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Nuclear and Mitochondrial Genome Defects in Autisms
UC Irvine UC Irvine Previously Published Works Title Nuclear and mitochondrial genome defects in autisms. Permalink https://escholarship.org/uc/item/8vq3278q Journal Annals of the New York Academy of Sciences, 1151(1) ISSN 0077-8923 Authors Smith, Moyra Spence, M Anne Flodman, Pamela Publication Date 2009 DOI 10.1111/j.1749-6632.2008.03571.x License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California THE YEAR IN HUMAN AND MEDICAL GENETICS 2009 Nuclear and Mitochondrial Genome Defects in Autisms Moyra Smith, M. Anne Spence, and Pamela Flodman Department of Pediatrics, University of California, Irvine, California In this review we will evaluate evidence that altered gene dosage and structure im- pacts neurodevelopment and neural connectivity through deleterious effects on synap- tic structure and function, and evidence that the latter are key contributors to the risk for autism. We will review information on alterations of structure of mitochondrial DNA and abnormal mitochondrial function in autism and indications that interactions of the nuclear and mitochondrial genomes may play a role in autism pathogenesis. In a final section we will present data derived using Affymetrixtm SNP 6.0 microar- ray analysis of DNA of a number of subjects and parents recruited to our autism spectrum disorders project. We include data on two sets of monozygotic twins. Col- lectively these data provide additional evidence of nuclear and mitochondrial genome imbalance in autism and evidence of specific candidate genes in autism. We present data on dosage changes in genes that map on the X chromosomes and the Y chro- mosome. -
Analysis of Gene Expression Data for Gene Ontology
ANALYSIS OF GENE EXPRESSION DATA FOR GENE ONTOLOGY BASED PROTEIN FUNCTION PREDICTION A Thesis Presented to The Graduate Faculty of The University of Akron In Partial Fulfillment of the Requirements for the Degree Master of Science Robert Daniel Macholan May 2011 ANALYSIS OF GENE EXPRESSION DATA FOR GENE ONTOLOGY BASED PROTEIN FUNCTION PREDICTION Robert Daniel Macholan Thesis Approved: Accepted: _______________________________ _______________________________ Advisor Department Chair Dr. Zhong-Hui Duan Dr. Chien-Chung Chan _______________________________ _______________________________ Committee Member Dean of the College Dr. Chien-Chung Chan Dr. Chand K. Midha _______________________________ _______________________________ Committee Member Dean of the Graduate School Dr. Yingcai Xiao Dr. George R. Newkome _______________________________ Date ii ABSTRACT A tremendous increase in genomic data has encouraged biologists to turn to bioinformatics in order to assist in its interpretation and processing. One of the present challenges that need to be overcome in order to understand this data more completely is the development of a reliable method to accurately predict the function of a protein from its genomic information. This study focuses on developing an effective algorithm for protein function prediction. The algorithm is based on proteins that have similar expression patterns. The similarity of the expression data is determined using a novel measure, the slope matrix. The slope matrix introduces a normalized method for the comparison of expression levels throughout a proteome. The algorithm is tested using real microarray gene expression data. Their functions are characterized using gene ontology annotations. The results of the case study indicate the protein function prediction algorithm developed is comparable to the prediction algorithms that are based on the annotations of homologous proteins. -
Supplement 1 Overview of Dystonia Genes
