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Pediatric Research Aug 2023Sengers syndrome characterized by hypertrophic cardiomyopathy is an extremely rare genetic disorder. Sengers syndrome associated with left ventricular non-compaction...
BACKGROUND
Sengers syndrome characterized by hypertrophic cardiomyopathy is an extremely rare genetic disorder. Sengers syndrome associated with left ventricular non-compaction (LVNC) has not been described.
METHODS
Genetic testing was used to identify candidate AGK variants in the proband. The predicted molecular structures were constructed by protein modeling. Exon skipping caused by the identified splicing mutations was verified by in silico analyses and in vitro assays. The genotypic and phenotypic features of patients with AGK splicing mutations were extracted by a systematic review.
RESULTS
The proband was characterized by Sengers syndrome and LVNC and caused by a novel compound heterozygous AGK splicing mutation. This compound mutation simultaneously perturbed the protein sequences and spatial conformation of the acylglycerol kinase protein. In silico and in vitro analyses demonstrated skipping of exons 7 and 8 and premature truncation as a result of exon 8 skipping. The systematic review indicated that patients with an AGK splicing mutation may have milder phenotypes of Sengers syndrome.
CONCLUSIONS
The genotypic and phenotypic spectrums of Sengers syndrome have been expanded, which will provide essential information for genetic counseling. The molecular mechanism in AGK mutations can offer insights into the potential targets for treatment.
IMPACT
First description of a child with Sengers syndrome and left ventricular non-compaction cardiomyopathy. A novel pathogenic compound heterozygous splicing mutation in AGK for Sengers syndrome was identified. The identified mutations led to exons skipping by in silico analyses and in vitro assays.
Topics: Humans; Cardiomyopathies; Genetic Testing; Mutation; Cataract; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 36759750
DOI: 10.1038/s41390-023-02515-3 -
Frontiers in Physiology 2019The pentatricopeptide repeat (PPR) family plays a major role in RNA stability, regulation, processing, splicing, translation, and editing. Leucine-rich...
The pentatricopeptide repeat (PPR) family plays a major role in RNA stability, regulation, processing, splicing, translation, and editing. Leucine-rich PPR-motif-containing protein (LRPPRC), a member of the PPR family, is a known gene mutation that causes Leigh syndrome French-Canadian. Recently, growing evidence has pointed out that LRPPRC dysregulation is related to various diseases ranging from tumors to viral infections. This review presents available published data on the LRPPRC protein function and its role in tumors and other diseases. As a multi-functional protein, LRPPRC regulates a myriad of biological processes, including energy metabolism and maturation and the export of nuclear mRNA. Overexpression of LRPPRC has been observed in various human tumors and is associated with poor prognosis. Downregulation of LRPPRC inhibits growth and invasion, induces apoptosis, and overcomes drug resistance in tumor cells. In addition, LRPPRC plays a potential role in Parkinson's disease, neurofibromatosis 1, viral infections, and venous thromboembolism. Further investigating these new functions of LRPPRC should provide novel opportunities for a better understanding of its pathological role in diseases from tumors to viral infections and as a potential biomarker and molecular target for disease treatment.
PubMed: 31178748
DOI: 10.3389/fphys.2019.00595 -
Prostate Cancer and Prostatic Diseases Sep 2020The androgen receptor (AR) is a key prostate cancer drug target. Suppression of AR signaling mediated by the full-length AR (AR-FL) is the therapeutic goal of all...
BACKGROUND
The androgen receptor (AR) is a key prostate cancer drug target. Suppression of AR signaling mediated by the full-length AR (AR-FL) is the therapeutic goal of all existing AR-directed therapies. AR-targeting agents impart therapeutic benefit, but lead to AR aberrations that underlie disease progression and therapeutic resistance. Among the AR aberrations specific to castration-resistant prostate cancer (CRPC), AR variants (AR-Vs) have emerged as important indicators of disease progression and therapeutic resistance.
METHODS
We conducted a systemic review of the literature focusing on recent laboratory studies on AR-Vs following our last review article published in 2016. Topics ranged from measurement and detection, molecular origin, regulation, genomic function, and preclinical therapeutic targeting of AR-Vs. We provide expert opinions and perspectives on these topics.
