Common Mutations Research Articles

Virologic Failure, Clinical Characteristics, and Common Viral Mutations in HIV Patients From Southwestern Colombia: A Nested Case-Control Study.

Introduction Virologic failure due to antiretroviral drug resistance is a threat to efforts to control the human immunodeficiency virus (HIV) epidemic. Understanding the factors that influence the genetic and clinical expression of drug resistance is fundamental for infection control. Methods A nested case-control study was conducted on a cohort of adult HIV patients between 2016 and 2022. The cases were defined as patients with a confirmed diagnosis of virologic failure due to drug resistance, as indicated by a viral genotype result. The control group consisted of patients who had not experienced virologic failure or undergone any documented changes to their antiretroviral treatment. The incidence of virologic failure over a defined period was calculated. The characteristics of each group were documented in frequency tables and measures of central tendency. To identify risk factors, multiple logistic regression models were employed, and post hoc tests were conducted. All calculations were performed with 95% confidence intervals, and p-values less than 0.05 were considered significant. Results The incidence of virologic failure over the seven-year study period was 9.2% (95% CI: 7.5-11.2%). Low CD4 T-lymphocyte count (≤200 cells/mm³) at diagnosis (adjOR 14.2, 95% CI: 3.1-64.5), history of opportunistic infections (adjOR 3.5, 95% CI: 1.9-6.4), and late enrollment into an HIV program after diagnosis (>1 year) (adjOR 9.2, 95% CI: 3.8-22.2) were identified as independent predictors of virologic failure. The drugs with the highest rates of resistance were nevirapine (84.6%), efavirenz (82.4%), emtricitabine (81.3%), lamivudine (81.3%), and atazanavir (6.6%). The most prevalent major mutations identified were K103N, M184V, and M46I/M. Approximately 50% of the secondary mutations were identified in protease regions. Conclusions The incidence of virologic failure was low in the study population. The identified risk characteristics allow for the prediction of the profile of patients susceptible to failure and for the early optimization of treatment regimens.

Clinical characteristics and prognostic analysis of thoracic SMARCA4-deficient undifferentiated tumor

Objective: To summarize and analyze the clinical characteristics and prognosis of thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT). Methods: A retrospective analysis was conducted on the clinical data of 51 patients with SMARCA4-UT who were diagnosed in the First Affiliated Hospital of Zhengzhou University from January 2018 to December 2023, and 52 patients with SMARCA4-intact non-small cell lung cancer (SMARCA4-iNSCLC) expression admitted during the same period were used as controls. The Kaplan-Meier survival analysis and log-rank test were used to analyze the survival difference between the two groups of patients, and the Cox regression model was used to explore the factors influencing the prognosis of the two groups of patients. Results: In the SMARCA4-UT group, there were 50 males and 1 female, with the age of (63.8±9.7) years. Compared to the SMARCA4-iNSCLC group, the SMARCA4-UT group exhibited a higher proportion of male patients and smokers, as well as a higher Ki-67 level (all P<0.05). SMARCA4-UT is mainly characterized by solid lesions with poor adhesion, and some of them exhibit rhabdomyoid morphology. Immunohistochemistry revealed negative results for BRG1, thyroid transcription factor-1, P40, NapsinA, and others were mostly negative, while some patients were positive for spalt-like transcription factor 4. There were a relatively large number of cases with Ki-67≥30% (47/51, 92%). Among the 10 patients in the SMARCA4-UT group who underwent next-generation sequencing genetic testing, 6 patients were found to have SMARCA4 mutations, often accompanied by TP53 (8/10, 80%), STK 11(3/10, 30%), KRAS(2/10, 20%), with fewer common driver gene mutations. The average tumor mutation burden was 16.12 mutations/Mb. Compared with SMARCA4-iNSCLC patients, the median overall survival of SMARCA4-UT patients was significantly shorter (12 months vs 45 months, P<0.001), and the median overall survival of patients with stage Ⅲ-Ⅳ SMARCA4-UT treated with immunotherapy was longer than that of patients without immunotherapy (23 months vs 7 months, P=0.027). The results of the multivariate Cox regression model analysis indicated that SMARCA4 deficiency is a risk factor for prognosis in patients with SMARCA4-UT and SMARCA4-iNSCLC [HR=7.954(95%CI： 2.764-22.890), P<0.001]. Conclusions: SMARCA4-UT is a rare undifferentiated tumour distinct from SMARCA4-iNSCLC, which is prevalent among elderly male smokers. It possesses high invasiveness and poor prognosis. The typical pathological characteristic is negative BRG1. Immunotherapy demonstrates a certain effect.

