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American Journal of Medical Genetics.... Jul 2020Variations in SLC9A9 gene expression and protein function are associated with multiple human diseases, which range from Attention-deficit/hyperactivity disorder (ADHD)...
Variations in SLC9A9 gene expression and protein function are associated with multiple human diseases, which range from Attention-deficit/hyperactivity disorder (ADHD) to glioblastoma multiforme. In an effort to determine the full spectrum of human disease associations with SLC9A9, we performed a systematic review of the literature. We also review SLC9A9's biochemistry, protein structure, and function, as well as its interacting partners with the goal of identifying mechanisms of disease and druggable targets. We report gaps in the literature regarding the genes function along with consistent trends in disease associations that can be used to further research into treating the respective diseases. We report that SLC9A9 has strong associations with neuropsychiatric diseases and various cancers. Interestingly, we find strong overlap in SLC9A9 disease associations and propose a novel role for SLC9A9 in neuropsychiatric comorbidity. In conclusion, SLC9A9 is a multifunctional protein that, through both its endosome regulatory function and its protein-protein interaction network, has the ability to modulate signaling axes, such as the PI3K pathway, among others.
Topics: Alternative Splicing; Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Autophagy; Comorbidity; Exons; Genetic Predisposition to Disease; HEK293 Cells; Humans; Mental Disorders; Phosphatidylinositol 3-Kinases; Protein Interaction Mapping; Protein Processing, Post-Translational; Signal Transduction; Sodium-Hydrogen Exchangers
PubMed: 32400953
DOI: 10.1002/ajmg.b.32787 -
Current HIV Research Jan 2009The human immunodeficiency virus (HIV-1) differentially controls viral protein expression at the level of splicing as well as nuclear export of incompletely spliced... (Review)
Review
The human immunodeficiency virus (HIV-1) differentially controls viral protein expression at the level of splicing as well as nuclear export of incompletely spliced viral RNA. This process, mediated by the Rev protein, interfaces with cellular components involved in post-transcriptional gene regulation. While a number of reviews have focused on the host proteins (i.e., Crm1, importin-beta and nucleoporins) that specifically regulate shuttling of Rev between the nucleus and cytoplasm, we could find no systematic review of other cellular proteins implicated in Rev function. Therefore, we will here focus on other Rev cofactors (eIF5a, hRIP, Sam68, RNA helicases, etc) and the role they play in Rev/RRE function and HIV-1 replication.
Topics: HIV-1; Host-Pathogen Interactions; Humans; Proteins; Virus Replication; rev Gene Products, Human Immunodeficiency Virus
PubMed: 19149558
DOI: 10.2174/157016209787048474 -
Prostate Cancer and Prostatic Diseases Sep 2020Approximately 10-30% of men with mCRPC will test positive for AR-V7 using one of two analytically and clinically validated circulating tumor cell (CTC)-based assays....
BACKGROUND
Approximately 10-30% of men with mCRPC will test positive for AR-V7 using one of two analytically and clinically validated circulating tumor cell (CTC)-based assays. These men have poor outcomes with approved AR-targeting therapies but may retain sensitivity to chemotherapy. Here, we discuss the clinical implications of testing and strategies that may benefit AR splice variant (AR-V)-positive men and discuss whether such variants are passengers or drivers of aggressive clinical behavior.
METHODS
We conducted a systemic review of the literature, covering updates since our 2016 review on androgen receptor variants in mCRPC, outcomes, and existing and novel approaches to therapy. We provide an expert opinion about management strategies for AR-V7-positive men and key unanswered research questions.
RESULTS
AR-V7-positive men, defined by Epic nuclear protein detection or the modified AdnaTest mRNA detection in CTCs, identify a subset of men with mCRPC that have a low probability of response to AR-targeting therapy with short progression-free and overall survival in multivariable analyses. AR-variants do not exist in isolation, but rather in the context of a complex, heterogeneous, and evolving mCRPC genome and phenotype as well as patient-specific clinical heterogeneity, and multiple mechanisms of resistance likely exist in patients regardless of AR-V7 detection. Efforts to develop broader resistance assays are needed, and effective treatment strategies beyond taxanes are needed to address the causal driver role of AR-variants and to benefit patients with AR-V-expressing prostate cancer.