RESULTS
Transcript sequences for 22 AR-Vs have been reported in the literature. Different AR-Vs may arise through different mechanisms, and can be regulated by splicing factors and dictated by genomic rearrangements, but a low-androgen environment is a prerequisite for generation of AR-Vs. The unique transcript structures allowed development of in situ and in-solution measurement and detection methods, including mRNA and protein detection, in both tissue and blood specimens. AR-V7 remains the main measurement target and the most extensively characterized AR-V. Although AR-V7 coexists with AR-FL, genomic functions mediated by AR-V7 do not require the presence of AR-FL. The distinct cistromes and transcriptional programs directed by AR-V7 and their coregulators are consistent with genomic features of progressive disease in a low-androgen environment. Preclinical development of AR-V-directed agents currently focuses on suppression of mRNA expression and protein degradation as well as targeting of the amino-terminal domain.
CONCLUSIONS
Current literature continues to support AR-Vs as biomarkers and therapeutic targets in prostate cancer. Laboratory investigations reveal both challenges and opportunities in targeting AR-Vs to overcome resistance to current AR-directed therapies.
Topics: Alternative Splicing; Androgen Receptor Antagonists; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Clinical Decision-Making; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Genetic Testing; Humans; Male; Precision Medicine; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Proteolysis; Receptors, Androgen; Transcriptional Activation
PubMed: 32139878
DOI: 10.1038/s41391-020-0217-3 -
Biology of Sex Differences Jan 2024The incidence of Alzheimer's disease (AD)-the most frequent cause of dementia-is expected to increase as life expectancies rise across the globe. While sex-based... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The incidence of Alzheimer's disease (AD)-the most frequent cause of dementia-is expected to increase as life expectancies rise across the globe. While sex-based differences in AD have previously been described, there remain uncertainties regarding any association between sex and disease-associated molecular mechanisms. Studying sex-specific expression profiles of regulatory factors such as microRNAs (miRNAs) could contribute to more accurate disease diagnosis and treatment.
METHODS
A systematic review identified six studies of microRNA expression in AD patients that incorporated information regarding the biological sex of samples in the Gene Expression Omnibus repository. A differential microRNA expression analysis was performed, considering disease status and patient sex. Subsequently, results were integrated within a meta-analysis methodology, with a functional enrichment of meta-analysis results establishing an association between altered miRNA expression and relevant Gene Ontology terms.
RESULTS
Meta-analyses of miRNA expression profiles in blood samples revealed the alteration of sixteen miRNAs in female and 22 miRNAs in male AD patients. We discovered nine miRNAs commonly overexpressed in both sexes, suggesting a shared miRNA dysregulation profile. Functional enrichment results based on miRNA profiles revealed sex-based differences in biological processes; most affected processes related to ubiquitination, regulation of different kinase activities, and apoptotic processes in males, but RNA splicing and translation in females. Meta-analyses of miRNA expression profiles in brain samples revealed the alteration of six miRNAs in female and four miRNAs in male AD patients. We observed a single underexpressed miRNA in female and male AD patients (hsa-miR-767-5p); however, the functional enrichment analysis for brain samples did not reveal any specifically affected biological process.
CONCLUSIONS
Sex-specific meta-analyses supported the detection of differentially expressed miRNAs in female and male AD patients, highlighting the relevance of sex-based information in biomedical data. Further studies on miRNA regulation in AD patients should meet the criteria for comparability and standardization of information.
Topics: Humans; Male; Female; Alzheimer Disease; MicroRNAs; Brain
PubMed: 38297404
DOI: 10.1186/s13293-024-00588-1 -
JAMA Neurology Apr 2013Hereditary spastic paraplegias (HSPs) are a group of diseases caused by corticospinal tract degeneration. Mutations in 3 genes (SPG4, SPG3, and SPG31) are said to be the... (Review)
Review
IMPORTANCE
Hereditary spastic paraplegias (HSPs) are a group of diseases caused by corticospinal tract degeneration. Mutations in 3 genes (SPG4, SPG3, and SPG31) are said to be the cause in half of the autosomal dominant HSPs (AD-HSPs). This study is a systematic review of families with HSP resulting from a population-based survey. Novel genotype-phenotype correlations were established.
OBJECTIVE
To describe the clinical, genetic, and epidemiological features of Portuguese AD-HSP families.
DESIGN
Retrospective medical record review.
