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American Journal of Hematology Jul 2024
Chronic lymphocytic leukemia patients with chromosome 6q deletion as the sole cytogenetic abnormality display a high frequency of RPS15 mutations and have a poor prognosis.
PubMed: 38949404
DOI: 10.1002/ajh.27421 -
The Journal of Clinical Investigation Jul 2024Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I...
Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I component NDUFAF2 has been identified in Leigh syndrome, a severe inherited mitochondriopathy. Mutations in ARMC9, which encodes a basal body protein, cause Joubert syndrome, a ciliopathy with defects in the brain, kidney, and eye. Here, we report a mechanistic link between mitochondria metabolism and primary cilia signaling. We discovered that loss of NDUFAF2 caused both mitochondrial and ciliary defects in vitro and in vivo and identified NDUFAF2 as a binding partner for ARMC9. We also found that NDUFAF2 was both necessary and sufficient for cilia formation and that exogenous expression of NDUFAF2 rescued the ciliary and mitochondrial defects observed in cells from patients with known ARMC9 deficiency. NAD+ supplementation restored mitochondrial and ciliary dysfunction in ARMC9-deficient cells and zebrafish and ameliorated the ocular motility and motor deficits of a patient with ARMC9 deficiency. The present results provide a compelling mechanistic link, supported by evidence from human studies, between primary cilia and mitochondrial signaling. Importantly, our findings have significant implications for the development of therapeutic approaches targeting ciliopathies.
Topics: Humans; Zebrafish; Leigh Disease; Cilia; Animals; Mitochondria; Kidney Diseases, Cystic; Electron Transport Complex I; Armadillo Domain Proteins; Retina; Eye Abnormalities; Mice; Abnormalities, Multiple; Cerebellum; Mitochondrial Proteins; Zebrafish Proteins; Male
PubMed: 38949024
DOI: 10.1172/JCI175560 -
World Journal of Hepatology Jun 2024Erythropoietic protoporphyria (EPP) is a rare genetic disorder stemming from ferrochelatase gene mutations, which leads to abnormal accumulation of protoporphyrin IX...
BACKGROUND
Erythropoietic protoporphyria (EPP) is a rare genetic disorder stemming from ferrochelatase gene mutations, which leads to abnormal accumulation of protoporphyrin IX primarily in erythrocytes, skin, bone marrow and liver. Although porphyria-related severe liver damage is rare, its consequences can be severe with limited treatment options.
CASE SUMMARY
This case study highlights a successful intervention for a 35-year-old male with EPP-related liver impairment, employing a combination of red blood cell (RBC) exchange and therapeutic plasma exchange (TPE). The patient experienced significant symptom relief and a decrease in bilirubin levels following multiple PE sessions and an RBC exchange.
CONCLUSION
The findings suggest that this combined approach holds promise for managing severe hepatic impairment in EPP.
PubMed: 38948434
DOI: 10.4254/wjh.v16.i6.966 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024Infertility affects approximately one-sixth of the people of childbearing age worldwide, causing not only economic burdens of treatment for families with fertility...
OBJECTIVE
Infertility affects approximately one-sixth of the people of childbearing age worldwide, causing not only economic burdens of treatment for families with fertility problems but also psychological stress for patients and presenting challenges to societal and economic development. Premature ovarian insufficiency (POI) refers to the loss of ovarian function in women before the age of 40 due to the depletion of follicles or decreased quality of remaining follicles, constituting a significant cause of female infertility. In recent years, with the help of the rapid development in genetic sequencing technology, it has been demonstrated that genetic factors play a crucial role in the onset of POI. Among the population suffering from POI, genetic studies have revealed that genes involved in processes such as meiosis, DNA damage repair, and mitosis account for approximately 37.4% of all pathogenic and potentially pathogenic genes identified. FA complementation group M () is a group of genes involved in the damage repair of DNA interstrand crosslinks (ICLs), including -. Abnormalities in the genes are associated with female infertility and gene knockout mice also exhibit phenotypes similar to those of POI. During the genetic screening of POI patients, this study identified a suspicious variant in . This study aims to explore the pathogenic mechanisms of the genes of the FA pathway and their variants in the development of POI. We hope to help shed light on potential diagnostic and therapeutic strategies for the affected individuals.
