Impact of YTHDF1 gene polymorphisms on Wilms tumor susceptibility: A five‐center case‐control study

BackgroundWilms tumor is the most frequent renal malignancy in children. YTHDF1 is associated with the development of several kinds of cancers, yet whether common variants of the YTHDF1 gene influence Wilms tumor risk is unknown. We present, here, a hospital‐based case‐control study specifically designed to investigate the role of YTHDF1 genetic variants on Wilms tumor.MethodsWe successfully genotyped samples of 408 Wilms tumor cases and 1198 controls which were collected from five hospitals across China. The unconditional logistic regression was adopted to analyze the contributions of YTHDF1 gene single nucleotide polymorphisms (SNPs) to the risk of Wilms tumor. The odds ratio (OR) and 95% confidence interval (CI) were generated to evaluate the conferring risk of YTHDF1 gene SNPs (rs6011668 C>T, rs6090311 A>G).ResultsNeither of the two SNPs could contribute to the risk of Wilms tumor. A negative association was also detected in the combined effects of protective genotypes on Wilms tumor risk. The stratification analysis revealed that compared with those with CC genotype, rs6011668 CT/TT genotype was associated with increased Wilms tumor risk in those ≤18 months (OR = 1.54, 95% CI = 1.02–2.30, p = 0.038), and with decreased Wilms tumor risk in those >18 months (OR = 0.70, 95% CI = 0.50–0.97, p = 0.034).ConclusionOur present work sheds some light on the potential role of YTHDF1 gene polymorphisms on Wilms tumor risk.     

COVID‐19 in HIV‐positive patients: A systematic review of case reports and case series

IntroductionCoronavirus disease 2019 (COVID‐19) and acquired immune deficiency syndrome (AIDS) are two viral diseases for which there are currently no definitive treatments. Nowadays, because of the health system''s focus on the COVID‐19 epidemic, the control of human immunodeficiency virus (HIV) has received less attention. In this review, we will discuss the characteristics of COVID‐19 in HIV‐positive patients.Material and MethodsUsing the PRISMA guideline, the databases of Scopus, PubMed, and Web of Science were searched systematically from January 1, 2019 to February 24, 2021. The following keywords were used: “Human Immunodeficiency Virus,” “acquired immune deficiency syndrome,” “HIV,” “AIDS,” “COVID‐19,” “severe acute respiratory syndrome coronavirus 2,” “novel coronavirus,” “SARS‐CoV‐2,” “nCoV disease,” “SARS2,” and “2019‐nCoV disease.”ResultsTwenty‐one percent of studies were conducted in the USA (n = 13), 16% in China (n = 10), and 13% in Italy (n = 8), respectively. The majority of the patients were men (74.3%). Tenofovir disoproxil fumarate was used in 47.4% of patients, emtricitabine in 58.4%, and lamivudine in 34.8% to treat HIV. Symptoms of HIV patients with COVID‐19 included coughing (81.3%), fever (62.8%), and dyspnea (60%). Hydroxychloroquine (39.34%) and azithromycin (36.58%) were the common treatment options for COVID‐19. The total death rate in HIV‐positive patients with COVID‐19 was about 9%.ConclusionIn the current systematic review, we demonstrated that HIV‐positive patients co‐infected with COVID‐19 have high comorbidity of hypertension and diabetes mellitus. HIV/COVID‐19 co‐infection might have negatively influenced the HIV treatment and diagnosis, which indicates the need to regularly screen HIV patients in the COVID‐19 pandemic.     

Novel splicing‐site mutation in DCAF17 gene causing Woodhouse‐Sakati syndrome in a large consanguineous family

