Literature Watch
Suspended polyhydroxyalkanoate microspheres as 3D carriers for mammalian cell growth.
Suspended polyhydroxyalkanoate microspheres as 3D carriers for mammalian cell growth.
Artif Cells Nanomed Biotechnol. 2018 Apr 13;:1-11
Authors: Wei DX, Dao JW, Liu HW, Chen GQ
Abstract
Different forms of biopolyester PHBVHHx microspheres were prepared so as to compare the mammalian cell behaviors in suspension cultivation system. Based on a microbial terpolyester PHBVHHx consisting of 3-hydroxybutyrate (HB), 3-hydroxyvalerate (HV), and 3-hydroxyhexanoate (HHx), solid microspheres (SMSs), hollow microspheres (HMSs), and porous microspheres (PMS) were successfully prepared by a modified solvent evaporation method involving gas-in-oil-in-water (G1/O/W2) double emulsion, water-in-oil-in-water (W1/O/W2) double emulsion and oil-in-water (O/W) single emulsion, respectively. Generally, PMSs have diameters ranging from 330 to 400 μm with pore sizes of 10 to 60 μm. The pores inside the PMSs were found well interconnected compared with PHBVHHx prepared by the traditional solvent evaporation method, resulting in the highest water uptake ratio. When inoculated with human osteoblast-like cells lasting 6 days, PMS showed much better cell attachment and proliferation compared with other less porous microspheres due to its large inner space as a 3 D carrier. Cell migration towards surface and other interconnected inner pores was clearly observable. Dead or apoptotic cells were found more common among less porous SMSs or HMSs compared with highly porous PMSs. It is therefore concluded that porous PHBVHHx microspheres with larger surface open pores and interconnected inner pores can serve as a carrier or scaffold supporting more and better cell growth for either injectable purposes or simply supporting cell growth.
PMID: 29653500 [PubMed - as supplied by publisher]
"systems biology"; +25 new citations
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Expanding the clinical spectrum of biallelic ZNF335 variants.
Expanding the clinical spectrum of biallelic ZNF335 variants.
Clin Genet. 2018 Apr 13;:
Authors: Stouffs K, Stergachis AB, Vanderhasselt T, Dica A, Janssens S, Vandervore L, Gheldof A, Bodamer O, Keymolen K, Seneca S, Liebaers I, Jayaraman D, Hill HE, Partlow JN, Walsh CA, Jansen AC
Abstract
ZNF335 plays an essential role in neurogenesis and biallelic variants in ZNF335 have been identified as the cause of severe primary autosomal recessive microcephaly in two unrelated families. We describe herein two additional affected individuals with biallelic ZNF335 variants, one individual with a homozygous c.1399T>C, p.(Cys467Arg) variant, and a second individual with compound heterozygous c.2171_2173delTCT, p.(Phe724del) and c.3998A>G, p.(Glu1333Gly) variants in ZNF335; with the latter variant predicted to affect splicing. Whereas the first case presented with early death and a severe phenotype characterized by anterior agyria with prominent extra-axial spaces, absent basal ganglia, and hypoplasia of the brainstem and cerebellum, the second case had a milder clinical presentation with hypomyelination and otherwise preserved brain structures on MRI. Our findings expand the clinical spectrum of ZNF335 associated microcephaly.
PMID: 29652087 [PubMed - as supplied by publisher]
Exploring the molecular mechanisms of Traditional Chinese Medicine components using gene expression signatures and connectivity map.
Exploring the molecular mechanisms of Traditional Chinese Medicine components using gene expression signatures and connectivity map.
Comput Methods Programs Biomed. 2018 Apr 04;:
Authors: Yoo M, Shin J, Kim H, Kim J, Kang J, Tan AC
Abstract
BACKGROUND AND OBJECTIVE: Traditional Chinese Medicine (TCM) has been practiced over thousands of years in China and other Asian countries for treating various symptoms and diseases. However, the underlying molecular mechanisms of TCM are poorly understood, partly due to the "multi-component, multi-target" nature of TCM. To uncover the molecular mechanisms of TCM, we perform comprehensive gene expression analysis using connectivity map.
