p < 0.001) and lower birth weight (33.3% vs. 3.2%, p = 0.030), with statistical significance. The patients with PARMs were more likely to have cardiovascular defects (64.9% vs. 27.3%, p = 0.063), cerebral hemorrhage (29.7% vs. 9.1%, p = 0.322) and seizures (37.8% vs. 9.1%, p = 0.151) than those with NPARMs, with no statistical significance. CONCLUSIONS: CCHS patients with PHOX2B NPARMs were more likely to have premature birth and low birth weight, while PHOX2B PARMs tended to be positively associated with the risk of cardiovascular defects, cerebral hemorrhage and seizures in Chinese population.

Impact of ferroptosis on preeclampsia: A review.

Preeclampsia (PE) is usually associated with the accumulation of reactive oxygen species (ROS) resulting from heightened oxidative stress (OS). Ferroptosis is a unique type of lipid peroxidation-induced iron-dependent cell death distinct from traditional apoptosis, necroptosis, and pyroptosis and most likely contributes considerable to PE pathogenesis. At approximately 10-12 weeks of gestation, trophoblasts create an environment rich in oxygen and iron. In patients with PE, ferroptosis-related genes such as HIF1 and MAPK8 are downregulated, whereas PLIN2 is upregulated. Furthermore, miR-30b-5p overexpression inhibits solute carrier family 11 member 2, resulting in a decrease in glutathione levels and an increase in the labile iron pool. At the maternal-fetal interface, physiological hypoxia/reperfusion and excessive iron result in lipid peroxidation and ROS production. Owing to the high expression of Fpn and polyunsaturated fatty acid-containing phospholipid-related enzymes, including acyl-CoA synthetase long-chain family member 4, lysophosphatidylcholine acyl-transferase 3, and spermidine/spermine N1-acetyltransferase 1, trophoblasts become more susceptible to OS and ROS damage. In stage 1, the injured trophoblasts exhibit poor invasion and incomplete uterine spiral artery remodeling caused by ferroptosis, leading to placental ischemia and hypoxia. Subsequently, ferroptosis marked by OS occurs in stage 2, eventually causing PE. We aimed to explore the new therapeutic target of PE through OS in ferroptosis.

Effect of the CYBA C242T Polymorphism on Preeclampsia Pathogenesis in the Chinese Population.

BACKGROUND: Although the mechanisms responsible for the pathogenesis of preeclampsia (PE) have not been entirely clarified, oxidative stress is thought to be its leading cause. As a major component responsible for reactive oxygen species (ROS) production during oxidative stress, p22phox, encoded by CYBA, is an essential subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The aim of this study was to investigate whether CYBA expression and its polymorphism are associated with PE. METHODS: Expression of CYBA was analysed in placentas from PE and control groups, as well as in HTR-8/SVneo cells stimulated with CoCl2 and TNF-α. Then, the CYBA C242T polymorphism in 1184 patients with PE and 1421 healthy controls was genotyped using the TaqMan probe, and the different distributions identified were confirmed by a case‒control association study. RESULTS: Expression of CYBA mRNA and protein in the placenta of pregnant women with PE was significantly increased compared to controls. Expression of CYBA mRNA was also increased in HTR-8/SVneo cells collected after 24 h of separate stimulation with cobalt chloride and TNF-α. There was no significant difference in the distribution of the C242T locus genotype and CYBA allele frequency between the case group and control group (P > 0.05). CONCLUSIONS: CYBA may play a role in the pathogenesis of oxidative stress in PE, in which it may function by cooperating with the TNF-α-related inflammatory pathway. Although no discrepant distribution of the CYBA C242T polymorphism in the Chinese population was detected, it is necessary to examine multiple CYBA SNPs in diverse populations and perform functional experiments to gain further insights into its pathogenesis.

Expression and immunogenicity of recombinant porcine epidemic diarrhea virus Nsp9.