CONCLUSIONS
CTC AR-V7 detection using the AdnaTest mRNA or Epic nuclear protein assays represents the first analytically and prospective clinically validated liquid biopsy assays that may inform treatment decisions in men with mCRPC, particularly after failure of first-line AR-therapy. The importance of AR-variants is likely to increase with the earlier use of AR-targeting strategies in other settings, and novel interventions for these men are needed.
Topics: Alternative Splicing; Androgen Receptor Antagonists; Antineoplastic Combined Chemotherapy Protocols; Clinical Decision-Making; Drug Resistance, Neoplasm; Genetic Testing; Humans; Male; Precision Medicine; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen
PubMed: 32094489
DOI: 10.1038/s41391-020-0215-5 -
Human Mutation Dec 2022ADAMTSL4 variants are one of the common causes of congenital ectopia lentis (EL), reported ocular comorbidities of which include iris anomalies, cataract, and glaucoma....
ADAMTSL4 variants are one of the common causes of congenital ectopia lentis (EL), reported ocular comorbidities of which include iris anomalies, cataract, and glaucoma. However, a genotype-phenotype correlation has not been established. Potentially pathogenic ADAMTSL4 variants were screened from a Chinese cohort of congenital EL using panel-based next-generation sequencing followed by multiple bioinformatics analyses. The genotype-phenotype correlation was assessed via a systematic review of ADAMTSL4 variants within our data and those from the literature. A total of 12 variants of ADAMTSL4, including seven frameshift variants, one nonsense variant, two splicing variants, and two missense variants, were found in nine probands. Combing genetic and clinical information from 72 probands in the literature revealed 37 ADAMTSL4 variants known to cause EL, and the ethnic difference was prominent. The lens was inclined to dislocate inferior temporally (22, 27.16%), while the pupil was always located oppositely (9, 81.82%). Several anterior segments anomalies were identified, including ectopia pupillae (15, 18.52%), persistent pupillary membrane (9, 11.10%), poor pupil dilation (4, 30.8%), cataract (13, 24.10%), and glaucoma (8, 13.33%). Genotype-phenotype analysis revealed that truncation variants had higher risks of combined iris anomalies, including either ectopia pupillae or a persistent pupillary membrane (p = 0.007). The data from this study not only extend our knowledge of the ADAMTSL4 variant spectrum but also suggest that deleterious variants of ADAMTSL4 might be associated with severe ocular phenotypes.
Topics: Humans; East Asian People; Pedigree; ADAMTS Proteins; Mutation; Ectopia Lentis; Cataract; Glaucoma
PubMed: 36208099
DOI: 10.1002/humu.24483 -
Critical Reviews in Oncology/hematology Sep 2019Long non-coding RNAs (lncRNAs), are over 200 nucleotides in length, and they rarely act as templates for protein synthesis. Mounting studies have shown that lncRNAs play...
Long non-coding RNAs (lncRNAs), are over 200 nucleotides in length, and they rarely act as templates for protein synthesis. Mounting studies have shown that lncRNAs play a crucial regulatory role in various processes that sustain life, such as epigenetic regulation, cell cycle control, splicing, and post-transcriptional regulation. LncRNAs were aberrantly expressed in most hematological malignancies including lymphoma, participating in tumor suppression or promoting oncogenesis and modulating key genes in different pathways. The specific expression patterns of lncRNAs in lymphoma make them good candidates to be used as diagnostic biomarkers or as therapeutic targets. LncRNAs can be targeted by multiple approaches including nucleic acid therapeutics, CRISPR/Cas genome editing techniques, small molecule inhibitors, and gene therapy. Efforts are made to develop therapeutic strategies aimed at targeting lncRNAs, but there are still some avenues to be covered before they can be applied to the clinical treatment of lymphoma.