METHODS: We interrogated gene expression signatures obtained 102 TCM components using the next generation Connectivity Map (CMap) resource. We performed systematic data mining and analysis on the mechanism of action (MoA) of these TCM components based on the CMap results.
RESULTS: We clustered the 102 TCM components into four groups based on their MoAs using next generation CMap resource. We performed gene set enrichment analysis on these components to provide additional supports for explaining these molecular mechanisms. We also provided literature evidence to validate the MoAs identified through this bioinformatics analysis. Finally, we developed the Traditional Chinese Medicine Drug Repurposing Hub (TCM Hub) - a connectivity map resource to facilitate the elucidation of TCM MoA for drug repurposing research. TCMHub is freely available in http://tanlab.ucdenver.edu/TCMHub.
CONCLUSIONS: Molecular mechanisms of TCM could be uncovered by using gene expression signatures and connectivity map. Through this analysis, we identified many of the TCM components possess diverse MoAs, this may explain the applications of TCM in treating various symptoms and diseases.
PMID: 29650251 [PubMed - as supplied by publisher]
Realizing drug repositioning by adapting a recommendation system to handle the process.
Realizing drug repositioning by adapting a recommendation system to handle the process.
BMC Bioinformatics. 2018 Apr 12;19(1):136
Authors: Ozsoy MG, Özyer T, Polat F, Alhajj R
Abstract
BACKGROUND: Drug repositioning is the process of identifying new targets for known drugs. It can be used to overcome problems associated with traditional drug discovery by adapting existing drugs to treat new discovered diseases. Thus, it may reduce associated risk, cost and time required to identify and verify new drugs. Nowadays, drug repositioning has received more attention from industry and academia. To tackle this problem, researchers have applied many different computational methods and have used various features of drugs and diseases.
RESULTS: In this study, we contribute to the ongoing research efforts by combining multiple features, namely chemical structures, protein interactions and side-effects to predict new indications of target drugs. To achieve our target, we realize drug repositioning as a recommendation process and this leads to a new perspective in tackling the problem. The utilized recommendation method is based on Pareto dominance and collaborative filtering. It can also integrate multiple data-sources and multiple features. For the computation part, we applied several settings and we compared their performance. Evaluation results show that the proposed method can achieve more concentrated predictions with high precision, where nearly half of the predictions are true.
CONCLUSIONS: Compared to other state of the art methods described in the literature, the proposed method is better at making right predictions by having higher precision. The reported results demonstrate the applicability and effectiveness of recommendation methods for drug repositioning.
PMID: 29649971 [PubMed - in process]
Drug-Induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Call for Optimum Patient Stratification and Theranostics via Pharmacogenomics.
Drug-Induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Call for Optimum Patient Stratification and Theranostics via Pharmacogenomics.
Annu Rev Genomics Hum Genet. 2018 Apr 13;:
Authors: Sukasem C, Katsila T, Tempark T, Patrinos GP, Chantratita W
Abstract
The Global Genomic Medicine Collaborative, a multinational coalition of genomic and policy experts working to implement genomics in clinical care, considers pharmacogenomics to be among the first areas in genomic medicine that can provide guidance in routine clinical practice, by linking genetic variation and drug response. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe life-threatening reactions to medications with a high incidence worldwide. Genomic screening prior to drug administration is a key opportunity and potential paradigm for using genomic medicine to reduce morbidity and mortality and ultimately eliminate one of the most devastating adverse drug reactions. This review focuses on the current understanding of the surveillance, pathogenesis, and treatment of SJS/TEN, including the role of genomics and pharmacogenomics in the etiology, treatment, and eradication of preventable causes of drug-induced SJS/TEN. Gaps, unmet needs, and priorities for future research have been identified for the optimal management of drug-induced SJS/TEN in various ethnic populations. Pharmacogenomics holds great promise for optimal patient stratification and theranostics, yet its clinical implementation needs to be cost-effective and sustainable. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 19 is August 31, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
PMID: 29652519 [PubMed - as supplied by publisher]
A Discrete Event Simulation Model to Assess the Economic Value of a Hypothetical Pharmacogenomics Test for Statin-Induced Myopathy in Patients Initiating a Statin in Secondary Cardiovascular Prevention.