BackgroundWoodhouse‐Sakati syndrome is a rare autosomal recessive disease with endocrine and neuroectodermal aberrations with heterogeneous phenotypes and disease course. The most common phenotypes of the disease are progressive sensorineural hearing loss and alopecia, mild‐to‐moderate mental retardation and hypogonadism. The disease results from mutations in the DCAF17 gene.MethodHere, we reported a large consanguineous pedigree with multiple affected individuals with Woodhouse‐Sakati syndrome phenotypes. Laboratory tests confirmed the endocrine perturbance in affected individuals. To find out the underlying genetic change, whole‐exome sequencing was carried out.ResultAnalysis of the exome data identified a splicing‐site deletion {"type":"entrez-nucleotide","attrs":{"text":"NM_025000.3","term_id":"259906387","term_text":"NM_025000.3"}}NM_025000.3:c.1423‐1_1425delGACA in DCAF17 gene. Sanger sequencing confirmed the co‐segregation of the variant with the disease phenotypes in the family.ConclusionThe variant is predicted to cause aberrant splicing, i.e., exon skipping, resulting in the translation of a truncated functionless protein which results in appearance of typical phenotypic features and clinical laboratory findings of Woodhouse‐Sakati syndrome in affected members of the family.     

Rapid progression of myelofibrosis in polycythemia vera patient carrying SRSF2 c.284C>A p.(Pro95His) and unique ASXL1 splice site c.1720‐2A>G variant

BackgroundThe prognosis in polycythemia vera (PV) is comparatively favorable, but individual myelofibrosis/leukemic progression risk is heterogeneous. About a quarter of patients progress to the fibrotic phase after 20 years.MethodsMultiplex PCR, allele‐specific qPCR, high‐resolution melt analysis, and Sanger sequencing were used to detect BCR‐ABL, JAK2, ASXL1, SRSF2, U2AF1, and IDH1/2 variants.ResultsHerein, we present a PV patient with rapid progression to secondary myelofibrosis probably due to the coexistence of homozygous JAK2 V617F mutation, SRSF2 c.284C>A p.(Pro95His) and splice site variant of ASXL1 c.1720‐2A>G. The detected ASXL1 variant was first described in Bohring–Opitz syndrome and has not been reported in hematological malignancies so far. In the presented case, the ASXL1 VAF was stable (50%) during the 4‐year follow‐up, despite an evident increase in the JAK2 V617F VAF. Family history revealed cerebral palsy in the patient''s grandson; however, germline character of the ASXL1 variant was excluded.ConclusionThe biological consequences of the variant acquisition by hematopoietic stem cells (HSC) seem to be similar to other mutations of ASXL1 responsible for the truncation of ASXL1 protein, formation of hyperactive ASXL1–BAP1 (BRCA1‐associated protein‐1) complexes, and finally, the promotion of aberrant myeloid differentiation of HSC. Our report supports the hypothesis that ASXL1 alteration cooperates with JAK2 V617F leading to biased lineage skewing, favoring erythroid and megakaryocytic differentiation, accelerating the progression of PV to the fibrotic phase.     

A novel heterozygous HTRA1 mutation in an Asian family with CADASIL‐like disease

Background HTRA1 gene mutations are related to the pathogenesis of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). However, heterozygous HTRA1 mutations at specific sites can also lead to rare autosomal dominant cerebral artery disease (CADASIL‐like disease). To date, 28 heterozygous mutations in the HTRA1 gene have been reported to be related to CADASIL‐like diseases. Only one case of this disease was caused by a heterozygous mutation of c.497G>T in exon 2 of the HTRA1 gene.MethodsIn this case, we report on an Asian family with CADASIL‐like disease caused by a heterozygous mutation of c.497G>T in exon 2 of the HTRA1 gene. The clinical and imaging characteristics of the proband were summarized, and gene mutations were verified by whole‐exome sequencing (WES) and direct Sanger sequencing.ResultsThe result of the gene sequencing showed a heterozygous missense mutation at the c.497G>T locus of the HTRA1 gene in the proband of one sick family member, resulting in a change in amino acid (p.arg166leu).ConclusionThis is the first reported pathogenic mutation at the c.497G>T locus of the HTRA1 gene in an Asian population. It provides an important theoretical basis for the specific gene‐based diagnosis and treatment of CADASIL‐like diseases.     