METHODS
One POI patient was included in the study. The inclusion criteria for POI patients were as follows: women under 40 years old exhibiting two or more instances of basal serum follicle-stimulating hormone levels>25 IU/L (with a minimum interval of 4 weeks inbetween tests), alongside clinical symptoms of menstrual disorders, normal chromosomal karyotype analysis results, and exclusion of other known diseases that can lead to ovarian dysfunction. We conducted whole-exome sequencing for the POI patient and identified pathogenic genes by classifying variants according to the standards and guidelines established by the American College of Medical Genetics and Genomics (ACMG). Subsequently, the identified variants were validated through Sanger sequencing and subjected to bioinformatics analysis. Plasmids containing wild-type and mutant genes were constructed and introduced into 293T cells. The 293T cells transfected with wild-type and mutant human plasmids and pEGFP-C1 empty vector plasmids were designated as the EGFP - group, the EGFP - group, and the EGFP group, respectively. To validate the production of truncated proteins, cell proteins were extracted 48 hours post-transfection from the three groups and confirmed using GFP antibody. In order to investigate the impact on DNA damage repair, immunofluorescence experiments were conducted 48 hours post-transfection in the EGFP WT group and the EGFP -MUT group to examine whether the variant affected FANCM's ability to localize on chromatin. Mitomycin C was used to induce ICLs damage in both the EGFP - group and the EGFP - group, which was followed by verification of its effect on ICLs damage repair using γ-H2AX antibody.
RESULTS
In a POI patient from a consanguineous family, we identified a homozygous variant in the gene, c.1152-1155del:p.Leu386Valfs*10. The patient presented with primary infertility, experiencing irregular menstruation since menarche at the age of 16. Hormonal evaluation revealed an FSH level of 26.79 IU/L and an anti-Müllerian hormone (AMH) level of 0.07 ng/mL. Vaginal ultrasound indicated unsatisfactory visualization of the ovaries on both sides and uterine dysplasia. The patient's parents were a consanguineous couple, with the mother having regular menstrual cycles. The patient had two sisters, one of whom passed away due to osteosarcoma, while the other exhibited irregular menstruation, had been diagnosed with ovarian insufficiency, and remained childless. Bioinformatics analysis revealed a deletion of four nucleotides (c.1152-1155del) in the exon 6 of the patient's gene. This variant resulted in a frameshift at codon 386, introducing a premature stop codon at codon 396, which ultimately led to the production of a truncated protein consisting of 395 amino acids. experiments demonstrated that this variant led to the production of a truncated FANCM protein of approximately 43 kDa and caused a defect in its nuclear localization, with the protein being present only in the cytoplasm. Following treatment with mitomycin C, there was a significant increase in γ-H2AX levels in 293T cells transfected with the mutant plasmid (<0.01), indicating a statistically significant impairment of DNA damage repair capability caused by this variant.
CONCLUSIONS
The homozygous variant in the gene, c.1152-1155del:p.Leu386Valfs*10, results in the production of a truncated FANCM protein. This truncation leads to the loss of its interaction site with the MHF1-MHF2 complex, preventing its entry into the nucleus and the subsequent recognition of DNA damage. Consequently, the localization of the FA core complex on chromatin is disrupted, impeding the normal activation of the FA pathway and reducing the cell's ability to repair damaged ICLs. By disrupting the rapid proliferation and meiotic division processes of primordial germ cells, the reserve of oocytes is depleted, thereby triggering premature ovarian insufficiency in females.
Topics: Female; Primary Ovarian Insufficiency; Humans; Mutation; Fanconi Anemia; Adult; Infertility, Female; DNA Helicases
PubMed: 38948269
DOI: 10.12182/20240560207 -
Cureus May 2024Premature aging syndrome is a rare condition characterized by premature aging and death. The exact pathogenic mechanisms underlying most premature aging syndromes are...
Premature aging syndrome is a rare condition characterized by premature aging and death. The exact pathogenic mechanisms underlying most premature aging syndromes are poorly understood. Here, we describe two sibling cases of premature aging syndrome of unknown etiology, with no identified significant genetic mutation, with the primary symptom of a prematurely aged appearance, and a chief complaint of marked short stature. The first patient was an eight-year-old Cambodian boy born to a third-degree consanguineous marriage. He visited our hospital with the chief complaint of short stature. His development was originally normal until he developed pneumonia when he was three years old. Neither of his parents had any symptoms or family history of similar abnormalities, except for his five-year-old sister, who also has a markedly short stature of 80.4 cm and a low body weight of 8.7 kg. Her face showed distinct macrognathia and relative macrocephaly. The brother's low-density lipoprotein cholesterol level was high (198 mg/dl), and brain magnetic resonance angiography and carotid ultrasound revealed severe atherosclerotic changes. Whole-exome sequencing results were insignificant for both patients. This case report aims to elucidate the pathogenesis and treatment of progeria. This report indicates the possibility of an unidentified type of premature aging syndrome.
PubMed: 38947695
DOI: 10.7759/cureus.61300 -
Clinical Case Reports Jul 2024Creutzfeldt-Jakob disease is a neurodegenerative disorder caused by brain accumulation of a misfolded form of the cellular prion protein, whose diagnosis is challenging,...