A Discrete Event Simulation Model to Assess the Economic Value of a Hypothetical Pharmacogenomics Test for Statin-Induced Myopathy in Patients Initiating a Statin in Secondary Cardiovascular Prevention.
Mol Diagn Ther. 2018 Apr 12;:
Authors: Mitchell D, Guertin JR, Dubois A, Dubé MP, Tardif JC, Iliza AC, Fanton-Aita F, Matteau A, LeLorier J
Abstract
BACKGROUND: Statin (HMG-CoA reductase inhibitor) therapy is the mainstay dyslipidemia treatment and reduces the risk of a cardiovascular (CV) event (CVE) by up to 35%. However, adherence to statin therapy is poor. One reason patients discontinue statin therapy is musculoskeletal pain and the associated risk of rhabdomyolysis. Research is ongoing to develop a pharmacogenomics (PGx) test for statin-induced myopathy as an alternative to the current diagnosis method, which relies on creatine kinase levels. The potential economic value of a PGx test for statin-induced myopathy is unknown.
METHODS: We developed a lifetime discrete event simulation (DES) model for patients 65 years of age initiating a statin after a first CVE consisting of either an acute myocardial infarction (AMI) or a stroke. The model evaluates the potential economic value of a hypothetical PGx test for diagnosing statin-induced myopathy. We have assessed the model over the spectrum of test sensitivity and specificity parameters.
RESULTS: Our model showed that a strategy with a perfect PGx test had an incremental cost-utility ratio of 4273 Canadian dollars ($Can) per quality-adjusted life year (QALY). The probabilistic sensitivity analysis shows that when the payer willingness-to-pay per QALY reaches $Can12,000, the PGx strategy is favored in 90% of the model simulations.
CONCLUSION: We found that a strategy favoring patients staying on statin therapy is cost effective even if patients maintained on statin are at risk of rhabdomyolysis. Our results are explained by the fact that statins are highly effective in reducing the CV risk in patients at high CV risk, and this benefit largely outweighs the risk of rhabdomyolysis.
PMID: 29651791 [PubMed - as supplied by publisher]
Identification of Common Genes Refers to Colorectal Carcinogenesis with Paired Cancer and Noncancer Samples.
Identification of Common Genes Refers to Colorectal Carcinogenesis with Paired Cancer and Noncancer Samples.
Dis Markers. 2018;2018:3452739
Authors: Zhang L, Yang Y, Cheng L, Cheng Y, Zhou HH, Tan ZR
Abstract
Colorectal cancer is a malignant tumor which harmed human beings' health. The aim of this study was to explore common biomarkers associated with colorectal carcinogenesis in paired cancer and noncancer samples. At first, fifty-nine pairs of colorectal cancer and noncancer samples from three gene expression datasets were collected and analyzed. Then, 181 upregulation and 282 downregulation common differential expression genes (DEGs) were found. Next, functional annotation was performed in the DAVID database with the DEGs. Finally, real-time polymerase chain reaction (PCR) assay was conducted to verify the analyses in sixteen colorectal cancer and individual-matched adjacent mucosa samples. Real-time PCR showed that MCM2, RNASEH2A, and TOP2A were upregulated in colorectal cancer compared with adjacent mucosa samples (MCM2, P < 0.001; RNASEH2A, P < 0.001; TOP2A, P = 0.001). These suggested that 463 DEGs might contribute to colorectal carcinogenesis.