Single-molecule imaging of SWI/SNF chromatin remodelers reveals bromodomain-mediated and cancer-mutants-specific landscape of multi-modal DNA-binding dynamics

Despite their prevalent cancer implications, the in vivo dynamics of SWI/SNF chromatin remodelers and how misregulation of such dynamics underpins cancer remain poorly understood. Using live-cell single-molecule tracking, we quantify the intranuclear diffusion and chromatin-binding of three key subunits common to all major human SWI/SNF remodeler complexes (BAF57, BAF155 and BRG1), and resolve two temporally distinct stable binding modes for the fully assembled complex. Super-resolved density mapping reveals heterogeneous, nanoscale remodeler binding “hotspots” across the nucleoplasm where multiple binding events (especially longer-lived ones) preferentially cluster. Importantly, we uncover distinct roles of the bromodomain in modulating chromatin binding/targeting in a DNA-accessibility-dependent manner, pointing to a model where successive longer-lived binding within “hotspots” leads to sustained productive remodeling. Finally, systematic comparison of six common BRG1 mutants implicated in various cancers unveils alterations in chromatin-binding dynamics unique to each mutant, shedding insight into a multi-modal landscape regulating the spatio-temporal organizational dynamics of SWI/SNF remodelers.

Characteristics of DNMT3a mutation in acute myeloid leukemia and its prognostic implication

BackgroundAcute myeloid leukemia (AML) is a clonal disorder arising from the differentiation arrest of myeloid precursor and malignant proliferation of a bone marrow derived, self-renewing stem or progenitor cells inside the bone marrow (BM) and blood due to numerous genetic mutations. Some mutations can also adjust DNA methylation and may play a critical function in pathogenesis in Cytogenetically Normal Acute Myeloid Leukemia (CN-AML). Somatic mutations in DNMT3a were pronounced in approximately 20% and ∼30–35% of overall AML and CN-AML, respectively. Most DNMT3a mutations in AML have been observed to be heterozygous, A missense mutation, R882, located inside Hot spot exon 23, has been found to be the maximum common mutation. This is a preliminary study conducted on 20 adult Egyptian patients newly diagnosed as AML where Sanger sequencing of Hotspot Exon 23 of DNMT3a gene was performed on their initial bone marrow samples and were followed up to 3 months post-induction therapy. Only De Novo AML patients were included in our study.ResultsOur results revealed that overall DNMT3a mutations were present in 25% of our patients, 10% having the R882 (rs147001633) mutation being 5% R882C and 5% R882H. Immunophenotyping analysis among Mutated DNMT3a (R882 and Non R882) and Wild DNMT3a revealed that AML markers exhibited no significant differences except for myeloperoxidase positivity which was significant among the groups (0.050). Regarding cytogenetics, only one case of the mutated DNMT3a had positive FISH inv (16), where the rest were FISH negative. After 28 days of induction, 75% of all our patients achieved complete response (CR), 20% achieve partial response (PR) out of which 75% are DNMT3a mutated. After 3 months follow-up, 10% of all patients faced mortality where 5% was DNMT3a wild type (died due to treatment-related mortality) and 5% was R882 mutated DNMT3a.ConclusionDNMT3a mutations are present in 25% (5/20) of our AML patients, with 10% (2/20) having the R882 mutation being 5% (1/20) R882C and 5% (1/20) R882H. R882 mutation is associated with resistance to chemotherapy, and poorer outcomes, highlighting its poorer prognostic significance in AML.

Spectrum of Clinical Variability with SEPT9 Gene Mutation in Hereditary Neuralgic Amyotrophy: Understanding the Pathogenesis Using Molecular Dynamics Simulation Study.