KEY CLINICAL MESSAGE
Creutzfeldt-Jakob disease is a neurodegenerative disorder caused by brain accumulation of a misfolded form of the cellular prion protein, whose diagnosis is challenging, particularly in early stages, due to the variability and nonspecificity of the clinical and radiological features. 18F-fluorodeoxyglucose positron-emitted tomography has the potential to be considered a crucial investigation in these patients, revealing metabolic abnormalities earlier than the conventional neuroimaging analysis.
ABSTRACT
A 59-year-old man, the military officer, was referred to our Units for the onset of neurological symptoms rapidly evolving within a month, characterized by akinetic mutism, constructional apraxia, and disorders of spatial orientation. Brain 18F-fluorodeoxyglucose (18F-FDG) positron-emitted tomography (PET)/CT depicted an asymmetric hypometabolism in the left fronto-temporo-parietal cortex, as well as in the left thalamus and the right cerebellar hemisphere, while the glucose metabolism appears to be preserved in the somatosensory cortex and the basal ganglia. Laboratory routine analyses, cerebrospinal fluid routine, infective tests, electroencephalography (EEG), and brain magnetic resonance (MR) were all unremarkable. A positive RT-QuIC result on cerebro-spinal fluid (CSF) was subsequently shown, without any pathogenic gene mutations and, therefore, the result was consistent with a diagnosis of sporadic Creutzfeld-Jacob disease. The clinical evolution was quickly unfavorable, and the patient died about 4 months after hospital admission. FDG PET/computed tomography (CT) has the potential to be considered a crucial investigation in these patients, documenting metabolic changes long time before other diagnostic investigations such as CSF, EEG, brain CT, and brain MR, thus suggesting a greater sensitivity of glucose metabolic evaluation in the early stage of the disease in question.
PubMed: 38947537
DOI: 10.1002/ccr3.8974 -
Molecular Therapy. Methods & Clinical... Jun 2024Hematopoietic stem cell gene therapy (HSCGT) is a promising therapeutic strategy for the treatment of neurodegenerative, metabolic disorders. The approach involves the...
Hematopoietic stem cell gene therapy (HSCGT) is a promising therapeutic strategy for the treatment of neurodegenerative, metabolic disorders. The approach involves the introduction of a missing gene into patients' own stem cells via lentiviral-mediated transduction (TD). Once transplanted back into a fully conditioned patient, these genetically modified HSCs can repopulate the blood system and produce the functional protein, previously absent or non-functional in the patient, which can then cross-correct other affected cells in somatic organs and the central nervous system. We previously developed an HSCGT approach for the treatment of Mucopolysaccharidosis type II (MPSII) (Hunter syndrome), a debilitating pediatric lysosomal disorder caused by mutations in the iduronate-2-sulphatase (IDS) gene, leading to the accumulation of heparan and dermatan sulfate, which causes severe neurodegeneration, skeletal abnormalities, and cardiorespiratory disease. In HSCGT proof-of-concept studies using lentiviral IDS fused to a brain-targeting peptide ApoEII (IDS.ApoEII), we were able to normalize brain pathology and behavior of MPSII mice. Here we present an optimized and validated good manufacturing practice hematopoietic stem cell TD protocol for MPSII in preparation for first-in-man studies. Inclusion of TEs LentiBOOST and protamine sulfate significantly improved TD efficiency by at least 3-fold without causing adverse toxicity, thereby reducing vector quantity required.
PubMed: 38946936
DOI: 10.1016/j.omtm.2024.101271 -
Frontiers in Cell and Developmental... 2024Duchenne muscular dystrophy (DMD) is a genetic disorder caused by mutations in the dystrophin-encoding gene that leads to muscle necrosis and degeneration with chronic...
INTRODUCTION
Duchenne muscular dystrophy (DMD) is a genetic disorder caused by mutations in the dystrophin-encoding gene that leads to muscle necrosis and degeneration with chronic inflammation during growth, resulting in progressive generalized weakness of the skeletal and cardiac muscles. We previously demonstrated the therapeutic effects of systemic administration of dental pulp mesenchymal stromal cells (DPSCs) in a DMD animal model. We showed preservation of long-term muscle function and slowing of disease progression. However, little is known regarding the effects of cell therapy on the metabolic abnormalities in DMD. Therefore, here, we aimed to investigate the mechanisms underlying the immunosuppressive effects of DPSCs and their influence on DMD metabolism.
METHODS
A comprehensive metabolomics-based approach was employed, and an ingenuity pathway analysis was performed to identify dystrophy-specific metabolomic impairments in the mice to assess the therapeutic response to our established systemic DPSC-mediated cell therapy approach.