Porcine epidemic diarrhea virus (PEDV) causes acute diarrhea, vomiting, dehydration, and high mortality in newborn piglets, which leads to significant economic losses. Coronavirus nonstructural protein 9 (Nsp9) is an essential RNA binding protein for coronavirus replication, which renders it a promising candidate for developing antiviral drugs and diagnosis targeting PEDV. In this study, PEDV Nsp9 protein fused with MBP protein and His-tag were expressed and purified in Escherichia coli. Furthermore, immunization of MBP-Nsp9 enhances both humoral and cellular immunity responses as compared with that of His-Nsp9 protein. Finally, the swine immunization showed that Nsp9 protein could stimulate the swine immunity system to carry out humoral immunity, and the generated antibody could inhibit the proliferation of PEDV in Vero cells. Altogether, our data provide direct evidence for the immunogenicity of PEDV Nsp9, which sheds light on the future developments of anti-PEDV drugs and vaccines for PED prevention.

Efficacy of resuscitative endovascular balloon occlusion of the aorta for hemorrhage control in patients with abnormally invasive placenta: a historical cohort study.

BACKGROUND: Patients with abnormally invasive placenta (AIP) are at high risk of massive postpartum hemorrhage. Resuscitative endovascular balloon occlusion of the aorta (REBOA), as an adjunct therapeutic strategy for hemostasis, offers the obstetrician an alternative for treating patients with AIP. This study aimed to evaluate the role of REBOA in hemorrhage control in patients with AIP. METHODS: This was a historical cohort study with prospectively collected data between January 2014 to July 2021 at a single tertiary center. According to delivery management, 364 singleton pregnant AIP patients desiring uterus preservation were separated into two groups. The study group (balloon group, n = 278) underwent REBOA during cesarean section, whereas the reference group (n = 86) did not undergo REBOA. Surgical details and maternal outcomes were collected. The primary outcome was estimated blood loss and the rate of uterine preservation. RESULTS: A total of 278 (76.4%) participants experienced REBOA during cesarean section. The patients in the balloon group had a smaller blood loss during cesarean Sect. (1370.5 [752.0] ml vs. 3536.8 [1383.2] ml; P < .001) and had their uterus salvaged more often (264 [95.0%] vs. 23 [26.7%]; P < .001). These patients were also less likely to be admitted to the intensive care unit after delivery (168 [60.4%] vs. 67 [77.9%]; P = .003) and had a shorter operating time (96.3 [37.6] min vs. 160.6 [45.5] min; P < .001). The rate of neonatal intensive care unit admission (176 [63.3%] vs. 52 [60.4%]; P = .70) and total maternal medical costs ($4925.4 [1740.7] vs. $5083.2 [1705.1]; P = .13) did not differ between the two groups. CONCLUSIONS: As a robust hemorrhage-control technique, REBOA can reduce intraoperative hemorrhage in patients with AIP. The next step is identifying associated risk factors and defining REBOA inclusion criteria to identify the subgroups of AIP patients who may benefit more.

On-chip ytterbium-doped lithium niobate waveguide amplifiers with high net internal gain.

Integrated optical systems based on lithium niobate on insulator (LNOI) have shown great potential in recent years. However, the LNOI platform is facing a shortage of active devices. Considering the significant progress made in rare-earth-doped LNOI lasers and amplifiers, the fabrication of on-chip ytterbium-doped LNOI waveguide amplifiers based on electron-beam lithography and inductively coupled plasma reactive ion etching was investigated. The signal amplification at lower pump power (<1 mW) was achieved by the fabricated waveguide amplifiers. A net internal gain of ∼18 dB/cm in the 1064 nm band was also achieved in the waveguide amplifiers under a pump power of 10 mW at 974 nm. This work proposes a new, to the best of our knowledge, active device for the LNOI integrated optical system. It may become an important basic component for lithium niobate thin-film integrated photonics in the future.

Two novel compound heterozygous variants of the GCDH gene in two Chinese families with glutaric acidaemia type I identified by high-throughput sequencing and a literature review.

