5,711 results match your criteria overexpression dominant-negative

Spatiotemporal Manipulation of the Mismatch Repair System of Accelerates Phenotype Emergence.

ACS Synth Biol 2021 Apr 12. Epub 2021 Apr 12.

The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Kongens Lyngby, Denmark.

The development of complex phenotypes in industrially relevant bacteria is a major goal of metabolic engineering, which encompasses the implementation of both rational and random approaches. In the latter case, several tools have been developed toward increasing mutation frequencies, yet the precise control of mutagenesis processes in cell factories continues to represent a significant technical challenge. species are endowed with one of the most efficient DNA mismatch repair (MMR) systems found in the bacterial domain. Read More

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RTN4B interacting protein FAM134C promotes ER membrane curvature and has a functional role in autophagy.

Mol Biol Cell 2021 Apr 7:mbcE20060409. Epub 2021 Apr 7.

Cell and Tissue Dynamics Research Program.

The endoplasmic reticulum (ER) is comprised of a controlled ratio of sheets and tubules, which are maintained by several proteins with multiple functions. Reticulons (RTNs), especially RTN4, and DP1/Yop1p family members are known to induce ER membrane curvature. RTN4B is the main RTN4 isoform expressed in non-neuronal cells. Read More

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The MicroRNA miR-696 is Regulated by SNARK and Reduces Mitochondrial Activity in Mouse Skeletal Muscle Through Pgc1α Inhibition.

Mol Metab 2021 Mar 31:101226. Epub 2021 Mar 31.

Obesity and Comorbidities Research Center, OCRC, IB, UNICAMP, Campinas, Brazil. Electronic address:

MicroRNAs (miRNA) are known to regulate expression of genes involved in several physiological processes including metabolism, mitochondrial biogenesis, proliferation, differentiation, and cell death. Using "in silico" analyses, we identified 219 unique miRNAs that potentially bind to the 3'UTR region of a critical mitochondrial regulator, the peroxisome proliferator-activated receptor gamma coactivator (PGC) 1 alpha (Pgc1α). Out of the 219 candidate miRNAs, miR-696 had one of the highest interactions at the 3'UTR of Pgc1α, suggesting that miR-696 may be involved in the regulation of Pgc1α. Read More

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Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor.

Sci Transl Med 2021 Mar;13(587)

Université de Paris, INSERM U944 and CNRS UMR 7212, Institut de Recherche Saint Louis, Hôpital Saint Louis, APHP, 75010 Paris, France.

The development and survival of cancer cells require adaptive mechanisms to stress. Such adaptations can confer intrinsic vulnerabilities, enabling the selective targeting of cancer cells. Through a pooled in vivo short hairpin RNA (shRNA) screen, we identified the adenosine triphosphatase associated with diverse cellular activities (AAA-ATPase) valosin-containing protein (VCP) as a top stress-related vulnerability in acute myeloid leukemia (AML). Read More

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Overexpression Enhances Expression .

Front Endocrinol (Lausanne) 2021 10;12:634191. Epub 2021 Mar 10.

Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Objective: The Iroquois homeobox 3 () gene was recently reported to be a functional downstream target of a common polymorphism in the gene, which encodes an obesity-associated protein; however, the role of in energy expenditure remains unclear. Studies have revealed that the overexpression of a dominant-negative form of IRX3 in the mouse hypothalamus and adipose tissue promoted energy expenditure by enhancing brown/browning activities. Meanwhile, we and others recently demonstrated that knockdown impaired the browning program of primary preadipocytes . Read More

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Newcastle Disease Virus Entry into Chicken Macrophages via a pH-Dependent, Dynamin and Caveola-Mediated Endocytic Pathway That Requires Rab5.

J Virol 2021 Mar 24. Epub 2021 Mar 24.

Division of Avian Infectious Diseases, the State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin 150069, the People's Republic of China

The cellular entry pathways and the mechanisms of Newcastle disease virus (NDV) entry into cells are poorly characterized. In this study, we demonstrated that chicken interferon-induced transmembrane protein 1 (chIFITM1) which is located in the early endosomes could limit the replication of NDV in chicken macrophage cell line HD11, suggesting the endocytic entry of NDV into chicken macrophages. Then, we presented a systematic study about the entry mechanism of NDV into chicken macrophages. Read More

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Requirement of Gαi1 and Gαi3 in interleukin-4-induced signaling, macrophage M2 polarization and allergic asthma response.