Supplement 1 Overview of genes that may cause dystonia in children and adolescents Gene (OMIM) Disease name/phenotype Mode of inheritance 1: (Formerly called) Primary dystonias (DYTs): TOR1A (605204) DYT1: Early-onset generalized AD primary torsion dystonia (PTD) TUBB4A (602662) DYT4: Whispering dystonia AD GCH1 (600225) DYT5: GTP-cyclohydrolase 1 AD deficiency THAP1 (609520) DYT6: Adolescent onset torsion AD dystonia, mixed type PNKD/MR1 (609023) DYT8: Paroxysmal non- AD kinesigenic dyskinesia SLC2A1 (138140) DYT9/18: Paroxysmal choreoathetosis with episodic AD ataxia and spasticity/GLUT1 deficiency syndrome-1 PRRT2 (614386) DYT10: Paroxysmal kinesigenic AD dyskinesia SGCE (604149) DYT11: Myoclonus-dystonia AD ATP1A3 (182350) DYT12: Rapid-onset dystonia AD parkinsonism PRKRA (603424) DYT16: Young-onset dystonia AR parkinsonism ANO3 (610110) DYT24: Primary focal dystonia AD GNAL (139312) DYT25: Primary torsion dystonia AD 2: Inborn errors of metabolism: GCDH (608801) Glutaric aciduria type 1 AR PCCA (232000) Propionic aciduria AR PCCB (232050) Propionic aciduria AR MUT (609058) Methylmalonic aciduria AR MMAA (607481) Cobalamin A deficiency AR MMAB (607568) Cobalamin B deficiency AR MMACHC (609831) Cobalamin C deficiency AR C2orf25 (611935) Cobalamin D deficiency AR MTRR (602568) Cobalamin E deficiency AR LMBRD1 (612625) Cobalamin F deficiency AR MTR (156570) Cobalamin G deficiency AR CBS (613381) Homocysteinuria AR PCBD (126090) Hyperphelaninemia variant D AR TH (191290) Tyrosine hydroxylase deficiency AR SPR (182125) Sepiaterine reductase -
Mitochondrial Rab Gaps Govern Autophagosome Biogenesis During Mitophagy Koji Yamano1, Adam I Fogel1, Chunxin Wang1, Alexander M Van Der Bliek2, Richard J Youle1*
RESEARCH ARTICLE elife.elifesciences.org Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy Koji Yamano1, Adam I Fogel1, Chunxin Wang1, Alexander M van der Bliek2, Richard J Youle1* 1Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States; 2Department of Biological Chemistry, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, United States Abstract Damaged mitochondria can be selectively eliminated by mitophagy. Although two gene products mutated in Parkinson’s disease, PINK1, and Parkin have been found to play a central role in triggering mitophagy in mammals, how the pre-autophagosomal isolation membrane selectively and accurately engulfs damaged mitochondria remains unclear. In this study, we demonstrate that TBC1D15, a mitochondrial Rab GTPase-activating protein (Rab-GAP), governs autophagosome biogenesis and morphology downstream of Parkin activation. To constrain autophagosome morphogenesis to that of the cargo, TBC1D15 inhibits Rab7 activity and associates with both the mitochondria through binding Fis1 and the isolation membrane through the interactions with LC3/ GABARAP family members. Another TBC family member TBC1D17, also participates in mitophagy and forms homodimers and heterodimers with TBC1D15. These results demonstrate that TBC1D15 and TBC1D17 mediate proper autophagic encapsulation of mitochondria by regulating Rab7 activity at the interface between mitochondria and isolation membranes. DOI: 10.7554/eLife.01612.001 *For correspondence: [email protected] Introduction Competing interests: See page 21 Autophagosomes enclose seemingly random portions of the cytoplasm to supply nutrients during starvation or they can specifically engulf cellular debris to maintain quality control (Mizushima et al., Funding: See page 21 2011). -
Differential Redox-Regulation and Mitochondrial Dynamics in Normal and Leukemic Hematopoietic Stem Cells a Potential Window
Critical Reviews in Oncology / Hematology 144 (2019) 102814 Contents lists available at ScienceDirect Critical Reviews in Oncology / Hematology journal homepage: www.elsevier.com/locate/critrevonc Differential redox-regulation and mitochondrial dynamics in normal and leukemic hematopoietic stem cells: A potential window for leukemia T therapy ⁎ Katharina Mattes, Edo Vellenga, Hein Schepers Department of Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands ARTICLE INFO ABSTRACT Keywords: The prognosis for many patients with acute myeloid leukemia (AML) is poor, mainly due to disease relapse HSC driven by leukemia stem cells (LSCs). Recent studies have highlighted the unique metabolic properties of LSCs, LSC which might represent opportunities for LSC-selective targeting. LSCs characteristically have low levels of re- Mitochondria active oxygen species (ROS), which apparently result from a combination of low mitochondrial activity and high ROS activity of ROS-removing pathways such as autophagy. Due to this low activity, LSCs are highly dependent on BCL-2 mitochondrial regulatory mechanisms. These include the anti-apoptotic protein BCL-2, which also has crucial Autophagy Venetoclax roles in regulating the mitochondrial membrane potential, and proteins involved in mitophagy. Here we review the different pathways that impact mitochondrial