Autosomal recessive glutaric acidaemia type I (GA-I) is a rare hereditary metabolic disease characterized by increased organic acids and neurologic symptoms. Although numerous variants in the GCDH gene have been identified to be connected with the pathogenesis of GA-I, the relationship between genotype and phenotype remains uncertain. In this study, we evaluated genetic data for two GA-I patients from Hubei, China, and we reviewed the previous research findings to clarify the genetic heterogeneity of GA-I and identify the potential causative variants. After we extracted genomic DNA from peripheral blood samples obtained from two unrelated Chinese families, we used target capture high-throughput sequencing combined with Sanger sequencing to determine likely pathogenic variants in the two probands. Electronic databases were also searched for the literature review. The genetic analysis revealed two compound heterozygous variants in the GCDH gene expected to lead to GA-I in the two probands (P1 and P2), with P1 carrying two known variants (c.892G > A/p. A298T and c.1244-2A > C/IVS10-2A > C) and P2 harbouring two novel variants (c.370G > T/p.G124W and c.473A > G/p.E158G). In the literature review, the most common alleles in low excretors (i.e., individuals with low excretion of GA) were R227P, V400M, M405V, and A298T, with variation in the severity of clinical phenotypes. Overall, we identified two novel GCDH gene candidate pathogenic variants in a Chinese patient, enriching the GCDH gene mutational spectrum and providing a solid foundation for the early diagnosis of GA-I patients with low excretion.

Mutation screening of eight genes and comparison of the clinical data in a Chinese cohort with congenital hypothyroidism.

BACKGROUND: Congenital hypothyroidism (CH) is a common neonatal endocrine disorder, characterized by irreversible intellectual disability and short stature if left untreated. It can be divided into thyroid dysgenesis (TD), including athyreosis, ectopy and hypoplasia, and dyshormonogenesis (DH), also referring to gland in situ (GIS), in which patients have eutopic thyroids with normal size or goiter. This study aims to analyze the clinical and genetic data of 375 Chinese CH patients without DUOX2 and thyroid transcription factor (TTF) variants, and to explore the mutation frequencies of the eight genes and the inheritance pattern of CH. METHODS: Targeted next generation sequencing (NGS) and statistical analysis were performed for mutation screening on eight CH-related genes and the comparison of clinical data in a cohort of 606 Chinese CH patients from Henan Province. RESULTS: A total of 104 variants were detected in genes required for thyroid formation (TSHR, GLIS3, BOREALIN, NTN1, JAG1 and TUBB1) and thyroid hormone synthesis (TG and TPO) in 83 subjects. Monogenic variants were the most prevalent with a percentage of 75.00% (78/104) followed by oligogenic variants (25.00%, 26/104). No differences were found in various clinical data between patients with and without variants. However, it should be noted that only initial L-T4 dose was statistically different between patients with monogenic variants and oligogenic variants. CONCLUSIONS: Our results suggested that apart from Mendelian monogenic inheritance, oligogenic inheritance of CH could not be excluded and also involves other factors, such as penetrance, epigenetic mechanisms and environmental factors.

Diagnostic value of non-coding RNAs in ovarian cancer.

The type of primary tumour of the ovary ranks first among all organs in the body. Although the incidence of malignant ovarian tumour ranks third among gynaecological malignancies, it is the most fatal type. A lack of effective diagnostic methods for early ovarian cancer remains, and the efficacy of advanced ovarian cancer is often unsatisfactory; the five-year survival rate of stage III-IV is less than 30%. Non-coding RNA is RNA that does not have protein-coding potential and was once considered as 'junk DNA'. However, increasing number of studies have shown that the disorder of non-coding RNA is related to a variety of diseases, including the occurrence and development of tumours. We summarised the dysregulated non-coding RNAs (miRNAs, circRNAs, and lncRNAs) reported currently in ovarian cancer and their functional mechanisms, and the clinical value of different types of ncRNAs as diagnostic or predictive markers for ovarian cancer, providing further evidence for non-coding RNAs to be considered as biomarkers of ovarian cancer.

Impact of SLC23A1 and SLC23A2 Polymorphisms on the Risk for Preeclampsia in a Chinese Han Population.