SETTING
A population-based systematic survey of hereditary ataxias and spastic paraplegias conducted in Portugal from 1993 to 2004.
PARTICIPANTS
Families with AD-HSP.
MAIN OUTCOME MEASURE
Mutation detection in the most prevalent genes.
RESULTS
We identified 239 patients belonging to 89 AD-HSP families. The prevalence was 2.4 in 100 000. Thirty-one distinct mutations (26 in SPG4, 4 in SPG3, and 1 in SPG31) segregated in 41% of the families (33.7%, 6.2%, and 1.2% had SPG4, SPG3 and SPG31 mutations, respectively). Seven of the SPG4 mutations were novel, and 7% of all SPG4 mutations were deletions. When disease onset was before the first decade, 31% had SPG4 mutations and 27% had SPG3 mutations. In patients with SPG4 mutations, those with large deletions had the earliest disease onset, followed by those with missense, frameshift, nonsense, and alternative-splicing mutations. Rate of disease progression was not significantly different among patients with SPG3 and SPG4 mutations in a multivariate analysis. For patients with SPG4 mutations, disease progression was worst in patients with later-onset disease.
CONCLUSIONS AND RELEVANCE
The prevalence of AD-HSP and frequency of SPG3 and SPG4 mutations in the current study were similar to what has been described in other studies except that the frequency of SPG4 deletions was lower. In contrast, the frequency of SPG31 mutations in the current study was rare compared with other studies. The most interesting aspects of this study are that even in patients with early-onset disease the probability of finding a SPG4 mutation was higher than for patients with SPG3 mutations; there was no difference in disease progression with genotype but an association with the age at onset; 7 new SPG4 mutations were identified; and for the first time, to our knowledge, the nature of the SPG4 mutations was found to predict the age at onset.
Topics: Adenosine Triphosphatases; Adult; Age of Onset; Bone and Bones; Cataract; DNA Mutational Analysis; Disability Evaluation; Disease Progression; Family Health; Female; GTP-Binding Proteins; Genes, Dominant; Genotype; Growth Disorders; Health Surveys; Humans; Male; Membrane Proteins; Middle Aged; Mutation; Neurologic Examination; Phenotype; Portugal; Retrospective Studies; Severity of Illness Index; Spastic Paraplegia, Hereditary; Spastin; Statistics as Topic
PubMed: 23400676
DOI: 10.1001/jamaneurol.2013.1956 -
Alcohol and Alcoholism (Oxford,... Mar 2015The aim of this review was to focus on the knowledge of the role of lipin-1 in the pathogenesis of alcoholic fatty liver. (Review)
Review
AIMS
The aim of this review was to focus on the knowledge of the role of lipin-1 in the pathogenesis of alcoholic fatty liver.
METHODS
Systematic review of animal clinical and cell level studies related to the function of lipin-1 on alcoholic fatty liver, alcoholic hepatitis and alcoholic liver cirrhosis disease.
RESULT
Ethanol could increase the expression of lipin-1 through the AMPK-SREBP-1 signaling and dramatically increase the ratio of Lpin1β to Lpin1α by SIRT1-SFRS10-Lpin1β/α axis in the liver. Moreover, research has shown that over-expression of lipin-1 could also remarkably suppress very low density lipoprotein-triacylglyceride secretion. Last, lipin-1 has potent anti-inflammatory property.
CONCLUSION
In conclusion, lipin-1 has dual functions in lipid metabolism. In the cytoplasm, lipin-1β functions as a Mg(2+)-dependent phosphatidic acid phosphohydrolase (PAP) enzyme in triglyceride synthesis pathways. In the nucleus, lipin-1α acts as a transcriptional co-regulator to regulate the capacity of the liver for fatty acid oxidation and activity of the lipogenic enzyme. In hepatocytes of alcoholic fatty liver disease (AFLD), ethanol increases the expression of lipin-1 through the AMPK-SREBP-1 signaling and the Lpin1β/α ratio by SIRT1-SFRS10- Lpin1β/α axis. Of course, in addition to that, ethanol could also produce the PAP activity and interrupt the nucleus function of lipin-1. Furthermore, over-expression of lipin-1 could remarkably suppress very low-density lipoprotein-triacylglyceride (VLDL-TAG) secretion. In the end, endogenous lipin-1 has potent anti-inflammatory property. Increased synthesis of TAG, decreased fatty acid oxidation, impaired VLDL-TAG secretion and activated inflammatory factors act together to exacerbate the development of AFLD.