PMID: 29651323 [PubMed - in process]
Genetic Variants in CPA6 and PRPF31 are Associated with Variation in Response to Metformin in Individuals with Type 2 Diabetes.
Genetic Variants in CPA6 and PRPF31 are Associated with Variation in Response to Metformin in Individuals with Type 2 Diabetes.
Diabetes. 2018 Apr 12;:
Authors: Rotroff DM, Yee SW, Zhou K, Marvel SW, Shah HS, Jack JR, Havener TM, Hedderson MM, Kubo M, Herman MA, Gao H, Mychaleckyi JC, McLeod HL, Doria A, Giacomini KM, Pearson ER, Wagner MJ, Buse JB, Motsinger-Reif AA, MetGen Investigators and the ACCORD/ACCORDion Investigators
Abstract
Metformin is the first line treatment for type 2 diabetes (T2D). Although widely prescribed, the glucose-lowering mechanism for metformin is incompletely understood. Here we used a genome-wide association approach in a diverse group of individuals with T2D from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial to identify common and rare variants associated with HbA1c response to metformin treatment, and followed up these findings in four replication cohorts. Common variants in PRPF31 and CPA6, were associated with worse and better metformin response, respectively (p<5×10-6), and meta-analysis in independent cohorts displayed similar associations with metformin response (p=1.2×10-8 and p=0.005, respectively). Previous studies have shown that PRPF31(+/-) knockout mice have increased total body fat (p=1.78×10-6) and increased fasted circulating glucose (p=5.73×10-6). Furthermore, rare variants in STAT3 associated with worse metformin response(q<0.1). STAT3 is a ubiquitously expressed pleiotropic transcriptional activator that participates in the regulation of metabolism and feeding behavior. Here we provide novel evidence for associations of common and rare variants in PRPF31, CPA6, and STAT3 with metformin response that may provide insight into mechanisms important for metformin efficacy in T2D.
PMID: 29650774 [PubMed - as supplied by publisher]
Is Plasma Renin Activity Genetically Determined and How Much Does It Matter for Treating Hypertension?
Is Plasma Renin Activity Genetically Determined and How Much Does It Matter for Treating Hypertension?
Circ Genom Precis Med. 2018 Apr;11(4):e002139
Authors: Alhenc-Gelas F, Menard J
PMID: 29650769 [PubMed - in process]
Genetic Variants Influencing Plasma Renin Activity in Hypertensive Patients From the PEAR Study (Pharmacogenomic Evaluation of Antihypertensive Responses).
Genetic Variants Influencing Plasma Renin Activity in Hypertensive Patients From the PEAR Study (Pharmacogenomic Evaluation of Antihypertensive Responses).
Circ Genom Precis Med. 2018 Apr;11(4):e001854
Authors: McDonough CW, Magvanjav O, Sá ACC, El Rouby NM, Dave C, Deitchman AN, Kawaguchi-Suzuki M, Mei W, Shen Y, Singh RSP, Solayman M, Bailey KR, Boerwinkle E, Chapman AB, Gums JG, Webb A, Scherer SE, Sadee W, Turner ST, Cooper-DeHoff RM, Gong Y, Johnson JA
Abstract
BACKGROUND: Plasma renin is an important regulator of blood pressure (BP). Plasma renin activity (PRA) has been shown to correlate with variability in BP response to antihypertensive agents. We conducted a genome-wide association study to identify single-nucleotide polymorphisms (SNPs) associated with baseline PRA using data from the PEAR study (Pharmacogenomic Evaluation of Antihypertensive Responses).
METHODS: Multiple linear regression analysis was performed in 461 whites and 297 blacks using an additive model, adjusting for age, sex, and ancestry-specific principal components. Top SNPs were prioritized by testing the expected direction of association for BP response to atenolol and hydrochlorothiazide. Top regions from the BP response prioritization were tested for functional evidence through differences in gene expression by genotype using RNA sequencing data. Regions with functional evidence were assessed for replication with baseline PRA in an independent study (PEAR-2).