Topics: Biomarkers, Pharmacological; Biomarkers, Tumor; Cell Transformation, Neoplastic; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Lymphoma; Molecular Targeted Therapy; RNA Interference; RNA, Long Noncoding
PubMed: 31202125
DOI: 10.1016/j.critrevonc.2019.05.007 -
Biomolecules Jun 2024Dilated cardiomyopathy (DCM) is a common cause of heart failure (HF) and heart transplantation (HTx), with genetic factors playing a significant role. In recent years,... (Review)
Review
Dilated cardiomyopathy (DCM) is a common cause of heart failure (HF) and heart transplantation (HTx), with genetic factors playing a significant role. In recent years, the RNA-binding protein motif 20 (), which affects the gene splicing of various proteins with different cellular functions, was identified as the first DCM gene with regulatory properties. Variants of have been associated with severe forms of DCM. The aim of this critical systematic review was to analyse cardiomyopathy clinical features and outcomes. According to PRISMA guidelines, a search was run in the PubMed, Scopus and Web of Science electronic databases using the following keywords: ""; "cardiomyopathy"; "arrhythmias"; "heart failure". A total of 181 records were screened, of which 27 studies were potentially relevant to the topic. Through the application of inclusion and exclusion criteria, eight papers reporting 398 patients with pathogenic variants were analysed. The mean age at presentation was 41 years. Familiarity with cardiomyopathy was available in 59% of cases, with 55% of probands reporting a positive family history. Imaging data indicated a mild reduction of left ventricular ejection fraction (mean LVEF 40%), while tissue characterization was reported in 24.3% of cases, showing late gadolinium enhancement in 33% of patients. Composite outcomes of sustained monomorphic ventricular tachycardia or ventricular fibrillation occurred in 19.4% of patients, with 12% undergoing HTx. There were no gender differences in arrhythmic outcomes, while 96.4% of patients who underwent HTx were male. In conclusion, cardiomyopathy exhibits a severe phenotypic expression, both in terms of arrhythmic burden and HF progression.
Topics: Humans; RNA-Binding Proteins; Cardiomyopathy, Dilated; Male; Female; Adult
PubMed: 38927106
DOI: 10.3390/biom14060702 -
The Prostate Dec 2011Although in recent years deleterious BRCA1 mutations have been extensively studied as a prostate cancer risk factor, results are inconclusive. To assess the contribution... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Although in recent years deleterious BRCA1 mutations have been extensively studied as a prostate cancer risk factor, results are inconclusive. To assess the contribution of the BRCA1 Galician founder mutation c.211A>G in prostate cancer morbidity we conducted a case-control study. Moreover, to better elucidate whether deleterious BRCA1 mutations are involved in the development of prostate cancer, we performed a systematic review and a meta-analysis of BRCA1 studies on prostate cancer.
METHODS
A total of 905 unselected men diagnosed with adenocarcinoma of the prostate and a control group of 936 unrelated men without history of prostate cancer were evaluated for c.211A>G. Adjusted by age Odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression. To construct the meta-analysis, genotype-based epidemiological studies reporting BRCA1 founder mutations on prostate cancer were identified by comprehensive and systematic bibliographic search. After extraction of relevant data, main and subgroup analysis by mutation were performed to assess the effect of BRCA1 on prostate cancer risk.
RESULTS
Four c.211A>G heterozygous individuals, one patient and three controls, were detected (OR = 0.27; 95% CI: 0.01-2.36; P = 0.28). Meta-analysis results from the integration of our data and other seven studies with BRCA1 genotyping data (5,705 prostate cancer cases and 13,218 controls) did not detect an association with prostate cancer risk (OR = 1.36; 95% CI: 0.87-2.14; P = 0.18).
CONCLUSIONS
Our conclusive trial demonstrates the lack of association between Galician splicing mutation c.211A>G in the BRCA1 gene and prostate cancer risk. Moreover, the result of the meta-analysis also discards the involvement of BRCA1 mutations in the development of prostate cancer.
Topics: Adenocarcinoma; Aged; Aged, 80 and over; BRCA1 Protein; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Prostatic Neoplasms; Risk Factors
PubMed: 21520156
DOI: 10.1002/pros.21394 -
Journal of the European Academy of... Oct 2017Epidermodysplasia verruciformis (EV) is a genodermatosis leading to infections with cutaneous HPV, persistent plane warts and a high rate of non-melanoma skin cancer... (Review)
Review
BACKGROUND
Epidermodysplasia verruciformis (EV) is a genodermatosis leading to infections with cutaneous HPV, persistent plane warts and a high rate of non-melanoma skin cancer (NMSC). Biallelic loss-of-function mutations in TMC6 and TMC8 are known to be causative.
OBJECTIVE
The aim of this study was to report EV-causing mutations in four patients with EV and to give an overview of all described patients with EV.