Topics: AMP-Activated Protein Kinases; Animals; Fatty Liver, Alcoholic; Hepatitis, Alcoholic; Lipid Metabolism; Lipoproteins, LDL; Liver; Liver Cirrhosis, Alcoholic; Mice; Nuclear Proteins; Phosphatidate Phosphatase; RNA-Binding Proteins; Serine-Arginine Splicing Factors; Signal Transduction; Sirtuin 1; Sterol Regulatory Element Binding Protein 1; Triglycerides
PubMed: 25595739
DOI: 10.1093/alcalc/agu102 -
Biological Psychiatry Oct 2019Many polymorphisms in dopamine genes are reported to affect cognitive, imaging, or clinical phenotypes. It is often inferred or assumed that such associations are... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Many polymorphisms in dopamine genes are reported to affect cognitive, imaging, or clinical phenotypes. It is often inferred or assumed that such associations are causal, mediated by a direct effect of the polymorphism on the gene product itself. However, the supporting evidence is not always clear.
METHODS
We conducted systematic reviews and meta-analyses to assess the empirical evidence for functional polymorphisms in genes encoding dopaminergic enzymes (COMT, DBH, DDC, MAOA, MAOB, and TH), dopamine receptors (DRD1, DRD2, DRD3, DRD4, and DRD5), the dopamine transporter (DAT), and vesicular transporters (VMAT1 and VMAT2). We defined functionality as an effect of the polymorphism on the expression, abundance, activity, or affinity of the gene product.
RESULTS
We screened 22,728 articles and identified 255 eligible studies. We found robust and medium to large effects for polymorphisms in 4 genes. For catechol-O-methyltransferase (COMT), the ValMet polymorphism (rs4680) markedly affected enzyme activity, protein abundance, and protein stability. Dopamine β-hydroxylase (DBH) activity was associated with rs1611115, rs2519152, and the DBH-STR polymorphism. Monoamine oxidase A (MAOA) activity was associated with a 5' VNTR polymorphism. Dopamine D receptor (DRD2) binding was influenced by the Taq1A (rs1800497) polymorphism, and rs1076560 affected DRD2 splicing.
CONCLUSIONS
Some widely studied dopaminergic polymorphisms clearly and substantially affect the abundance or activity of the encoded gene product. However, for other polymorphisms, evidence of such an association is negative, inconclusive, or lacking. These findings are relevant when selecting polymorphisms as "markers" of dopamine function, and for interpreting the biological plausibility of associations between these polymorphisms and aspects of brain function or dysfunction.
Topics: Brain; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Polymorphism, Single Nucleotide; Receptors, Dopamine
PubMed: 31303260
DOI: 10.1016/j.biopsych.2019.05.014 -
European Journal of Endocrinology Nov 2023Pseudohypoparathyroidism type 1a (PHP1a) is a rare endocrine disease caused by partial defects of the α subunit of the stimulatory Guanosin triphosphate (GTP) binding...
BACKGROUND
Pseudohypoparathyroidism type 1a (PHP1a) is a rare endocrine disease caused by partial defects of the α subunit of the stimulatory Guanosin triphosphate (GTP) binding protein (Gsα) resulting from maternal GNAS gene variation. The clinical manifestations are related to PTH resistance (hypocalcemia, hyperphosphatemia, and elevated serum intact PTH) in the presence or absence of multihormone resistance, and Albright's hereditary osteodystrophy (AHO).
OBJECTIVES
To summarize the molecular genetics results and clinical characteristics as well as to explore the correlations between them.
METHODS
Articles pertaining to PHP1a until May, 31, 2021 were reviewed and 527 patients with genetic diagnosis were included in the data analysis. The clinical characteristics and molecular genetics results of these patients were analyzed and compared to explore the correlations between them.
RESULTS
A total of 258 GNAS rare variants (RVs) were identified in 527 patients. The RVs were most commonly found in exons 1 and 7 (17.6% each), with frameshift (36.8%), and missense (31.3%) being the main types of RVs. The median age of onset was 5.0 years old. The most common clinical manifestations were elevation of PTH (86.7%) and AHO (87.5%). Thyroid stimulating hormone resistance was the most common hormone resistance (75.5%) other than PTH resistance. Patients with missense and in-frame RVs had lower incidence rates of the round face (P = .001) and subcutaneous ossifications (P < .001) than those with loss-of-function (non-sense, frameshift, splicing site variants, and large deletions) variants.