RESULTS AND DISCUSSION
We identified DMD-specific impairments in metabolites and their responses to systemic DPSC treatment. Our results demonstrate the feasibility of the metabolomics-based approach and provide insights into the therapeutic effects of DPSCs in DMD. Our findings could help to identify molecular marker targets for therapeutic intervention and predict long-term therapeutic efficacy.
PubMed: 38946797
DOI: 10.3389/fcell.2024.1363541 -
Circulation Research Jul 2024Exercise intolerance is an independent predictor of poor prognosis in diabetes. The underlying mechanism of the association between hyperglycemia and exercise...
BACKGROUND
Exercise intolerance is an independent predictor of poor prognosis in diabetes. The underlying mechanism of the association between hyperglycemia and exercise intolerance remains undefined. We recently demonstrated that the interaction between ARRDC4 (arrestin domain-containing protein 4) and GLUT1 (glucose transporter 1) regulates cardiac metabolism.
OBJECTIVE
To determine whether this mechanism broadly impacts diabetic complications, we investigated the role of ARRDC4 in the pathogenesis of diabetic cardiac and skeletal myopathy.
METHODS AND RESULTS
High glucose promoted translocation of MondoA into the nucleus, which upregulated transcriptional expression, increased lysosomal GLUT1 trafficking, and blocked glucose transport in cardiomyocytes, forming a feedback mechanism. This role of was confirmed in human muscular cells from type 2 diabetic patients. Prolonged hyperglycemia upregulated myocardial expression in multiple types of mouse models of diabetes. We then analyzed hyperglycemia-induced cardiac and skeletal muscle abnormalities in insulin-deficient mice. Hyperglycemia increased advanced glycation end-products and elicited oxidative and endoplasmic reticulum stress leading to apoptosis in the heart and peripheral muscle. However, deletion of augmented tissue glucose transport and mitochondrial respiration, protecting the heart and muscle from tissue damage. Stress hemodynamic analysis and treadmill exhaustion test uncovered that -knockout mice had greater cardiac inotropic/chronotropic reserve with higher exercise endurance than wild-type (WT) animals under diabetes. While multiple organs were involved in the mechanism, cardiac-specific overexpression (beyond levels observed during diabetes) using adenoassociated virus suggests that high levels of myocardial have the potential to contribute to exercise intolerance by interfering with cardiac metabolism through its interaction with GLUT1 in diabetes. Importantly, the mutation mouse line exhibited greater exercise tolerance, showing the potential therapeutic impact on diabetic cardiomyopathy by disrupting the interaction between ARRDC4 and GLUT1.
CONCLUSIONS
ARRDC4 serves as a regulator of hyperglycemia-induced toxicities toward cardiac and skeletal muscle, revealing a new molecular framework that connects hyperglycemia to cardiac/skeletal myopathy to exercise intolerance.
PubMed: 38946541
DOI: 10.1161/CIRCRESAHA.123.323158 -
Journal of Neurochemistry Jul 2024Alzheimer's disease (AD) is characterized by the accumulation of abnormally folded amyloid β-protein (Aβ) in the brain parenchyma and phosphorylated tau in neurons....
Alzheimer's disease (AD) is characterized by the accumulation of abnormally folded amyloid β-protein (Aβ) in the brain parenchyma and phosphorylated tau in neurons. Presenilin (PS, PSEN) 1 and PS2 are essential components of γ-secretase, which is responsible for the cleavage of amyloid precursor protein (APP) to generate Aβ. PSEN mutations are associated with tau aggregation in frontotemporal dementia, regardless of the presence or absence of Aβ pathology. However, the mechanism by which PS regulates tau aggregation is still unknown. Here, we found that tau phosphorylation and secretion were significantly increased in PS double-knock-out (PS1/2) fibroblasts compared with wild-type fibroblasts. Tau-positive vesicles in the cytoplasm were significantly increased in PS1/2 fibroblasts. Active GSK-3β was increased in PS1/2 fibroblasts, and inhibiting GSK3β activity in PS1/2 fibroblasts resulted in decreased tau phosphorylation and secretion. Transfection of WT human PS1 and PS2 reduced the secretion of phosphorylated tau and active GSK-3β in PS1/2 fibroblasts. However, PS1D257A without γ-secretase activity did not decrease the secretion of phosphorylated tau. Furthermore, nicastrin deficiency also increased tau phosphorylation and secretion. These results suggest that deficient PS complex maturation may increase tau phosphorylation and secretion. Thus, our studies discover a new pathway by which PS regulates tau phosphorylation/secretion and pathology independent of Aβ and suggest that PS serves as a potential therapeutic target for treating neurodegenerative diseases involving tau aggregation.
PubMed: 38946496
DOI: 10.1111/jnc.16155