Theranostics 2021 4;11(10):4894-4909. Epub 2021 Mar 4.

Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.

IL-4 induces Akt activation in macrophages, required for full M2 (alternative) polarization. We examined the roles of Gαi1 and Gαi3 in M2 polarization using multiple genetic methods. In MEFs and primary murine BMDMs, Gαi1/3 shRNA, knockout or dominant negative mutations attenuated IL-4-induced IL4Rα endocytosis, Gab1 recruitment as well as Akt activation, leaving STAT6 signaling unaffected. Read More

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Porcine Circovirus Type 3 Enters Into PK15 Cells Through Clathrin- and Dynamin-2-Mediated Endocytosis in a Rab5/Rab7 and pH-Dependent Fashion.

Front Microbiol 2021 16;12:636307. Epub 2021 Feb 16.

Beijing Key Laboratory for Prevention and Control of Infectious Diseases in Livestock and Poultry, Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, Beijing, China.

Porcine circovirus type 3 (PCV3) invades multiple tissues and organs of pigs of different ages and are widely spread throughout pig farms, emerging as an important viral pathogen that can potentially damage the pig industry worldwide. Since PCV3 is a newly discovered virus, many aspects of its life cycle remain unknown. Porcine kidney epithelial cells are important host targets for PCV3. Read More

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February 2021

Role of PI3-Kinase in Angiotensin II-Induced Cardiac Hypertrophy: Class I Versus Class III.

Front Pharmacol 2021 16;12:608523. Epub 2021 Feb 16.

Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, United States.

Cardiac hypertrophy is an adaptive response to cardiac overload initially but turns into a decompensated condition chronically, leading to heart failure and sudden cardiac death. The molecular mechanisms involved in cardiac hypertrophy and the signaling pathways that contribute to the switch from compensation to decompensation are not fully clear. The aim of the current study was to examine the role of PI3-kinases Class I (PI3KC1) and Class III (PI3KC3) in angiotensin (Ang) II-induced cardiac hypertrophy. Read More

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February 2021

Protein kinase C fusion proteins are paradoxically loss-of-function in cancer.

J Biol Chem 2021 Feb 19:100445. Epub 2021 Feb 19.

Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA. Electronic address:

Within the AGC kinase superfamily, gene fusions resulting from chromosomal rearrangements have been most frequently described for protein kinase C (PKC), with gene fragments encoding either the C-terminal catalytic domain or the N-terminal regulatory moiety fused to other genes. Kinase fusions that eliminate regulatory domains are typically gain-of-function and often oncogenic. However, several quality control pathways prevent accumulation of aberrant PKC, suggesting that PKC fusions may paradoxically be loss-of-function. Read More

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February 2021

Tumor associated macrophages (TAMs) promote the metastasis and growth of non-small cell lung cancer (NSCLC) cells through NF-κB/PP2Ac positive feedback loop.

Cancer Sci 2021 Feb 20. Epub 2021 Feb 20.

Department of Radiation Oncology, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.

Non-small-cell lung cancer (NSCLC), with an aggressive biological behavior, is one of the most diagnosed cancers. Tumor-associated inflammatory cells play important roles in the interaction between chronic inflammation and lung cancer. However, the mechanisms involved are far from defined. Read More

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February 2021

SNRNP200 Mutations Cause Autosomal Dominant Retinitis Pigmentosa.

Front Med (Lausanne) 2020 21;7:588991. Epub 2021 Jan 21.

The Clinical Research Center of the First Affiliated Hospital of Shantou University Medical College, Shantou, China.

The small nuclear ribonucleoprotein 200 kDa (SNRNP200) gene plays a key role in the maturation of pre-message RNA (pre-mRNA) splicing with the indication for the etiology of retinitis pigmentosa (RP). Gene recognition can facilitate the diagnosis of these patients for better clinical management, treatment and counseling. This study aimed to outline the causative mutation in a Chinese family and the pathogenic mechanism of this SNRNP200 mutation in RP. Read More

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January 2021

Arabidopsis lysin motif/F-box-containing protein InLYP1 fine-tunes glycine metabolism by degrading glycine decarboxylase GLDP2.

Plant J 2021 Jan 28. Epub 2021 Jan 28.

State Key Laboratory of Biocontrol, Guangdong Provincial Key Laboratory of Plant Resources, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.