Solute carrier family 23 member 1 (SVCT1) and solute carrier family 23 member 2 (SVCT2), encoded by SLC23A1 and SLC23A2, may be associated with preeclampsia (PE). The purpose of this study was to investigate the association between polymorphisms of SLC23A1 and SLC23A2 and PE in Chinese Han population. The primers and double-labeled probes were designed according to the SNPs of rs10063949 in SLC23A1, rs6133175 and rs1279683 in SLC23A2. Genomic DNA was extracted from peripheral blood of 2,066 subjects (1,029 with PE and 1,037 without PE), and Taqman real-time PCR was used to detect the three SNPs. We observed a significant difference in genotypic frequency of the SLC23A2 rs6133175 polymorphism (χ2=8.08, p=0.02) between PE patients and controls, while no significant differences were found in the allelic frequencies (χ2=1.45, p=0.23). Then we fractionized these samples into the dominant model of the allele G (GG/AG+AA group) or the recessive model of the A allele (AA/AG+GG group), and observed a significant difference under the recessive model of the A allele (p=0.01, OR=0.71, 95% CI 0.55-0.92). Furthermore, there were no significant differences in the genotypic and allelic frequencies of rs10063949 and rs1279683 between PE patients and controls (for rs10063949, χ2=2.96, p=0.23 by genotype, χ2=2.11, p=0.15 by allele; for rs1279683, χ2=1.52, p=0.47 by genotype, χ2=0.64, p=0.44 by allele). We first found that SLC23A2 rs6133175 may be the certain genetic polymorphisms modulating their effects in the development of PE in a Chinese Han population and the AG or GG genotypes may be a risk factor for PE.

[Analysis of genetic variant in a patient with juvenile meterochromic leukodystrophy].

OBJECTIVE: To explore the genetic basis for a child with metachromatic leukodystrophy (MLD). METHODS: Clinical data of the patient was collected. Genomic DNA was extracted from peripheral blood samples of the child and his family members. Potential variant was screened by whole exome sequencing (WES), and candidate variant was verified by Sanger sequencing. The pathogenicity the variant was analyzed by multiple sequence alignment of the amino acid sequence and three-dimensional model prediction of its protein product. RESULTS: The child was found to harbor compound heterozygous variants c.257G>A (p.R86Q) and c.467del (p.G156Afs*6) of the ARSA gene, among which the c.467del (p.G156Afs*6) frameshift variation was unreported previously. Multiple sequence alignment showed that the site of the c.257G>A (p.R86Q) missense variant is highly conserved. Three-dimensional structure modeling analysis showed that the partial deletion due to the p.G156Afs*6 variant may cause significant alteration of the structure of ARSA protein. CONCLUSION: The discovery of novel variant in ARSA has enriched the mutational spectrum of MLD and may facilitate the understanding of the genotype-phenotype correlation of MLD.

Two Chinese siblings of combined oxidative phosphorylation deficiency 14 caused by compound heterozygous variants in FARS2.

BACKGROUND: As a rare mitochondrial disease, combined oxidative phosphorylation deficiency 14 (COXPD14) is caused by biallelic variants in the phenylalanyl-tRNA synthetase 2, mitochondrial gene (FARS2) with clinical features of developmental delay, an elevated lactate level, early-onset encephalopathy, liver failure, and hypotonia. The objectives of this study were to analyze the clinical and molecular features of two Chinese siblings affected with COXPD14, and to review relevant literature. METHODS: Mutation screening was performed by whole exome sequencing (WES) in combination with Sanger sequencing validation to identify the disease-causing variants of the two patients. RESULTS: The two siblings presented with severe clinical features and both progressed aggressively and failed to survive after treatment abandonment. We identified two compound heterozygous FARS2 variants c.925G>A p.Gly309Ser and c.943G>C p.Gly315Arg in this proband, which were inherited from the unaffected father and mother, respectively. In addition, Sanger sequencing confirmed that the elder affected sister carried the same compound heterozygous variants. The c.925G>A p.Gly309Ser variant is known and commonly reported in COXPD14 patients, while c.943G>C p.Gly315Arg is a novel one. Neither of the variants was found in 100 Chinese healthy controls. Both variants were classified as "deleterious" and were located in the highly conserved regions of the protein. The above results suggested that the two variants were likely causative in this COXPD14-affected pedigree. CONCLUSIONS: Our study expands the mutation spectrum of FARS2 and highlights the importance of genetic testing in the diagnosis of diseases with a wide variety of phenotypes, especially in the differential diagnosis of diseases.