CONCLUSIONS
This study revealed the correlation between loss-of-function RVs with round faces and subcutaneous ossifications in PHP 1a patients. Further exploration of genotype-phenotype correlations through more standardized and prospective studies with long-term follow-up is necessary.
Topics: Humans; Child, Preschool; Prospective Studies; Chromogranins; Pseudohypoparathyroidism; GTP-Binding Protein alpha Subunits, Gs; Genetic Association Studies
PubMed: 37837607
DOI: 10.1093/ejendo/lvad142 -
Autoimmunity Reviews Jul 2019Alternative splicing is an important form of RNA processing that affects nearly all human genes. The differential expression of specific transcript and protein isoforms...
OBJECTIVE
Alternative splicing is an important form of RNA processing that affects nearly all human genes. The differential expression of specific transcript and protein isoforms holds the potential of novel biomarkers for complex diseases. In this systematic review, we compiled the existing literature on aberrant alternative splicing events in multiple sclerosis (MS).
METHODS
A systematic literature search in the PubMed database was carried out and supplemented by screening the reference lists of the identified articles. We selected only MS-related original research studies which compared the levels of different isoforms of human protein-coding genes. A narrative synthesis of the research findings was conducted. Additionally, we performed a case-control analysis using high-density transcriptome microarray data to reevaluate the genes that were examined in the reviewed studies.
RESULTS
A total of 160 records were screened. Of those, 36 studies from the last two decades were included. Most commonly, peripheral blood samples were analyzed (32 studies), and PCR-based techniques were usually employed (27 studies) for measuring the expression of selected genes. Two studies used an exploratory genome-wide approach. Overall, 27 alternatively spliced genes were investigated. Nine of these genes appeared in at least two studies (CD40, CFLAR, FOXP3, IFNAR2, IL7R, MOG, PTPRC, SP140 and TNFRSF1A). The microarray data analysis confirmed differential alternative pre-mRNA splicing for 19 genes.
CONCLUSIONS
An altered RNA processing of genes mediating immune signaling pathways has been repeatedly implicated in MS. The analysis of individual exon-level expression patterns is stimulated by the advancement of transcriptome profiling technologies. In particular, the examination of genes encoded in MS-associated genetic regions may provide important insights into the pathogenesis of the disease and help to identify new biomarkers.
Topics: Alternative Splicing; Gene Expression; Humans; Multiple Sclerosis
PubMed: 31059848
DOI: 10.1016/j.autrev.2019.05.010 -
Iranian Journal of Pathology 2018Acute myeloid leukemia (AML) as a distortion of blood cells involves the differ entiation of hematopoietic stem cells. Several studies established the irregular over... (Review)
Review
Acute myeloid leukemia (AML) as a distortion of blood cells involves the differ entiation of hematopoietic stem cells. Several studies established the irregular over expression of specific genes is a common finding in patients with AML. The ectopic viral integration site-1 () gene is a protooncogene subject to alternative splicing, and encodes a zincfinger protein that acts as a transcriptional regulator in early devel opment. Forced overexpression of in hematopoietic progenitors later induced a myeloid differentiation block. The current review aimed at determining the prognos tic value of expression in patients with AML in the age range of one month to fifteen years. The scientific databases including PubMed, Google Scholar, EMBASE, Scopus, and ISI published up to January 2016 were searched using the conformity keywords and a total of four articles were studied. Three articles declared higher overexpression of in patients with mixed-lineage leukemia (MLL) rearrangements. The percentage of overall survival (OS), reported in two articles, decreased in AML patients with high EVI1 expression. A study reported that the relationship between EVI1 expression and OS was negligible in cases with and without expression. Another study showed significant differences in event free survival (EFS) and OS in the group of patients with positive MLL-AF9 between + and patients. The current study revealed that high expression was not a poor prognostic factor in pediatric patients with AML. And this gene expression was mainly prognostic concomitantly by other factors such as MLL rearrangement, expression, and white blood cell (WBC) count.
PubMed: 30636951
DOI: No ID Found