Lysin motif (LysM) is a carbohydrate-binding module often found in secreted or transmembrane proteins in living organisms from prokaryotes to eukaryotes. Thus far, all characterized LysM-containing proteins in plants are plasma membrane-resident receptors or co-receptors playing roles in plant-microbe interactions. Here, we interrogate the Arabidopsis LysM/F-box-containing protein InLYP1 and reveal its function in glycine metabolism. Read More

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January 2021

Dosage sensitivity of JDPs, a valuable tool for understanding their function: a case study on Caj1 overexpression-mediated filamentous growth in budding yeast.

Curr Genet 2021 Jan 25. Epub 2021 Jan 25.

Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Room Number 117, Academic Block 3, Bhopal, MP, 462066, India.

J-domain proteins (JDPs) partner with Hsp70s to oversee proper synthesis, folding, transport and turnover of proteins in the cell. In any subcellular compartment, often multiple JDPs collaborate with a single Hsp70 to perform a variety of functions. Being co-localized, JDPs may exhibit complex genetic and physical interactions with each other, their clients as well as the Hsp70 partners. Read More

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January 2021

Dusp1 modulates activin/smad2 mediated germ layer specification via FGF signal inhibition in embryos.

Anim Cells Syst (Seoul) 2020 Nov 27;24(6):359-370. Epub 2020 Nov 27.

Department of Biochemistry, Institute of Cell Differentiation and Aging, College of Medicine, Hallym University, Chuncheon, Gangwon-Do, Republic of Korea.

Activin, a member of the transforming growth factor (TGF-β) superfamily, induces mesoderm, endoderm and neuro-ectoderm formation in embryos. Despite several previous studies, the complicated gene regulatory network and genes involved in this induction await more elaboration. We identified expression of various fibroblast growth factor (FGF) genes in activin/ treated animal cap explants (AC) of embryos. Read More

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November 2020

Effects of decreased Rac activity and malignant state on oral squamous cell carcinoma in vitro.

PLoS One 2021 14;16(1):e0212323. Epub 2021 Jan 14.

The First Department of Oral & Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan.

Rac proteins, members of the Rho family of small GTP-binding proteins, have been implicated in transducing a number of signals for various biological mechanisms, including cell cytoskeleton organization, transcription, proliferation, migration, and cancer cell motility. Among human cancers, Rac proteins are highly activated by either overexpression of the genes, up-regulation of the protein, or by mutations that allow the protein to elude normal regulatory signaling pathways. Rac proteins are involved in controlling cell survival and apoptosis. Read More

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Upregulation of DUSP6 impairs infectious bronchitis virus replication by negatively regulating ERK pathway and promoting apoptosis.

Vet Res 2021 Jan 11;52(1). Epub 2021 Jan 11.

Waterfowl Viral Infectious Diseases Team, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241, P. R. China.

Elucidating virus-cell interactions is fundamental to understanding viral replication and identifying targets for therapeutic control of viral infection. The extracellular signal-regulated kinase (ERK) pathway has been shown to regulate pathogenesis during many viral infections, but its role during coronavirus infection is undetermined. Infectious bronchitis virus is the representative strain of Gammacoronavirus, which causes acute and highly contagious diseases in the poultry farm. Read More

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January 2021

Combinatorial Modulation of Linalool Synthase and Farnesyl Diphosphate Synthase for Linalool Overproduction in .

J Agric Food Chem 2021 Jan 11;69(3):1003-1010. Epub 2021 Jan 11.

Institute of Bioengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, PR China.

Linalool, as a fragrant monoterpene, is an important feedstock for food, pharmaceuticals, and cosmetics industries. Although our previous study had significantly increased linalool production by the directed evolution of linalool synthase and overexpression of the whole mevalonate pathway genes, the engineered yeast strain suffered from dramatically reduced biomass. Herein, a stress-free linalool-producing yeast cell factory was constructed by the combinational regulation of linalool synthase and farnesyl diphosphate synthase instead of multienzyme overexpression. Read More

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January 2021

Sarcomeres regulate murine cardiomyocyte maturation through MRTF-SRF signaling.