WWC1, a target of miR-138-5p, facilitates the progression of prostate cancer.

BACKGROUND: WWC1 is known to be involved in the development of cancer. Therefore, it is critical to study the molecular mechanisms and cellular roles of WWC1 in cancer therapy. METHODS: In this study, we examined the effect of WWC1 on prostate cancer tumorigenesis and the role of miR-138-5p in prostate cancer. The expression levels of miR-138-5p and WWC1 in prostate cancer (Pca) tissues and cells were detected by real-time quantitative reverse transcription PCR and western blotting. Cell counting kit-8 and BrdU assays were performed to study cell proliferation and caspase-3 activity assay to detect apoptosis. Migration experiments were conducted to observe the movement ability of the cells. RESULTS: The expression of WWC1 in Pca tissues or cell lines was increased, whereas miR-138-5p expression was decreased. MiR-138-5p targeted and partially neutralized the role of WWC1 in Pca cells. Moreover, reduced expression of WWC1 in Pca cell lines suppressed cell proliferation and migration and promoted apoptosis in vitro. CONCLUSIONS: Collectively, these findings reveal a novel mechanism by which miR-138-5p negatively regulates WWC1 in Pca.

ASH1L may contribute to the risk of Tourette syndrome: Combination of family-based analysis and case-control study.

OBJECTIVE: Tourette syndrome (TS) is a childhood neurodevelopmental disorder caused by various genetic and environmental factors and presents with apparent genetic heterogeneity. As ASH1L potentially contributes to neurodevelopmental diseases, especially in TS, we aim to investigate the susceptibility of ASH1L on TS in the Chinese Han population. METHODS: Three tag single nucleotide polymorphisms (SNPs) (rs5005770, rs12734374, and rs35615695) in ASH1L were screened in 271 TS nuclear family trios and 337 healthy subjects by the TaqMan assays real time. A case-control study combined with family-based analysis was applied to study the genetic susceptibility of common variants of ASH1L. RESULTS: The results revealed a significant over-transmission of rs35615695 and rs5005770 (for rs35615695, transmission disequilibrium test, χ2  = 57.375, p = .000, HHRR, χ2  = 4.807, p = .028; for rs5005770, HRR, χ2  = 4.116, p = .042, HHRR, χ2  = 8.223, p = .004) in family-based study. Furthermore, rs5005770 and rs35615695 still remained significant after Bonferroni correction (p < .017). However, the two SNPs (rs5005770 and rs35615695) were found not to be associated with TS in case-control study. CONCLUSIONS: Our study suggests that ASH1L may contribute to TS susceptibility in the Han Chinese population and involved in TS development as a risk factor.

Role of histidine decarboxylase gene in the pathogenesis of Tourette syndrome.

Tourette syndrome (TS) is caused by complex genetic and environmental factors and is characterized by tics. Histidine decarboxylase (HDC) mutation is a rare genetic cause with high penetrance in patients with TS. HDC-knockout (KO) mice have similar behavioral and neurochemical abnormalities as patients with TS. Therefore, HDC-KO mice are considered a valuable TS pathophysiological model as it reveals the underlying pathological mechanisms that cannot be obtained from patients with TS, thus advancing the development of treatment strategies for TS and other tic disorders. This review summarizes some of the recent research hotspots and progress in HDC-KO mice, aiming to deepen our understanding of brain mechanisms relevant to TS. Furthermore, we encapsulate the possible brain nerve cell changes in HDC-KO mice and their potential roles in TS to provide multiple directions for the future research on tics.