Hereditary Neuralgic Amyotrophy (HNA) is an autosomal dominant disorder characterized by episodes of severe pain and amyotrophy affecting the brachial plexus as well as other sites. Mutations in the SEPTIN9 gene have been identified as genetic abnormality for HNA. Although the genetic mutations are known, their pathogenesis for the causation of this disorder is not exactly elucidated. In this study, we have investigated the phenotypic and genetic features in a large pedigree with HNA. We report the clinical spectrum and genetic analysis of a family with 9 affected members. Clinical heterogeneity has been reported in the individuals having mutations in SEPTIN9 gene. After taking informed consent, we have done genetic analysis of 6 affected and 4 unaffected members of the family to identify the molecular abnormalities of SEPTIN9 gene. Genetic analysis has identified the presence of NM_001113491.2:p.Arg106Trp mutation in SEPTIN9 gene. The same mutation has been identified in 6 affected members of the family. Molecular simulation study has revealed that the mutation has significantly altered the conformation of septin-9 protein, thereby impairing the microtubule binding and bundling ability. Although the affected members shared a common recurrent mutation, they have a wide spectrum of clinical variability. This may be due to the variable penetrance of the mutation and different epigenetic influences in the family. This is the first genetically confirmed case series of HNA reported from India.

1263P Biomarker analysis of plasma samples in YAMATO study: A randomized phase II trial comparing switching treatment of osimertinib following 8 months of afatinib (A) and osimertinib alone (B) in untreated advanced NSCLC patients with common EGFR mutation (TORG1939/WJOG12919L)

1263P Biomarker analysis of plasma samples in YAMATO study: A randomized phase II trial comparing switching treatment of osimertinib following 8 months of afatinib (A) and osimertinib alone (B) in untreated advanced NSCLC patients with common EGFR mutation (TORG1939/WJOG12919L)

336P Determination of the most common hereditary mutations associated with breast cancer and ovarian cancer in the population of Ukrainian women

336P Determination of the most common hereditary mutations associated with breast cancer and ovarian cancer in the population of Ukrainian women

Comparative Whole-Genome Sequencing Analysis of In-situ and Invasive Acral Lentiginous Melanoma: Markedly Increased Copy Number Gains of GAB2 , PAK1 , UCP2 , and CCND1 are Associated with Melanoma Invasion.

Acral lentiginous melanoma (ALM) is the most common subtype of acral melanoma. Even though recent genetic studies are reported in acral melanomas, the genetic differences between in-situ and invasive ALM remain unclear. We aimed to analyze specific genetic changes in ALM and compare genetic differences between in-situ and invasive lesions to identify genetic changes associated with the pathogenesis and progression of ALM. We performed whole genome sequencing of 71 tissue samples from 29 patients with ALM. Comparative analyses were performed, pairing in-situ ALMs with normal tissues and, furthermore, invasive ALMs with normal and in-situ tissues. Among 21 patients with in-situ ALMs, 3 patients (14.3%) had SMIM14 , SLC9B1 , FRG1 , FAM205A , ESRRA , and ESPN mutations, and copy number (CN) gains were identified in only 2 patients (9.5%). Comparing 13 invasive ALMs with in-situ tissues, CN gains were identified in GAB2 in 8 patients (61.5%), PAK1 in 6 patients (46.2%), and UCP2 and CCND1 in 5 patients (38.5%). Structural variants were frequent in in-situ and invasive ALM lesions. Both in-situ and invasive ALMs had very low frequencies of common driver mutations. Structural variants were common in both in-situ and invasive ALMs. Invasive ALMs had markedly increased CN gains, such as GAB2 , PAK1 , UCP2 , and CCND1 , compared with in-situ lesions. These results suggest that they are associated with melanoma invasion.

Age and Sex Affects the Frequency and Mutation Type of FGFR2 Alterations in Cholangiocarcinoma