Proc Natl Acad Sci U S A 2021 Jan;118(2)

Department of Cardiology, Boston Children's Hospital, Boston, MA 02115;

The paucity of knowledge about cardiomyocyte maturation is a major bottleneck in cardiac regenerative medicine. In development, cardiomyocyte maturation is characterized by orchestrated structural, transcriptional, and functional specializations that occur mainly at the perinatal stage. Sarcomeres are the key cytoskeletal structures that regulate the ultrastructural maturation of other organelles, but whether sarcomeres modulate the signal transduction pathways that are essential for cardiomyocyte maturation remains unclear. Read More

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January 2021

Arsenic suppresses GDF1 expression via ROS-dependent downregulation of specificity protein 1.

Environ Pollut 2021 Feb 15;271:116302. Epub 2020 Dec 15.

Department of Genetics, National Research Institute for Family Planning, Beijing, China; Graduate School of Peking Union Medical College, Beijing, China. Electronic address:

Inorganic arsenic, an environmental contaminant, has adverse health outcomes. Our previous studies showed that arsenic causes abnormal cardiac development in zebrafish embryos by downregulating Dvr1/GDF1 expression and that folic acid protects against these effects. However, the mechanism by which arsenic represses Dvr1/GDF1 expression remains unknown. Read More

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February 2021

Phosphatidylinositol 4-kinase β mutations cause nonsyndromic sensorineural deafness and inner ear malformation.

J Genet Genomics 2020 10 28;47(10):618-626. Epub 2020 Oct 28.

Experimental and Clinical Research Center (ECRC), A Joint Cooperation Between the Charité Medical Faculty and the Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association (MDC), Lindenberger Weg.80, Berlin, 13125, Germany. Electronic address:

Congenital hearing loss is a common disorder worldwide. Heterogeneous gene variation accounts for approximately 20-25% of such patients. We investigated a five-generation Chinese family with autosomal-dominant nonsyndromic sensorineural hearing loss (SNHL). Read More

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October 2020

p90RSK-MAGI1 Module Controls Endothelial Permeability by Post-translational Modifications of MAGI1 and Hippo Pathway.

Front Cardiovasc Med 2020 13;7:542485. Epub 2020 Nov 13.

Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, United States.

Previously, we reported that post-translational modifications (PTMs) of MAGI1, including S741 phosphorylation and K931 de-SUMOylation, both of which are regulated by p90RSK activation, lead to endothelial cell (EC) activation. However, roles for p90RSK and MAGI1-PTMs in regulating EC permeability remain unclear despite MAGI1 being a junctional molecule. Here, we show that thrombin (Thb)-induced EC permeability, detected by the electric cell-substrate impedance sensing (ECIS) based system, was decreased by overexpression of dominant negative p90RSK or a MAGI1-S741A phosphorylation mutant, but was accelerated by overexpression of p90RSK, siRNA-mediated knockdown of , or the MAGI1-K931R SUMOylation mutant. Read More

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November 2020

Ncor2/PPARα-Dependent Upregulation of MCUb in the Type 2 Diabetic Heart Impacts Cardiac Metabolic Flexibility and Function.

Diabetes 2021 Mar 10;70(3):665-679. Epub 2020 Dec 10.

Department of Medicine, University of California, San Diego, La Jolla, CA

The contribution of altered mitochondrial Ca handling to metabolic and functional defects in type 2 diabetic (T2D) mouse hearts is not well understood. In this study, we show that the T2D heart is metabolically inflexible and almost exclusively dependent on mitochondrial fatty acid oxidation as a consequence of mitochondrial calcium uniporter complex (MCUC) inhibitory subunit MCUb overexpression. Using a recombinant endonuclease-deficient Cas9-based gene promoter pulldown approach coupled with mass spectrometry, we found that MCUb is upregulated in the T2D heart due to loss of glucose homeostasis regulator nuclear receptor corepressor 2 repression, and chromatin immunoprecipitation assays identified peroxisome proliferator-activated receptor α as a mediator of MCUb gene expression in T2D cardiomyocytes. Read More

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Molecular Modification of Transient Receptor Potential Canonical 6 Channels Modulates Calcium Dyshomeostasis in a Mouse Model Relevant to Malignant Hyperthermia.

Anesthesiology 2021 02;134(2):234-247

Background: Pharmacologic modulation has previously shown that transient receptor potential canonical (TRPC) channels play an important role in the pathogenesis of malignant hyperthermia. This study tested the hypothesis that genetically suppressing the function of TRPC6 can partially ameliorate muscle cation dyshomeostasis and the response to halothane in a mouse model relevant to malignant hyperthermia.