The utility of SARS‐CoV‐2 nucleocapsid protein in laboratory diagnosis

BackgroundThe Coronavirus Disease 2019 (COVID‐19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which has now become a global pandemic owing to its high transmissibility. The SARS‐CoV‐2 nucleocapsid protein tests are playing an important role in screening and diagnosing patients with COVID‐19, and studies about the utility of SARS‐CoV‐2 nucleocapsid protein tests are increasing now.MethodsIn this review, all the relevant original studies were assessed by searching in electronic databases including Scopus, Pubmed, Embase, and Web of Science. “SARS‐CoV‐2”, “COVID‐19”, “nucleocapsid protein”, and “antigen detection” were used as keywords.ResultsIn this review, we summarized the utility of SARS‐CoV‐2 nucleocapsid protein in laboratory diagnosis. Among the representative researches, this review analyzed, the sensitivity of SARS‐CoV‐2 nucleocapsid protein detection varies from 13% to 87.9%, while the specificity could almost reach 100% in most studies. As a matter of fact, the sensitivity is around 50% and could be higher or lower due to the influential factors.ConclusionIt is well suggested that SARS‐CoV‐2 nucleocapsid protein is a convenient method with a short turnaround time of about half an hour, and the presence of N antigen is positively related to viral transmissibility, indicating that SARS‐CoV‐2 N protein immunoassays contribute to finding out those infected people rapidly and segregating them from the uninfected people.     

Current state of technologies and recognition of anti‐SSA/Ro antibodies in China: A multi‐center study

BackgroundPrevious studies have demonstrated that Ro60 and Ro52 have different clinical implications, and anti‐Ro52 antibodies are an independent serum marker of systemic autoimmune diseases, including Sjögren''s syndrome. Many different assays have been adopted to detect anti‐Sjögren''s syndrome antigen A (SSA)/Ro antibodies, while to date no specific approach has been recommended as optimal for anti‐SSA/Ro antibody testing. Herein, we performed a multi‐center study to explore the current clinical utility of different strategies for anti‐SSA/Ro antibody testing in China.MethodsTwenty‐one tertiary care centers were included in this questionnaire‐based study. The self‐administered questionnaire mainly includes testing methods for anti‐SSA/Ro antibodies, reporting system of results, and interpretation of results by clinicians.ResultsSix different methods were applied to detect anti‐SSA/Ro antibodies in the 21 centers. Line immunoassay (eight different commercial kits) was the most frequently adopted method (21/21, 100%), with different cutoff values and strategies for intensity stratification. There were two reporting systems: One was reported as “anti‐SSA antibodies” and “anti‐Ro52 antibodies” (12/21, 57%), while the other was “anti‐SSA/Ro60 antibodies” and “anti‐SSA/Ro52 antibodies” (9/21, 43%). Notably, six centers (29%) considered either positive anti‐Ro60 or anti‐Ro52 antibodies as positive anti‐SSA antibodies, all of which adopted the latter reporting system.ConclusionSignificant variabilities existed among anti‐SSA/Ro assays. Nearly 30% of centers misinterpreted the definition of positive anti‐SSA antibodies, which may be attributed to the confusing reporting systems of line immunoassay. Therefore, we advocate standardization of the nomenclature of anti‐SSA/Ro antibodies, changing the “anti‐SSA/Ro52” label in favor of the “anti‐Ro52” antibodies for a clear designation.     

Association of ISL1 polymorphisms and eosinophilic levels among otitis media patients

BackgroundOtitis media (OM) is a middle ear inflammatory complex disorder involving genetic and environmental factors. It onsets during childhood and often recurs and perplexes in genetically susceptible patients. Previously, murine models had shown the association of ISL LIM homeobox 1 (ISL1) gene with otitis media with effusion.AimTo investigate the association of ISL1 genetic variants with otitis media.Subjects and methodsA total of 285 cases and 277 controls were recruited for the study. The entire coding region of ISL1 gene was genotyped using Sanger sequencing or single‐strand conformation polymorphism methods. Genotype, haplotype, in silico analysis, and linkage disequilibrium analysis were performed.ResultsThe variants rs2303751 (c.504A>G) and rs121913540 (c.513G>A) were associated with OM, and the OR (95%CI) was 0.74 (0.57–0.95) and 0.43 (0.20–0.91), respectively. Besides, the rs2303751 AA genotype was associated with elevated eosinophil numbers in OM when compared to controls. The 5 SNP haplotype analysis of SNPs c.‐492A>G, c.504A>G, c.513G>A, c.576C>T, and c.*651A>T revealed A‐A‐G‐C‐A to be a risk haplotype in females whereas the 3 SNP haplotype analysis of SNPs c.504A>G, c.513G>A, and c.567C>T suggested G‐A‐C as protective and A‐G‐C to be a risk haplotype for otitis media.ConclusionOurs is the first report which shows a significant association of ISL1 variants (rs2303751 and rs121913540) with hearing‐related disorder like otitis media in humans. These results implicate the possible role of ISL1 gene in the etiopathology of otitis media. The replication of the study in other ethnic populations may strengthen our findings.     