PURPOSE FGFR2 alterations are infrequent but currently represent the most common targetable mutation in cholangiocarcinoma. We performed a large-scale genomic analysis to assess associations between FGFR2 and other driver gene alterations in cholangiocarcinoma with patient demographics. METHODS Clinical and molecular data for patients with intrahepatic cholangiocarcinoma were abstracted from the Foundation Medicine (FMI) and Genomics, Evidence, Neoplasia, Information, Exchange (GENIE) genomic databases. The Chi-squared test was used to assess the association between sex and alterations in driver genes. FGFR2 fusion partners were analyzed using descriptive statistics. RESULTS Across both FMI (N = 7,859) and GENIE (N = 1,395) cohorts, FGFR2 rearrangements were more frequent in female than male patients with cholangiocarcinoma (odds ratio, 1.69 and 2.45). By contrast, FGFR2 missense mutations, TP53 mutations, and KRAS mutations were not associated with sex. Stratifying patients by age groups showed that FGFR2 rearrangements were specifically enriched in younger ages (&lt;45 years). Although the most common FGFR2 fusion partners were shared across both sexes, a subset of fusion partners was recurrent and uniquely associated with female or male patients. CONCLUSION FGFR2 rearrangements but not other driver alterations in cholangiocarcinoma are concentrated in young female patients, where the prevalence reached nearly 20% across two large patient cohorts. These results suggest that the molecular basis of FGFR2 rearrangements may be distinct between sexes. These results indicate the importance of genetic testing in cholangiocarcinoma, particularly for younger patients, and suggest that patient recruitment strategies in trials for FGFR2-targeting therapies should seek to reduce barriers to enhance the enrollment of young female patients.

The oral ferroportin inhibitor vamifeport prevents liver iron overload in a mouse model of hemochromatosis.

Hemochromatosis is an inherited iron overload condition caused by mutations that reduce the levels of the iron-regulatory hormone hepcidin or its binding to ferroportin. The hepcidin-ferroportin axis is pivotal to iron homeostasis, providing opportunities for therapeutic intervention in iron overload disorders like hemochromatosis. The aim of this study was to evaluate the efficacy of the oral ferroportin inhibitor vamifeport in the Hfe C282Y mouse model, which carries the most common mutation found in patients with hemochromatosis. A single oral dose of vamifeport lowered serum iron levels in Hfe C282Y mice, with delayed onset and shorter duration than observed in wild-type mice. Vamifeport induced transient hypoferremia by inhibiting ferroportin and resulted in a feedback regulation of liver Hamp in wild-type mice, which was absent in Hfe C282Y mice, reflecting the dysregulated systemic iron sensing in this hemochromatosis model. Chronic dosing with vamifeport led to sustained serum and liver iron reductions in Hfe C282Y mice, as well as markedly reducing liver Hamp expression in Hfe C282Y mice, suggesting distinct regulation of liver Hamp expression following acute or continuous iron restriction via vamifeport. At the tested dose, vamifeport retained its activity when combined with phlebotomy and did not significantly interfere with liver iron removal by phlebotomy in Hfe C282Y mice. These data demonstrate that chronic vamifeport treatment significantly reduces serum iron levels and prevents liver iron loading in the Hfe C282Y mouse model of hemochromatosis, thus providing preclinical proof of concept for the efficacy of vamifeport in hemochromatosis with or without phlebotomy.

A Single Multiplex PCR and Single-Nucleotide Extension Assay for the Detection of Common Thanatophoric Dysplasia I and II Mutations

Mutation analysis is used to provide confirmation of a clinical and radiological diagnosis of Thanatophoric dysplasia types I and II (TDI & II). We developed a single multiplexed PCR and a single nucleotide extension (SNE) assay to identify 14 common mutations causing 99% of TD I and TD II, including the challenging three adjacent mutations in the stop codon of exon 18 of the FGFR3 gene. The assay design also provides a solution for resolving SNE PCR product sizing using performance optimized polymer-7 (POP-7).The assay was validated using thirty-seven previously characterized, de-identified patient samples representing the nine wild-types and 10/14 mutant genotypes. Four artificial templates were synthesized to mimic four TD I mutations not represented in the available patient samples. Fragment size and fluorophore channel for each SNE product from 10 samples and the four artificial templates were used to define bins and panels for analysis with GeneMarker v3.0 and GeneMapper v6.0 software. Allele calls (bin placement within the panels) were verified using the remaining 27 previously characterized samples.This TD I and II PCR and SNE assay is a robust multiplexed assay, streamlined, to identify 14 mutations in one single reaction. Turnaround time required for this assay performance and analysis is decreased in comparison to traditional Sanger or next generation sequencing.