activity and redox-regulation, and highlight their relevance for the functionality of both HSCs and LSCs. Additionally, novel AML therapy strategies that are based on interference with those pathways, including the promising BCL-2 inhibitor Venetoclax, are summar- ized. 1. Introduction and scope of this review regulating ROS production and mitochondrial health. HSCs rely on glycolysis as their main energy source, which results in less oxidative Current treatment strategies for acute myeloid leukemia (AML) re- burden compared to mitochondrial oxidative phosphorylation (OX- sult in an initial reduction of leukemic blasts in the majority of patients. -
Appoptosin Interacts with Mitochondrial Outer-Membrane Fusion Proteins and Regulates Mitochondrial Morphology
© 2016. Published by The Company of Biologists Ltd | Journal of Cell Science (2016) 129, 994-1002 doi:10.1242/jcs.176792 RESEARCH ARTICLE Appoptosin interacts with mitochondrial outer-membrane fusion proteins and regulates mitochondrial morphology Cuilin Zhang1, Zhun Shi1, Lingzhi Zhang1, Zehua Zhou1, Xiaoyuan Zheng1, Guiying Liu1, Guojun Bu1, Paul E. Fraser2, Huaxi Xu1,3 and Yun-wu Zhang1,* ABSTRACT mitochondrial mobility, mitophagy, cell mitosis and apoptosis Mitochondrial morphology is regulated by fusion and fission (Youle and van der Bliek, 2012). – machinery. Impaired mitochondria dynamics cause various Mitochondrial fusion comprises two events outer-membrane diseases, including Alzheimer’s disease. Appoptosin (encoded by fusion and inner-membrane fusion. In mammalian cells, two SLC25A38) is a mitochondrial carrier protein that is located in the GTPases MFN1 and MFN2, which anchor on the outer mitochondrial inner membrane. Appoptosin overexpression causes membrane of mitochondria, are responsible for the outer- overproduction of reactive oxygen species (ROS) and caspase- membrane fusion (Chen et al., 2003; Koshiba et al., 2004). dependent apoptosis, whereas appoptosin downregulation abolishes However, compared to MFN2, MFN1 is relatively specific in β-amyloid-induced mitochondrial fragmentation and neuronal death regulating mitochondrial fusion (Shen et al., 2007). MFN1- during Alzheimer’s disease. Herein, we found that overexpression harboring mitochondria have a higher tethering efficiency than of appoptosin resulted in mitochondrial fragmentation in a manner those with MFN2, and purified MFN1 also possesses higher independent of its carrier function, ROS production or caspase GTPase activity than MFN2 (Ishihara et al., 2004). In contrast, activation. Although appoptosin did not affect levels of mitochondrial MFN2 is more tissue specific in its expression pattern than MFN1 outer-membrane fusion (MFN1 and MFN2), inner-membrane fusion (Liesa et al., 2009). -
Blueprint Genetics BCS1L Single Gene Test
BCS1L single gene test Test code: S00213 Phenotype information Bjornstad syndrome GRACILE syndrome Leigh syndrome Mitochondrial complex III deficiency, nuclear type 1 Alternative gene names BCS, BJS, Hs.6719, h-BCS Panels that include the BCS1L gene Syndromic Hearing Loss Panel Comprehensive Hearing Loss and Deafness Panel Resonate Program Panel 3-M Syndrome / Primordial Dwarfism Panel Ectodermal Dysplasia Panel Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders Panel Comprehensive Metabolism Panel Organic Acidemia/Aciduria & Cobalamin Deficiency Panel Comprehensive Short Stature Syndrome Panel Non-coding disease causing variants covered by the test Gene Genomic location HG19 HGVS RefSeq RS-number BCS1L Chr2:219524871 c.-147A>G NM_004328.4 BCS1L Chr2:219525123 c.-50+155T>A NM_004328.4 rs386833855 Test Strengths The strengths of this test include: CAP accredited laboratory CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance Careful construction of clinically effective and scientifically justified gene panels Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level Our publicly available analytic validation demonstrating complete details of test performance ~2,000 non-coding disease causing variants in our clinical grade NGS assay for panels (please see ‘Non-coding disease causing variants -
Relationships Between Expression of BCS1L, Mitochondrial Bioenergetics, and Fatigue Among Patients with Prostate Cancer