Two novel SASH1 mutations in Chinese families with dyschromatosis universalis hereditaria

BackgroundDyschromatosis universalis hereditaria (DUH) is a rare genodermatosis characterized by hyper‐ and hypo‐pigmented macules on the face, trunk, and extremities. The condition causes severe cosmetic problem which can lead to significant psychological distress to the patients and bear a negative impact on society. DUH is a condition with genetic heterogeneity. The SASH1 gene was recently identified as pathogenic genes in DUH patients.MethodsTwo families clinically diagnosed with dyschromatosis universalis hereditaria were enrolled. Whole‐exome sequencing combined with Sanger sequencing and bioinformatics analysis was performed in the probands. MutationTaster, CADD, SIFT, PolyPhen‐2, and LRT software, and The American College of Medical Genetics and Genomics Standards and Guidelines were employed to assess the pathogenicity of detected missense mutations. One hundred healthy unrelated Chinese individuals were used as controls. All participants signed an informed consent form.ResultsGenetic screening revealed a heterozygous SASH1 c.1547G>A (p.Ser516Asn) mutation for patients in family 1, and SASH1 c.1547G>T (p.Ser516Ile) for family 2. Both such de novo mutations are located in a highly conserved SLY domain in SASH1, have not been previously reported in any publication, and were not detected in any control databases.ConclusionsThe novel heterozygous mutations, SASH1 c.1547G>A and c.1547G>T, are likely responsible for the DUH phenotype in these two families. Our study expands the mutation spectrum of DUH. Whole‐exome sequencing showed its efficiency in the diagnostic of hereditary skin disorders.     

A novel de novo missense mutation in EFTUD2 identified by whole‐exome sequencing in mandibulofacial dysostosis with microcephaly

BackgroundMandibulofacial dysostosis with microcephaly (MFDM) is a rare multiple malformation syndrome characterized by malar and mandibular hypoplasia and congenital‐ or postnatal‐onset microcephaly induced by haploinsufficiency of (elongation factor Tu GTP‐binding domain‐containing 2) EFTUD2.MethodsWe report the case of a 16‐month‐old boy with MFDM symptoms, including malar and mandibular hypoplasia, microcephaly, micrognathia, midline cleft palate, microtia, auditory canal atresia, severe sensorineural hearing loss, and developmental delay. Whole‐exome sequencing (WES) analysis of the patient''s family was performed to identify the genetic etiology responsible for this phenotype.ResultsWe identified a novel de novo missense mutation (c.671G>T, p.Gly224Val) in the EFTUD2. According to the American College of Medical Genetics and Genomics (ACMG) 2015 guidelines, the c.671G>T mutation was classified as likely pathogenic (PS2, PM1, PM2, and PP3). Based on our findings, prenatal diagnosis was performed on the second baby of the proband''s parents to exclude the mutation and it was confirmed that the baby did not have the MFDM phenotype after 14 months of follow‐up. Furthermore, the zebrafish model confirmed that the EFTUD2 c.671G>T mutation caused a loss of gene function in EFTUD2, and the pathogenicity of the EFTUD2 c.671G>T mutation was classified as pathogenic (PS2, PS3, PM1, and PM2).ConclusionOur results indicate that WES is a useful tool for identifying potentially pathogenic mutations, particularly in rare disorders, and is advantageous for genetic counseling and subsequent prenatal diagnosis. Moreover, the importance of functional assays cannot be underestimated, which could further confirm the pathogenicity of the genetic variants.     