Abstract 57: Macrolides for KCNJ5–mutated Aldosterone-Producing Adenoma (MAPA): a Study for Personalized Management of Primary Aldosteronism

Background: Somatic mutations in the KCNJ5 potassium channel involve up to 70% of the patients presenting with primary aldosteronism (PA) caused by an aldosterone-producing adenoma (APA). Macrolides corrected the altered function of the two common mutations G151R and L168R, in vitro suggesting their potential usefulness for personalized management of patients with KCNJ5-mutated APA. Hence, we investigated if the macrolide roxithromycin that restored the KCNJ5 channel function could lower plasma aldosterone and blood pressure (BP) in KCNJ5-mutated APA patients. Methods and Design: In a within-patient study we assessed changes of plasma aldosterone, active renin, cortisol and BP induced by an oral roxithromycin (150-300 mg) challenge, in consenting consecutive hypertensive patients. In parallel, we investigated the vascular and BP effects of macrolides ex vivo and in vivo in mice. Results: We recruited 425 consecutive patients: 19 had G151R - or L168R - mutated APA, 27 KCNJ5 wild-type APA, and the rest had no identifiable cause of hypertension. Roxithromycin lowered the plasma aldosterone concentration (p&lt;0.001), not BP, in the G151R- and L168R-mutated APA patients, but not in the wild-type. However, an aldosterone-independent BP decrease was seen in the much larger cohort of hypertensive patients without PA. In mice experiments, studies showed that this was accounted far by a significant anti-hypertensive effect of macrolides that involved an endothelium-NO-dependent vasodilatory action. Conclusions: The roxithromycin-induced fall of plasma aldosterone concentration might be a marker of the presence of KCNJ5-mutated APA. Moreover, our studies unveiled an anti-hypertensive effect of macrolides that involves endothelium- and NO-dependent vasodilation.

Mutant p53 Exploits Enhancers to Elevate Immunosuppressive Chemokine Expression and Impair Immune Checkpoint Inhibitors in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective treatments. It is characterized by activating KRAS mutations and p53 alterations. However, how these mutations dysregulate cancer-cell-intrinsic gene programs to influence the immune landscape of the tumor microenvironment (TME) remains poorly understood. Here, we show that p53R172H establishes an immunosuppressive TME, diminishes the efficacy of immune checkpoint inhibitors (ICIs), and enhances tumor growth. Our findings reveal that the upregulation of the immunosuppressive chemokine Cxcl1 mediates these pro-tumorigenic functions of p53R172H. Mechanistically, we show that p53R172H associates with the distal enhancers of the Cxcl1 gene, increasing enhancer activity and Cxcl1 expression. p53R172H occupies these enhancers in an NF-κB-pathway-dependent manner, suggesting NF-κB's role in recruiting p53R172H to the Cxcl1 enhancers. Our work uncovers how a common mutation in a tumor-suppressor transcription factor appropriates enhancers, stimulating chemokine expression and establishing an immunosuppressive TME that diminishes ICI efficacy in PDAC.

YBX1 as a therapeutic target to suppress the LRP1-β-catenin-RRM1 axis and overcome gemcitabine resistance in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is highly malignant and has a poor prognosis, without effective therapeutic targets in common gene mutations. Gemcitabine, a first-line chemotherapeutic for PDAC, confers <10 % 5-year survival rate because of drug resistance. Y-box binding protein 1 (YBX1), associated with multidrug-resistance gene activation, remains unelucidated in PDAC gemcitabine resistance. In vivo and in vitro, we verified YBX1's promotional effects, especially gemcitabine resistance, in pancreatic cancer cells. YBX1-induced LRP1 transcription by binding to the LRP1 promoter region significantly altered the concentration and distribution of β-catenin in pancreatic cancer cells. Through TCF3, β-catenin bound to the promoter region of RRM1, a key gene for gemcitabine resistance, that promotes RRM1 expression. Combination therapy with the YBX1 inhibitor SU056 and gemcitabine effectively reduced gemcitabine resistance in in vivo and in vitro experiments. High YBX1 expression promoted pathogenesis and gemcitabine resistance in pancreatic cancer through the YBX1-LRP1-β-catenin-RRM1 axis. Combining YBX1 inhibitors with gemcitabine may provide a new direction for combination chemotherapy to overcome gemcitabine resistance, which frequently occurs during chemotherapy for pancreatic cancer.