RESULTS: Our top SNP rs3784921 was in the SNN-TXNDC11 gene region. The G allele of rs3784921 was associated with higher baseline PRA (β=0.47; P=2.09×10-6) and smaller systolic BP reduction in response to hydrochlorothiazide (β=2.97; 1-sided P=0.006). In addition, TXNDC11 expression differed by rs3784921 genotype (P=0.007), and rs1802409, a proxy SNP for rs3784921 (r2=0.98-1.00), replicated in PEAR-2 (β=0.15; 1-sided P=0.038). Additional SNPs associated with baseline PRA that passed BP response prioritization were in/near the genes CHD9, XIRP2, and GHR. CONCLUSIONS: We identified multiple regions associated with baseline PRA that were prioritized through BP response signals to 2 mechanistically different antihypertensive drugs.
CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00246519.
PMID: 29650764 [PubMed - in process]
Pharmacogenetics of androgen signaling in prostate cancer: Focus on castration resistance and predictive biomarkers of response to treatment.
Pharmacogenetics of androgen signaling in prostate cancer: Focus on castration resistance and predictive biomarkers of response to treatment.
Crit Rev Oncol Hematol. 2018 May;125:51-59
Authors: Del Re M, Crucitta S, Restante G, Rofi E, Arrigoni E, Biasco E, Sbrana A, Coppi E, Galli L, Bracarda S, Santini D, Danesi R
Abstract
Tumor heterogeneity strongly affects the molecular mechanisms driving resistance to hormonal therapies in castration-resistant prostate cancer. Since the current use of available treatments can be optimized on the basis of the molecular profile of tumor, the present review focuses on genetic biomarkers in prostate cancer and their application to a personalized treatment.
PMID: 29650277 [PubMed - in process]
Mechanism of action of trabectedin in desmoplastic small round cell tumor cells.
Mechanism of action of trabectedin in desmoplastic small round cell tumor cells.
BMC Cancer. 2017 Feb 06;17(1):107
Authors: Uboldi S, Craparotta I, Colella G, Ronchetti E, Beltrame L, Vicario S, Marchini S, Panini N, Dagrada G, Bozzi F, Pilotti S, Galmarini CM, D'Incalci M, Gatta R
Abstract
BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare and highly aggressive disease, that can be described as a member of the family of small round blue cell tumors. The molecular diagnostic marker is the t(11;22)(p13;q12) translocation, which creates an aberrant transcription factor, EWS-WT1, that underlies the oncogenesis of DSRCT. Current treatments are not very effective so new active drugs are needed. Trabectedin, now used as a single agent for the treatment of soft tissue sarcoma, was reported to be active in some pre-treated DSRCT patients. Using JN-DSRCT-1, a cell line derived from DSRCT expressing the EWS-WT1 fusion protein, we investigated the ability of trabectedin to modify the function of the chimeric protein, as in other sarcomas expressing fusion proteins. After detailed characterization of the EWS-WT1 transcripts structure, we investigated the mode of action of trabectedin, looking at the expression and function of the oncogenic chimera.
METHODS: We characterized JN-DSRCT-1 cells using cellular approaches (FISH, Clonogenicity assay) and molecular approaches (Sanger sequencing, ChIP, GEP).
RESULTS: JN-DSRCT-1 cells were sensitive to trabectedin at nanomolar concentrations. The cell line expresses different variants of EWS-WT1, some already identified in patients. EWS-WT1 mRNA expression was affected by trabectedin and chimeric protein binding on its target gene promoters was reduced. Expression profiling indicated that trabectedin affects the expression of genes involved in cell proliferation and apoptosis.