The variations in human orphan G protein‐coupled receptor QRFPR affect PI3K‐AKT‐mTOR signaling

Background QRFPR is a recently identified member of the G protein‐coupled receptor and is an orphan receptor for 26Rfa, which plays important role in the regulation of many physiological functions.MethodsHere, we employed whole exome sequencing (WES) to examine the patients with intellectual disability (ID) and difficulty in feeding. We performed SIFT and PolyPhen2 predictions for the variants. The structure model was built from scratch by I‐TASSER. Here, results derived from a number of cell‐based functional assays, including shRNA experiment, intracellular Ca²⁺ measurement, the expression of PI3 K‐AKT‐mTOR, and phosphorylation. The functional effect of QRFPR variants on PI3K‐AKT‐mTOR signaling was evaluated in vitro transfection experiments.ResultHere, we identified two QRFPR variants at c.202 T>C (p.Y68H) and c.1111C>T (p.R371W) in 2 unrelated individuals. Structural analysis revealed that p.Y68H and p.R371W variants may affect the side chain structure of adjacent amino acids causing reduced binding of QRFPR to 26Rfa. The results show that QRFPR stimulated by 26Rfa leading to the transient rise of intracellular Ca²⁺. The QRFPR variations p.Y68H and p.R371 W can reduce the mobilization of intracellular Ca²⁺. The phosphorylation levels of the PI3K, Akt, and mTOR were significantly up‐ or downregulated by QRFPR overexpression or silencing, respectively. The QRFPR variations inhibited PI3K‐AKT‐mTOR signaling, resulting in downregulation of p‐mTOR.ConclusionsOur findings suggest that QRFPR acts as important role in neurodevelopment, and the effects of QRFPR are likely to be mediated by the Ca²⁺‐dependent PI3K‐AKT‐mTOR pathways. Importantly, these findings provide a foundation for future elucidation of GPCR‐mediated signaling and the physiological implications.     

Kynurenine pathway in Coronavirus disease (COVID‐19): Potential role in prognosis

BackgroundIt is known that inflammatory responses play an important role in the pathophysiology of COVID‐19.AimsIn this study, we aimed to examine the role of kynurenine (KYN) metabolism on the severity of COVID‐19 disease AQ5.Materials & MethodsSeventy COVID‐19 patients of varying severity and 30 controls were included in the study. In addition to the classical laboratory parameters, KYN, tryptophan (TRP), kynurenic acid (KYNA), 3 hydroxykynurenine (3OHKYN), quinolinic acid (QA), and picolinic acid (PA) were measured with mass spectrometry.ResultsTRP, KYN, KYN:TRP ratio, KYNA, 3OHKYN, PA, and QA results were found to be significantly different in COVID‐19 patients (p < 0.001 for all). The KYN:TRP ratio and PA of severe COVID‐19 patients was statistically higher than that of mild‐moderate COVID‐19 patients (p < 0.001 for all). When results were examined, statistically significant correlations with KYN:TRP ratio, IL‐6, ferritin, and procalcitonin were only found in COVID‐19 patients. ROC analysis indicated that highest AUC values were obtained by KYN:TRP ratio and PA (0.751 vs 0.742). In determining the severity of COVID‐19 disease, the odd ratios (and confidence intervals) of KYN:TRP ratio and PA levels that were adjusted according to age, gender, and comorbidity were determined to be 1.44 (1.1–1.87, p = 0.008) and 1.06 (1.02–1.11, p = 0.006), respectively.Discussion & ConclusionAccording to the results of this study, KYN metabolites play a role in the pathophysiology of COVID‐19, especially KYN:TRP ratio and PA could be markers for identification of severe COVID‐19 cases.     

Assessment of serum phenylalanine and tyrosine isomers in patients with ST‐segment elevation vs non‐ST‐segment elevation myocardial infarction