Immunophenotypic, genetic, and clinical characterization of adult T-cell leukemia/lymphoma: A single tertiary care center experience in the United States.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive mature T-cell neoplasm caused by human T-cell lymphotropic virus type 1 (HTLV-1). Its most common immunophenotype is CD4+/CD7-/CD25+, although unusual immunophenotypes can occur and may lead to misdiagnosis. The immunophenotypes, cytogenetics, molecular features, clinical presentations, treatment, and prognosis of 131 patients with ATLL were retrospectively studied in a large tertiary medical center in the United States. All cases showed loss of CD7 expression. While 82.4% of cases demonstrated CD4+, 17.6% exhibited unusual phenotypes, including CD4+/CD8+ (6.9%), CD4-/CD8- (2.3%), CD5- (3.1%), CD2-, and CD3-. The most common cytogenetics abnormalities included polysomy 3 (34.6%), translocation 1 (23.1%), and abnormalities found on chromosome 11 (30.8%) and chromosome 14 (26.9%). The common gene mutations identified by the next-generation sequencing study were TP53 (16.7%), TBL1XR1 (16.7%), EP300 (14.3%), and NOTCH1 (14.3%). TBL1XR1 mutation is associated with genetic instabilities. There was no significant difference between the clinical presentations of these 2 groups. Adult T-cell leukemia/lymphoma exhibits versatile immunophenotypic, cytogenetic, and molecular features. Simultaneous involvement of blood, lymph nodes, and other organs, along with hypercalcemia in a patient from an endemic area, necessitates HTLV-1 testing to avoid underdiagnosis of this dismal disease that might need aggressive chemotherapy followed by bone marrow transplant.

Mutant induced neurons and humanized mice enable identification of Niemann-Pick type C1 proteostatic therapies.

Therapeutics that rescue folding, trafficking, and function of disease-causing missense mutants are sought for a host of human diseases, but efforts to leverage model systems to test emerging strategies have met with limited success. Such is the case for Niemann-Pick type C1 disease, a lysosomal disorder characterized by impaired intracellular cholesterol trafficking, progressive neurodegeneration, and early death. NPC1, a multipass transmembrane glycoprotein, is synthesized in the endoplasmic reticulum and traffics to late endosomes/lysosomes, but this process is often disrupted in disease. We sought to identify small molecules that promote folding and enable lysosomal localization and functional recovery of mutant NPC1. We leveraged a panel of isogenic human induced neurons expressing distinct NPC1 missense mutations. We used this panel to rescreen compounds that were reported previously to correct NPC1 folding and trafficking. We established mo56-hydroxycholesterol (mo56Hc) as a potent pharmacological chaperone for several NPC1 mutants. Furthermore, we generated mice expressing human I1061T NPC1, a common mutation in patients. We demonstrated that this model exhibited disease phenotypes and recapitulated the protein trafficking defects, lipid storage, and response to mo56Hc exhibited by human cells expressing I1061T NPC1. These tools established a paradigm for testing and validation of proteostatic therapeutics as an important step toward the development of disease-modifying therapies.

Integrated multi-omics characterization of SMAD4 mutant colorectal cancer

Colorectal cancer is one of the most common cancers around the world, which is a severe threat to people’s health. SMAD4 belongs to the dwarfin/SMAD family, which plays a crucial role in TGF-β and BMP signal pathways. As the molecular characterization of colon cancer patients following SMAD4 mutations remains unclear, we integrated multi-omics data of SMAD4 mutant patients to reveal the profile of molecular characterization of SMAD4 mutation. A missense mutation is the most common mutant type of SMAD4. Patients with SMAD4 mutation had worse survival. Tumor tissues from patients carrying the SMAD4 mutation showed a reduction in various immune cells, such as CD4 + memory T cells and memory B cells. Many differential genes were identified compared to the SMAD4 mutation-free group and could be significantly enriched for tumor- and immune-related signaling pathways. In addition, the mutant group had different drug sensitivities than the non-mutant group.

Astrocytic LRRK2 Controls Synaptic Connectivity via Regulation of ERM Phosphorylation.