Cancer Management and Research Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Relationships between expression of BCS1L, mitochondrial bioenergetics, and fatigue among patients with prostate cancer This article was published in the following Dove Press journal: Cancer Management and Research Chao-Pin Hsiao1,2 Introduction: Cancer-related fatigue (CRF) is the most debilitating symptom with the Mei-Kuang Chen3 greatest adverse side effect on quality of life. The etiology of this symptom is still not Martina L Veigl4 understood. The purpose of this study was to examine the relationship between mitochon- Rodney Ellis5 drial gene expression, mitochondrial oxidative phosphorylation, electron transport chain Matthew Cooney6 complex activity, and fatigue in prostate cancer patients undergoing radiotherapy (XRT), Barbara Daly1 compared to patients on active surveillance (AS). Methods: The study used a matched case–control and repeated-measures research design. Charles Hoppel7 Fatigue was measured using the revised Piper Fatigue Scale from 52 patients with prostate 1The Frances Payne Bolton School of cancer. Mitochondrial oxidative phosphorylation, electron-transport chain enzymatic activity, Nursing, Case Western Reserve ’ University, Cleveland, OH, USA; 2School and BCS1L gene expression were determined using patients peripheral mononuclear cells. of Nursing, Taipei Medical University, Data were collected at three time points and analyzed using repeated measures ANOVA. 3 Taipei , Taiwan; Department of Results: The fatigue score was significantly different over time between patients undergoing XRT Psychology, University of Arizona, fi Tucson, AZ, USA; 4Gene Expression & and AS (P<0.05). Patients undergoing XRT experienced signi cantly increased fatigue at day 21 Genotyping Facility, Case Comprehensive and day 42 of XRT (P<0.01). -
COX5A Plays a Vital Role in Memory Impairment Associated with Brain Aging Via the BDNF/ERK1/2 Signaling Pathway
ORIGINAL RESEARCH published: 10 July 2020 doi: 10.3389/fnagi.2020.00215 COX5A Plays a Vital Role in Memory Impairment Associated With Brain Aging via the BDNF/ERK1/2 Signaling Pathway Yan-Bin Xiyang 1†, Ruan Liu 1, Xu-Yang Wang 2, Shan Li 1, Ya Zhao 1, Bing-Tuan Lu 1, Zhi-Cheng Xiao 3, Lian-Feng Zhang 4, Ting-Hua Wang 1* and Jie Zhang 5*† 1Institute of Neuroscience, Basic Medical College, Kunming Medical University, Kunming, China, 2Department of Neurosurgery, Shanghai Jiao Tong University Affiliated 6th People’s Hospital, Shanghai, China, 3Monash Immunology and Stem Cell Laboratories (MISCL), Monash University, Clayton, VIC, Australia, 4Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) and Comparative Medicine Centre, Peking Union Medical College (PUMC), Beijing, China, 5Yunnan Provincial Key Laboratory for Birth Defects and Genetic Diseases, Department of Medical Genetics, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, China Cytochrome c oxidase subunit Va (COX5A) is involved in maintaining normal mitochondrial function. However, little is known on the role of COX5A in the development and progress of Alzheimer’s disease (Martinez-Losa et al., 2018). In this Edited by: study, we established and characterized the genomic profiles of genes expressed Mercè Pallàs, University of Barcelona, Spain in the hippocampus of Senescence-Accelerated Mouse-prone 8 (SAMP8) mice, and Reviewed by: revealed differential expression of COX5A among 12-month-aged SAMP8 mice and Susan Anne Farr, 2-month-aged SAMP8 mice. -
Regulation of Mitochondrial Dynamics and Cell Fate Rimpy Dhingra, Phd; Lorrie A
Advance Publication by-J-STAGE Circulation Journal REVIEW Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp Regulation of Mitochondrial Dynamics and Cell Fate Rimpy Dhingra, PhD; Lorrie A. Kirshenbaum, PhD Though the mitochondrion was initially identified as a key organelle essentially required for energy production and oxidative metabolism, there is considerable evidence that mitochondria are intimately involved in regulating vital cellular processes, such as programmed cell death, proliferation and autophagy. Discovery of mitochondrial “shaping proteins” (Dynamin-related protein (Drp), mitofusins (Mfn) etc.) has revealed that mitochondria are highly dynamic organelles continually changing morphology by fission and fusion processes. Several human pathologies, including cancer, Parkinson’s disease, Alzheimer’s disease and cardiovascular diseases, have been linked to abnormalities in proteins that govern mitochondrial fission or fusion respectively. Notably, in the context of the heart, defects in mitochondrial dynamics resulting in too many fused and/or fragmented mitochondria have been associated with impaired cardiac development, autophagy, and contractile dysfunction. Understanding the mechanisms that govern mitochondrial fission/ fusion is paramount in developing new treatment strategies for human diseases in which defects in fission or fusion is the primary underlying defect. Here, we provide a comprehensive overview of the cellular targets and molecular signal- ing pathways that govern mitochondrial dynamics -