BackgroundUnder conditions of oxidative stress, hydroxyl radicals can oxidize phenylalanine (Phe) into various tyrosine (Tyr) isomers (meta‐, ortho‐, and para‐tyrosine; m‐, o‐, and p‐Tyr), depending on the location of the hydroxyl group on the oxidized benzyl ring. This study aimed to compare patients with ST‐segment elevation myocardial infarction (STEMI) and non‐STEMI (NSTEMI) and the serum levels of Phe and Tyr isomers at the aortic root and distal to the culprit lesion in both groups.MethodsForty‐four patients participated in the study: 23 with STEMI and 21 with NSTEMI. Arterial blood samples were taken from the aortic root through a guiding catheter and from the culprit vessel segment distal from the primary lesion with an aspiration catheter, during the percutaneous coronary intervention. Serum levels of Phe, p‐Tyr, m‐Tyr, and o‐Tyr were determined using reverse‐phase high‐performance liquid chromatography.ResultsSerum levels of Phe were significantly higher distal to the culprit lesion compared to the aortic root in patients with STEMI. Serum p‐Tyr/Phe and m‐Tyr/Phe concentration ratios were both lower distal to the culprit lesion than at the aortic root in patients with STEMI. There were no statistically significant differences with respect to changes in serum Phe and Tyr isomers distal to the culprit lesion compared to the aortic root in patients with NSTEMI.ConclusionOur data suggest that changes in serum levels of different Tyr isomers can mediate the effects of oxidative stress during myocardial infarction.     

Prolonged SARS‐Cov‐2 shedding with rapid IgG antibody decay in a COVID‐19 patient: A case report

BackgroundThe coronavirus disease 2019 (COVID‐19) epidemic is still spreading rapidly around the world. Recent cases with prolonged severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) RNA detection have been successively reported, and the phenomenon of false‐negative real‐time polymerase chain reaction (RT‐PCR) results of SARS‐CoV‐2 RNA or “repositive” was also described in COVID‐19 patients.MethodsWe report a 69‐year‐old female patient with hypertension, suspected lung tumor, and previous history of total hysterectomy for hysteromyoma who presented with moderate COVID‐19 symptoms and was positive for SARS‐CoV‐2 RNA by RT‐PCR when she traveled from the USA to China.ResultsThe patient required second and third re‐hospitalizations due to “repositive” SARS‐CoV‐2 throat swab test results during post‐charge solitary isolation and observation, and serum SARS‐CoV‐2‐IgG decayed rapidly before disappearing on illness Day 139 when the throat swab was still positive. The virus shedding lasted for at least 146 days (the last positive throat swab test result was on illness Day 146, and the first true‐negative test result was on illness Day 151) since her initial positive test.ConclusionProlonged SARS‐CoV‐2 RNA viral shedding is prone to occur in an immunocompromised host, wherein changes in the host immune status can lead to repeated positive SARS‐CoV‐2 detection. Moreover, the SARS‐CoV‐2‐IgG may decrease rapidly and disappear before virus removal, indicating there may be certain limitations on the protective effect of the SARS‐CoV‐2 antibody, which deserves clinical attention.     

Hematological changes associated with COVID‐19 infection

BackgroundThe unresolved COVID‐19 pandemic considerably impacts the health services in Iraq and worldwide. Consecutive waves of mutated virus increased virus spread and further constrained health systems. Although molecular identification of the virus by polymerase chain reaction is the only recommended method in diagnosing COVID‐19 infection, radiological, biochemical, and hematological studies are substantially important in risk stratification, patient follow‐up, and outcome prediction.AimThis narrative review summarized the hematological changes including the blood indices, coagulative indicators, and other associated biochemical laboratory markers in different stages of COVID‐19 infection, highlighting the diagnostic and prognostic significance.MethodsLiterature search was conducted for multiple combinations of different hematological tests and manifestations with novel COVID‐19 using the following key words: “hematological,” “complete blood count,” “lymphopenia,” “blood indices,” “markers” "platelet" OR "thrombocytopenia" AND "COVID‐19," "coronavirus2019," "2019‐nCoV," OR "SARS‐CoV‐2." Articles written in the English language and conducted on human samples between December 2019 and January 2021 were included.ResultsHematological changes are not reported in asymptomatic or presymptomatic COVID‐19 patients. In nonsevere cases, hematological changes are subtle, included mainly lymphocytopenia (80.4%). In severe, critically ill patients and those with cytokine storm, neutrophilia, lymphocytopenia, elevated D‐dimer, prolonged PT, and reduced fibrinogen are predictors of disease progression and adverse outcome.ConclusionMonitoring hematological changes in patients with COVID‐19 can predict patients needing additional care and stratify the risk for severe course of the disease. More studies are required in Iraq to reflect the hematological changes in COVID‐19 as compared to global data.     