Astrocytes, a major glial cell type of the brain, regulate synapse numbers and function. However, whether astrocyte dysfunction can cause synaptic pathologies in neurological disorders such as Parkinson's Disease (PD) is unknown. Here, we investigated the impact of the most common PD-linked mutation in the leucine-rich repeat kinase 2 (LRRK2) gene (G2019S) on the synaptic functions of astrocytes. We found that both in human and mouse cortex, the LRRK2 G2019S mutation causes astrocyte morphology deficits and enhances the phosphorylation of the ERM proteins (Ezrin, Radixin, and Moesin), which are important components of perisynaptic astrocyte processes. Reducing ERM phosphorylation in LRRK2 G2019S mouse astrocytes restored astrocyte morphology and corrected excitatory synaptic deficits. Using an in vivo BioID proteomic approach, we found Ezrin, the most abundant astrocytic ERM protein, interacts with the Autophagy-Related 7 (Atg7), a master regulator of catabolic processes. The Ezrin/Atg7 interaction is inhibited by Ezrin phosphorylation, thus diminished in the LRRK2 G2019S astrocytes. Importantly, Atg7 function is required to maintain proper astrocyte morphology. These studies reveal an astrocytic molecular mechanism that could serve as a therapeutic target in PD.

Investigating common mutations in ATP7B gene and the prevalence of Wilson's disease in the Thai population using population-based genome-wide datasets.

Wilson's disease (WD) is a rare metabolic disorder caused by variations in the ATP7B gene. It usually manifests hepatic, neurologic, and psychiatric symptoms due to excessive copper accumulation. The prevalence of WD and its common variants differ across populations. This study aimed to examine these aspects of WD within the Thai population, where information has been limited. We reviewed ClinVar and the Wilson Disease Mutation Database, organizing variants classified as pathogenic or likely pathogenic in one or both databases as "relaxed" and "strict" lists. Allele frequencies were estimated from genotyping array data (Asian Screening Array: ASA; Illumina Corp, CA) of 6291 Thai subjects, which also underwent genotype imputation. The prevalence of WD in the Thai population was estimated assuming Hardy-Weinberg Equilibrium. The strict list yielded a prevalence of 1/24,128 (carrier frequency=1/78), while the relaxed list yielded a prevalence of 1/9971 (carrier frequency=1/50). The most common WD variants in Thai subjects were c.2333 G > T, c.3443 T > C, and c.813 C > A from the strict list, and c.3316 G > A and c.2605 G > A from the relaxed list. The ASA chip covered approximately 59 and 24% of WD variants from the strict and relaxed lists, respectively. Based on the estimated prevalence, a carrier screening program for WD is not currently required in Thailand. However, as genotyping services become more affordable and accessible, such a program would facilitate early identification, treatment, and prevention of WD.

Clinico-Laboratory Profile of Hypertriglyceridemia Thalassemia Syndrome: A Case Series in a Paediatric Tertiary Care Centre.

Increased hemolysis and repeated blood transfusion trigger oxidative stress resulting in numerous adverse effects in beta-thalassemia patients. Extreme elevation of triglyceride level is a rare clinical entity seen in these patients. It is presumed to be caused due to an increase in oxidative stress and is termed Hypertriglyceridemia Thalassemia Syndrome. To assess the clinical and laboratory characteristics of beta-thalassemia patients presenting with hypertriglyceridemia and its correlation with the pre-transfusion hemoglobin level. Methods: This hospital record-based retrospective study was conducted at the Dr B C Roy Post Graduate Institute of Paediatric Sciences, Kolkata, India. The study comprised 12 pediatric beta-thalassemia patients whose plasma appeared milky or chylous during a complete hemogram. Clinical examination and laboratory investigations were done to describe their clinico-laboratory features. A whole exome sequencing was carried out to assess their genetic background. Blood hemoglobin and serum triglyceride estimation was carried out initially and at follow-up to determine any correlation between the two. Results: Out of 1482 patients, 12 (0.80 %) were diagnosed with Hypertriglyceridemia Thalassemia Syndrome. The median age of presentation was 12.5 months (Q1:10 months, Q3:14 months)., and the pretransfusion hemoglobin was 4.82 ± 1.16 g/dL. The lipid profile showed a triglyceride level of 858.3 ± 198.4 mg/dl and a total cholesterol level of 117.4± 16.15 mg/dl. Analysis revealed that the triglyceride levels were negatively correlated with the pretransfusion hemoglobin level (repeated measures correlation (rmcorr) = -0.65, 95% CI[-0.794, -0.425], p < 0.001). A genetic study highlighted c.92+5G>C as the commonest mutation. Hypertriglyceridemia was a rare presentation in transfusion-dependent beta-thalassemia patients. The serum triglyceride level significantly reduced when blood transfusion at regular intervals restored the patient's hemoglobin level.