CONCLUSIONS: The JN-DSRCT-1 cell line, in vitro, is sensitive to trabectedin: after drug exposure, EWS-WT1 chimera expression decreases as well as binding on its target promoters. Probably the heterogeneity of chimera transcripts is an obstacle to precisely defining the molecular mode of action of drugs, calling for further cellular models of DSRCT, possibly growing in vivo too, to mimic the biological complexity of this disease.
PMID: 28166781 [PubMed - indexed for MEDLINE]
Delivering drugs to the lungs: The history of repurposing in the treatment of respiratory diseases.
Delivering drugs to the lungs: The history of repurposing in the treatment of respiratory diseases.
Adv Drug Deliv Rev. 2018 Apr 10;:
Authors: Newman SP
Abstract
The repurposing of drug delivery by the pulmonary route has been applied to treatment and prophylaxis of an increasingly wide range of respiratory diseases. Repurposing has been most successful for the delivery of inhaled bronchodilators and corticosteroids in patients with asthma and chronic obstructive pulmonary disease (COPD). Repurposing utilizes the advantages that the pulmonary route offers in terms of more targeted delivery to the site of action, the use of smaller doses, and a lower incidence of side-effects. Success has been more variable for other drugs and treatment indications. Pulmonary delivery is now well established for delivery of inhaled antibiotics in cystic fibrosis (CF), and in the treatment of pulmonary arterial hypertension (PAH). Other inhaled treatments such as those for idiopathic pulmonary fibrosis (IPF), lung transplant rejection or tuberculosis may also become routine. Repurposing has progressed in parallel with the development of new drugs, inhaler devices and formulations.
PMID: 29653129 [PubMed - as supplied by publisher]
Aspergillus-induced superoxide production by cystic fibrosis phagocytes is associated with disease severity.
Aspergillus-induced superoxide production by cystic fibrosis phagocytes is associated with disease severity.
ERJ Open Res. 2018 Apr;4(2):
Authors: Brunel SF, Willment JA, Brown GD, Devereux G, Warris A
Abstract
Aspergillus fumigatus infects up to 50% of cystic fibrosis (CF) patients and may play a role in progressive lung disease. As cystic fibrosis transmembrane conductance regulator is expressed in cells of the innate immune system, we hypothesised that impaired antifungal immune responses play a role in CF-related Aspergillus lung disease. Peripheral blood mononuclear cells, polymorphonuclear cells (PMN) and monocytes were isolated from blood samples taken from CF patients and healthy volunteers. Live-cell imaging and colorimetric assays were used to assess antifungal activity in vitro. Production of reactive oxygen species (ROS) was measured using luminol-induced chemiluminescence and was related to clinical metrics as collected by case report forms. CF phagocytes are as effective as those from healthy controls with regards to phagocytosis, killing and restricting germination of A. fumigatus conidia. ROS production by CF phagocytes was up to four-fold greater than healthy controls (p<0.05). This effect could not be replicated in healthy phagocytes by priming with lipopolysaccharide or serum from CF donors. Increased production of ROS against A. fumigatus by CF PMN was associated with an increased number of clinical exacerbations in the previous year (p=0.007) and reduced lung function (by forced expiratory volume in 1 s) (p=0.014). CF phagocytes mount an intrinsic exaggerated release of ROS upon A. fumigatus stimulation which is associated with clinical disease severity.
PMID: 29651422 [PubMed]
Clinical variability and onset age modifiers in an extended Belgian GRN founder family.
Clinical variability and onset age modifiers in an extended Belgian GRN founder family.