Proline‐rich transmembrane protein 2 specifically binds to GluA1 but has no effect on AMPA receptor‐mediated synaptic transmission

BackgroundProline‐rich transmembrane protein 2 (PRRT2) is a neuron‐specific protein associated with seizures, dyskinesia, and intelligence deficit. Previous studies indicate that PRRT2 regulates neurotransmitter release from presynaptic membranes. However, PRRT2 can also bind AMPA‐type glutamate receptors (AMPARs), but its postsynaptic functions remain unclear.Methods and resultsWhole‐exome sequencing used to diagnose a patient with mental retardation identified a nonsense mutation in the PRRT2 gene (c.649C>T; p.R217X). To understand the pathology of the mutant, we cloned mouse Prrt2 cDNA and inserted a premature stop mutation at Arg223, the corresponding site of Arg217 in human PRRT2. In mouse hippocampal tissues, Prrt2 interacted with GluA1/A2 AMPAR heteromers but not GluA2/A3s, via binding to GluA1. Additionally, Prrt2 suppressed GluA1 expression and localization on cell membranes of HEK 293T cells. However, when Prrt2 was overexpressed in individual hippocampal neurons using in utero electroporation, AMPAR‐mediated synaptic transmission was unaffected. Deletion of Prrt2 with the CRIPR/Cas9 technique did not affect AMPAR‐mediated synaptic transmission. Furthermore, deletion or overexpression of Prrt2 did not affect GluA1 expression and distribution in primary neuronal culture.ConclusionsThe postsynaptic functions of Prrt2 demonstrate that Prrt2 specifically interacts with the AMPAR subunit GluA1 but does not regulate AMPAR‐mediated synaptic transmission. Therefore, our study experimentally excluded a postsynaptic regulatory mechanism of Prrt2. The pathology of PRRT2 variants in humans likely originates from defects in neurotransmitter release from the presynaptic membrane as suggested by recent studies.     

LncRNA UCA1, miR‐26a,and miR‐195 in coronary heart disease patients: Correlation with stenosis degree,cholesterol levels,inflammatory cytokines,and cell adhesion molecules

BackgroundLong noncoding RNA urothelial cancer‐associated 1 (lnc‐UCA1) targets microRNA‐26a (miR‐26a) and microRNA‐195 (miR‐195) to participate in coronary heart disease (CHD) progression via regulation of vascular smooth muscle cell and microvascular endothelial cell viability and mobility. Therefore, this study set out to further explore the relationship between lnc‐UCA1 and miR‐26a and miR‐195, along with their roles in the management of patients with CHD.MethodsOne hundred and thirty‐six CHD patients and 70 age‐/gender‐matched controls were recruited in this case‐control study. Their peripheral blood mononuclear cell samples were collected for lnc‐UCA1, miR‐26a, and miR‐195 measurement. Furthermore, serum samples from CHD patients were obtained for inflammatory cytokines and cell adhesion molecules measurement. The Gensini score was used to evaluate the stenosis severity in CHD patients.ResultsLnc‐UCA1 expression tend to be increased, while miR‐26a and miR‐195 expressions were reduced in patients with CHD compared to that of controls (all p < 0.001). In CHD patients, lnc‐UCA1 was negatively correlated with miR‐26a (p < 0.001) and miR‐195 (p = 0.014). Besides, lnc‐UCA1 was positively correlated with Gensini score (p < 0.001), total cholesterol (p = 0.019), low‐density lipoprotein cholesterol (p = 0.002), and C‐reactive protein (p < 0.001), while miR‐26a (p < 0.001) and miR‐195 (p = 0.002) were negatively correlated with Gensini score. What''s more, lnc‐UCA1 was positively correlated with tumor necrosis factor (TNF)‐α (p = 0.004), interleukin (IL)‐1β (p = 0.041), vascular cell adhesion molecule‐1 (VCAM‐1) (p = 0.010), and intercellular adhesion molecule‐1 (ICAM‐1) (p < 0.001). While miR‐26a was negatively correlated with some of the individual inflammatory cytokines and cell adhesion molecules.ConclusionLnc‐UCA1, miR‐26a, and miR‐195 may serve as potential biomarkers for CHD management.