Mitochondrial Dynamic Abnormalities in Alzheimer's Disease Sirui Jiang Case Western Reserve University
MITOCHONDRIAL DYNAMIC ABNORMALITIES IN ALZHEIMER’S DISEASE by SIRUI JIANG Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Dissertation Advisor: Dr. Xiongwei Zhu Department of Pathology CASE WESTERN RESERVE UNIVERSITY January 2019 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of SIRUI JIANG Candidate for the degree of Doctor of Philosophy* Dr. Shu Chen (Committee Chair) Dr. Xiongwei Zhu Dr. Xinglong Wang Dr. George Dubyak Dr. Charles Hoppel August 15, 2018 *We also certify that written approval has been obtained for any proprietary material contained therein Table of Contents Table of Contents 1 List of Figures 3 Acknowledgements 5 List of Abbreviations 7 Abstract 10 Chapter 1. Introduction 12 Introduction to Alzheimer’s Disease 13 General Information 13 Pathology 14 Pathogenesis 15 Introduction to Mitochondrial Dynamics 20 Mitochondrial Function and Neuronal Health 20 Mitochondrial Dynamics 21 Mitochondrial Dynamics and Mitochondrial Function 23 Mitochondrial Dynamics and Mitochondrial Transport 24 Mitochondrial Deficits in AD 26 Mitochondrial Dysfunction in AD 26 Aβ and Mitochondrial Dysfunction 27 Mitochondrial Dynamic Abnormalities in AD: Recent Advances 28 Conclusion 34 1 Chapter 2. Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex 36 Abstract 37 Background 39 Methods 43 Results 47 Discussion 54 Figures 60 Chapter 3. DLP1 Cleavage by Calpain in Alzheimer’s Disease 71 Abstract 72 Background 73 Methods 77 Results 80 Discussion 85 Figures 89 Chapter 4. Summary, Discussion and Future Directions 96 References 108 2 List of Figures Figure 2.1 Cre-mediated ablation of Mfn2 expression in the hippocampus and cortex of Mfn2 cKO mice 60 Figure 2.2 Quantification of DLP1 and OPA1 in cKO mice 61 Figure 2.3 Mfn2 ablation caused mitochondrial fragmentation and ultrastructural damage in the hippocampus in vivo as evidenced by electron microscopic analysis. -
GRACILE Syndrome, a Lethal Metabolic Disorder with Iron
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Am. J. Hum. Genet. 71:863–876, 2002 GRACILE Syndrome, a Lethal Metabolic Disorder with Iron Overload, Is Caused by a Point Mutation in BCS1L Ilona Visapa¨a¨,1,3 Vineta Fellman,7 Jouni Vesa,1 Ayan Dasvarma,8 Jenna L. Hutton,2 Vijay Kumar,5 Gregory S. Payne,2 Marja Makarow,5 Rudy Van Coster,9 Robert W. Taylor,10 Douglass M. Turnbull,10 Anu Suomalainen,6 and Leena Peltonen1,3,4 Departments of 1Human Genetics and 2Biological Chemistry, University of California Los Angeles School of Medicine, Los Angeles; 3Department of Molecular Medicine, National Public Health Institute, 4Department of Medical Genetics, 5Institute of Biotechnology, and 6Department of Neurology and Programme of Neurosciences, University of Helsinki, and 7Hospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki; 8Murdoch Children’s Research Institute, Melbourne, Australia; 9Department of Pediatrics, Ghent University Hospital, Ghent, Belgium; and 10Department of Neurology, University of Newcastle upon Tyne, Newcastle, United Kingdom GRACILE (growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death) syndrome is a recessively inherited lethal disease characterized by fetal growth retardation, lactic acidosis, aminoaciduria, cholestasis, and abnormalities in iron metabolism. We previously localized the causative gene to a 1.5-cM region on chromosome 2q33-37. In the present study, we report the molecular defect causing this metabolic disorder, by identifying a homozygous missense mutation that results in an S78G amino acid change in the BCS1L gene in Finnish patients with GRACILE syndrome, as well as five different mutations in three British infants.