Neurobiol Aging. 2018 Mar 10;67:84-94
Authors: Wauters E, Van Mossevelde S, Sleegers K, van der Zee J, Engelborghs S, Sieben A, Vandenberghe R, Philtjens S, Van den Broeck M, Peeters K, Cuijt I, De Coster W, Van Langenhove T, Santens P, Ivanoiu A, Cras P, De Bleecker JL, Versijpt J, Crols R, De Klippel N, Martin JJ, De Deyn PP, Cruts M, Van Broeckhoven C, Belgian Neurology (BELNEU) Consortium
Abstract
We previously reported a granulin (GRN) null mutation, originating from a common founder, in multiple Belgian families with frontotemporal dementia. Here, we used data of a 10-year follow-up study to describe in detail the clinical heterogeneity observed in this extended founder pedigree. We identified 85 patients and 40 unaffected mutation carriers, belonging to 29 branches of the founder pedigree. Most patients (74.4%) were diagnosed with frontotemporal dementia, while others had a clinical diagnosis of unspecified dementia, Alzheimer's dementia or Parkinson's disease. The observed clinical heterogeneity can guide clinical diagnosis, genetic testing, and counseling of mutation carriers. Onset of initial symptomatology is highly variable, ranging from age 45 to 80 years. Analysis of known modifiers, suggested effects of GRN rs5848, microtubule-associated protein tau H1/H2, and chromosome 9 open reading frame 72 G4C2 repeat length on onset age but explained only a minor fraction of the variability. Contrary, the extended GRN founder family is a valuable source for identifying other onset age modifiers based on exome or genome sequences. These modifiers might be interesting targets for developing disease-modifying therapies.
PMID: 29653316 [PubMed - as supplied by publisher]
[A de novo GJA1 mutation identified by whole-exome sequencing in a patient with oculodentodigital dysplasia].
[A de novo GJA1 mutation identified by whole-exome sequencing in a patient with oculodentodigital dysplasia].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2018 Apr 10;35(2):268-271
Authors: Zeng H, Xie L, Tang M, Yang Y, Tan Z
Abstract
OBJECTIVE: To explore the genetic basis for a patient with oculodentodigital dysplasia.
METHODS: Genomic DNA was extracted from peripheral blood samples from the patient and his parents. Whole-exome sequencing was carried out for the trio family. Suspected mutation was verified by Sanger sequencing.
RESULTS: A de novo c.412G>A mutation of the GJA1 gene was identified in the patient, which was validated by Sanger sequencing.
CONCLUSION: The c.412G>A mutation of the GJA1 gene probably underlies the disease in the patient.
PMID: 29653008 [PubMed - in process]
Systematic reconstruction of autism biology from massive genetic mutation profiles.
Systematic reconstruction of autism biology from massive genetic mutation profiles.
Sci Adv. 2018 Apr;4(4):e1701799
Authors: Luo W, Zhang C, Jiang YH, Brouwer CR
Abstract
Autism spectrum disorder (ASD) affects 1% of world population and has become a pressing medical and social problem worldwide. As a paradigmatic complex genetic disease, ASD has been intensively studied and thousands of gene mutations have been reported. Because these mutations rarely recur, it is difficult to (i) pinpoint the fewer disease-causing versus majority random events and (ii) replicate or verify independent studies. A coherent and systematic understanding of autism biology has not been achieved. We analyzed 3392 and 4792 autism-related mutations from two large-scale whole-exome studies across multiple resolution levels, that is, variants (single-nucleotide), genes (protein-coding unit), and pathways (molecular module). These mutations do not recur or replicate at the variant level, but significantly and increasingly do so at gene and pathway levels. Genetic association reveals a novel gene + pathway dual-hit model, where the mutation burden becomes less relevant. In multiple independent analyses, hundreds of variants or genes repeatedly converge to several canonical pathways, either novel or literature-supported. These pathways define recurrent and systematic ASD biology, distinct from previously reported gene groups or networks. They also present a catalog of novel ASD risk factors including 118 variants and 72 genes. At a subpathway level, most variants disrupt the pathway-related gene functions, and in the same gene, they tend to hit residues extremely close to each other and in the same domain. Multiple interacting variants spotlight key modules, including the cAMP (adenosine 3',5'-monophosphate) second-messenger system and mGluR (metabotropic glutamate receptor) signaling regulation by GRKs (G protein-coupled receptor kinases). At a superpathway level, distinct pathways further interconnect and converge to three biology themes: synaptic function, morphology, and plasticity.