PATIENTS AND METHODS
We investigated four patients with classical features of EV from two families. All patients were affected by plane warts with typical EV histology since early childhood, and β-HPVs were detected on their skin. One patient had recurring cutaneous squamous cell carcinomas (cSCC) and carcinomas in situ (Bowen type). We sequenced both TMC6/8 for disease-causing mutations and quantified levels of gene expression. We also performed a systematic literature review to discuss these patients in the context of previously reported cases, mutations already identified, as well as HPV types.
RESULTS
Three patients of one family carried a homozygous splice site mutation in TMC8 resulting in aberrantly spliced transcripts that were not degraded. By contrast, no TMC6/8 mutation was detected in the patient from the other family. A systematic literature review revealed 501 described patients with EV. Around 40% of patients with EV analysed for genetic alterations carried no mutation in TMC6/8. While β-HPVs were identified in the majority of cases, α-HPVs were detected in several individuals.
CONCLUSION
The relatively high proportion of EV patients without mutation in TMC6/8 indicates the existence of EV-causing mutations in additional, presently unknown gene(s). However, a homozygous TMC8 splice site mutation in our patients resulted in aberrant transcripts which cannot retain the healthy phenotype. The literature review revealed that HPV-5 is the most commonly identified HPV in patients with EV, but HPV-3, HPV-14 and HPV-20 were unexpectedly identified more frequently than HPV-8.
Topics: Adolescent; Child; Epidermodysplasia Verruciformis; Female; Humans; Male; Membrane Proteins; Middle Aged; Mutation; Papillomavirus Infections; RNA Splicing
PubMed: 28646613
DOI: 10.1111/jdv.14431 -
Acta Neurologica Belgica Dec 2019Recent discovery of nusinersen, an antisense oligonucleotide drug, has provided encouragement for improving treatment of spinal muscular atrophy. No therapeutic options...
Recent discovery of nusinersen, an antisense oligonucleotide drug, has provided encouragement for improving treatment of spinal muscular atrophy. No therapeutic options currently exist for this autosomal recessive motor neuron disorder. Nusinersen is developed for intrathecal use and binds to a specific sequence within the survival motor neuron 2 pre-messenger RNA, modifying the splicing process to promote expression of full-length survival motor neuron protein. We performed a MEDLINE and CENTRAL search to investigate the current evidence for treatment with nusinersen in patients with spinal muscular atrophy. Four papers were withheld, including two phase-3 randomized controlled trials, one phase-2 open-label clinical trial and one phase-1 open-label clinical trial. Outcome measures concerned improvement in motor function and milestones, as well as event-free survival and survival. Results of these trials are hopeful with significant and clinically meaningful improvement due to treatment with intrathecal nusinersen in patients with early- and later-onset spinal muscular atrophy, although this does not restore age-appropriate function. Intrathecal nusinersen has acceptable safety and tolerability. Further trials regarding long-term effects and safety aspects as well as trials including broader spinal muscular atrophy and age categories are required and ongoing.
Topics: Cell Survival; Evidence-Based Medicine; Humans; Motor Neurons; Muscular Atrophy, Spinal; Oligonucleotides; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 31388901
DOI: 10.1007/s13760-019-01199-z -
Future Oncology (London, England) Dec 2018In September 2017, the US FDA announced re-approval of gemtuzumab ozogamicin (GO), a CD33-targeting immunoconjugate, for treatment of newly diagnosed and... (Meta-Analysis)
Meta-Analysis
In September 2017, the US FDA announced re-approval of gemtuzumab ozogamicin (GO), a CD33-targeting immunoconjugate, for treatment of newly diagnosed and relapsed/refractory acute myeloid leukemia (AML). This is a very significant step toward defining new treatment regimens in AML, as the treatment has essentially stayed unchanged with the '7 + 3 induction regimen' (7 days cytarabine and 3 days of anthracycline) since 1973. GO is the first antibody-drug conjugate to receive FDA approval for treating cancer. This review article discusses the challenges faced and lessons learned during the journey of GO for AML treatment. Selected trials that have made significant contribution in our understanding of the most efficacious and safe use of GO for treating AML patients as well as factors influencing GO response are highlighted in this article.
Topics: Age Factors; Aminoglycosides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Biomarkers, Tumor; Drug Discovery; France; Gemtuzumab; Humans; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Randomized Controlled Trials as Topic; Sialic Acid Binding Ig-like Lectin 3; Treatment Outcome; United States
PubMed: 30039981
DOI: 10.2217/fon-2018-0325