Methods: This study examined the effect of overexpressing a muscle-specific nonconducting dominant-negative TRPC6 channel in 20 RYR1-p. Read More

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February 2021

Proline-rich tyrosine kinase 2 mediates transforming growth factor-beta-induced hepatic stellate cell activation and liver fibrosis.

Sci Rep 2020 12 3;10(1):21018. Epub 2020 Dec 3.

Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro Gangnam-gu, Seoul, 06351, Korea.

Hepatic fibrogenesis is characterized by activation of hepatic stellate cells (HSCs) and accumulation of extracellular matrix (ECM). The impact of ECM on TGF-β-mediated fibrogenic signaling pathway in HSCs has remained obscure. We studied the role of non-receptor tyrosine kinase focal adhesion kinase (FAK) family members in TGF-β-signaling in HSCs. Read More

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December 2020

HuD regulates SOD1 expression during oxidative stress in differentiated neuroblastoma cells and sporadic ALS motor cortex.

Neurobiol Dis 2021 01 1;148:105211. Epub 2020 Dec 1.

Genomic and post-Genomic Center, IRCCS Mondino Foundation, Via Mondino 2, Pavia 27100, Italy. Electronic address:

The neuronal RNA-binding protein (RBP) HuD plays an important role in brain development, synaptic plasticity and neurodegenerative diseases such as Parkinson's (PD) and Alzheimer's (AD). Bioinformatics analysis of the human SOD1 mRNA 3' untranslated region (3'UTR) demonstrated the presence of HuD binding adenine-uridine (AU)-rich instability-conferring elements (AREs). Using differentiated SH-SY5Y cells along with brain tissues from sporadic amyotrophic lateral sclerosis (sALS) patients, we assessed HuD-dependent regulation of SOD1 mRNA. Read More

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January 2021

SRP54 mutations induce congenital neutropenia via dominant-negative effects on XBP1 splicing.

Blood 2021 Mar;137(10):1340-1352

Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.

Heterozygous de novo missense variants of SRP54 were recently identified in patients with congenital neutropenia (CN) who display symptoms that overlap with Shwachman-Diamond syndrome (SDS). Here, we investigate srp54 knockout zebrafish as the first in vivo model of SRP54 deficiency. srp54-/- zebrafish experience embryonic lethality and display multisystemic developmental defects along with severe neutropenia. Read More

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Brassinosteroid Signaling Converges With Auxin-Mediated C3H17 to Regulate Xylem Formation in .

Front Plant Sci 2020 27;11:586014. Epub 2020 Oct 27.

Key Laboratory of Biofuels, Shandong Provincial Key Laboratory of Energy Genetics, Shandong Institute of Energy Technology, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, China.

Brassinosteroid (BR) signaling has long been reported to have an effect on xylem development, but the detailed mechanism remains unclear, especially in tree species. In this study, we find PdC3H17, which was demonstrated to mediate xylem formation driven by auxin in our previous report, is also involved in BR-promoted xylem development. Y1H analysis, EMSA, and transcription activation assay confirmed that was directly targeted by PdBES1, which is a key transcriptional regulator in BR signaling. Read More

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October 2020

De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment.

Am J Hum Genet 2020 12 12;107(6):1129-1148. Epub 2020 Nov 12.

Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK. Electronic address:

The endosomal sorting complexes required for transport (ESCRTs) are essential for multiple membrane modeling and membrane-independent cellular processes. Here we describe six unrelated individuals with de novo missense variants affecting the ATPase domain of VPS4A, a critical enzyme regulating ESCRT function. Probands had structural brain abnormalities, severe neurodevelopmental delay, cataracts, growth impairment, and anemia. Read More

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December 2020

Analysis of CRISPR/Cas9 Induced Atlastin Pathological Mutations in .

Front Neurosci 2020 15;14:547746. Epub 2020 Oct 15.

Laboratory of Molecular Biology, Scientific Institute IRCCS E. Medea, Lecco, Italy.

The endoplasmic reticulum (ER) is a highly dynamic network whose shape is thought to be actively regulated by membrane resident proteins. Mutation of several such morphology regulators cause the neurological disorder Hereditary Sp astic Paraplegia (HSP), suggesting a critical role of ER shape maintenance in neuronal activity and function. Human Atlastin-1 mutations are responsible for SPG3A, the earliest onset and one of the more severe forms of dominant HSP. Read More

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October 2020