PMID: 29651456 [PubMed - in process]
Comprehensive analysis of the mutation spectrum in 301 German ALS families.
Comprehensive analysis of the mutation spectrum in 301 German ALS families.
J Neurol Neurosurg Psychiatry. 2018 Apr 12;:
Authors: Müller K, Brenner D, Weydt P, Meyer T, Grehl T, Petri S, Grosskreutz J, Schuster J, Volk AE, Borck G, Kubisch C, Klopstock T, Zeller D, Jablonka S, Sendtner M, Klebe S, Knehr A, Günther K, Weis J, Claeys KG, Schrank B, Sperfeld AD, Hübers A, Otto M, Dorst J, Meitinger T, Strom TM, Andersen PM, Ludolph AC, Weishaupt JH, German ALS network MND-NET
Abstract
OBJECTIVES: Recent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions.
METHODS: Here we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS. We report C9orf72 mutations as well as variants in consensus splice sites and non-synonymous variants in protein-coding regions of ALS genes. We furthermore estimate their pathogenicity by taking into account type and frequency of the respective variant as well as segregation within the families.
RESULTS: 49% of our German ALS families carried a likely pathogenic variant in at least one of the earlier identified ALS genes. In 45% of the ALS families, likely pathogenic variants were detected in C9orf72, SOD1, FUS, TARDBP or TBK1, whereas the relative contribution of the other ALS genes in this familial ALS cohort was 4%. We identified several previously unreported rare variants and demonstrated the absence of likely pathogenic variants in some of the recently described ALS disease genes.
CONCLUSIONS: We here present a comprehensive genetic characterisation of German familial ALS. The present findings are of importance for genetic counselling in clinical practice, for molecular research and for the design of diagnostic gene panels or genotype-specific therapeutic interventions in Europe.
PMID: 29650794 [PubMed - as supplied by publisher]
MLL leukemia induction by t(9;11) chromosomal translocation in human hematopoietic stem cells using genome editing.
MLL leukemia induction by t(9;11) chromosomal translocation in human hematopoietic stem cells using genome editing.
Blood Adv. 2018 Apr 24;2(8):832-845
Authors: Schneidawind C, Jeong J, Schneidawind D, Kim IS, Duque-Afonso J, Wong SHK, Iwasaki M, Breese EH, Zehnder JL, Porteus M, Cleary ML
Abstract
Genome editing provides a potential approach to model de novo leukemogenesis in primary human hematopoietic stem and progenitor cells (HSPCs) through induction of chromosomal translocations by targeted DNA double-strand breaks. However, very low efficiency of translocations and lack of markers for translocated cells serve as barriers to their characterization and model development. Here, we used transcription activator-like effector nucleases to generate t(9;11) chromosomal translocations encoding MLL-AF9 and reciprocal AF9-MLL fusion products in CD34+ human cord blood cells. Selected cytokine combinations enabled monoclonal outgrowth and immortalization of initially rare translocated cells, which were distinguished by elevated MLL target gene expression, high surface CD9 expression, and increased colony-forming ability. Subsequent transplantation into immune-compromised mice induced myeloid leukemias within 48 weeks, whose pathologic and molecular features extensively overlap with de novo patient MLL-rearranged leukemias. No secondary pathogenic mutations were revealed by targeted exome sequencing and whole genome RNA-sequencing analyses, suggesting the genetic sufficiency of t(9;11) translocation for leukemia development from human HSPCs. Thus, genome editing enables modeling of human acute MLL-rearranged leukemia in vivo, reflecting the genetic simplicity of this disease, and provides an experimental platform for biological and disease-modeling applications.
PMID: 29650777 [PubMed - in process]
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