An mtDNA Mutation in the Initiation Codon of the Cytochrome C Oxidase Subunit II Gene Results in Lower Levels of the Protein and a Mitochondrial Encephalomyopathy

Slides:

Advertisements

Similar presentations

Fig. 7 Localization of the element(s) responsible for the transcriptional suppression by PPAR-γ. A, Rat VSMCs were transfected with either −1969/+104-luc,

Advertisements

Volume 68, Issue 4, Pages (October 2005)

Myopodin, a Synaptopodin Homologue, Is Frequently Deleted in Invasive Prostate Cancers Fan Lin, Yan-Ping Yu, Jeff Woods, Kathleen Cieply, Bill Gooding,

Increase in Elastin Gene Expression and Protein Synthesis in Arterial Smooth Muscle Cells Derived From Patients with Moyamoya Disease by Mari Yamamoto,

UVB Increases Urokinase-Type Plasminogen Activator Receptor (uPAR) Expression1 Christoph Marschall, Toshiko Nobutoh, Evelyn Braungart, Kathrin Douwes,

CLPB Variants Associated with Autosomal-Recessive Mitochondrial Disorder with Cataract, Neutropenia, Epilepsy, and Methylglutaconic Aciduria Carol Saunders,

Volume 116, Issue 6, Pages (June 1999)

Constitutive Phosphorylation of Focal Adhesion Kinase Is Involved in the Myofibroblast Differentiation of Scleroderma Fibroblasts Yoshihiro Mimura, Hironobu.

Signal transduction pathways triggered by the FcϵRIIb receptor (CD23) in human monocytes lead to nuclear factor-κB activation Rosa M. Ten, MD, PhDa,

Counterregulation of Interleukin-18 mRNA and Protein Expression During Cutaneous Wound Repair in Mice Heiko Kämpfer, Heiko Mühl, Josef Pfeilschifter,

Cotranscriptionally Formed DNA:RNA Hybrids Mediate Transcription Elongation Impairment and Transcription-Associated Recombination Pablo Huertas, Andrés.

Simultaneous Detection and Quantification of Mitochondrial DNA Deletion(s), Depletion, and Over-Replication in Patients with Mitochondrial Disease Ren-Kui.

Recessive Mutations in TRMT10C Cause Defects in Mitochondrial RNA Processing and Multiple Respiratory Chain Deficiencies Metodi D. Metodiev, Kyle Thompson,

The homeodomain protein Cdx2 regulates lactase gene promoter activity during enterocyte differentiation Rixun Fang, Nilda A. Santiago, Lynne C. Olds,

BM-40(Osteonectin, SPARC) Is Expressed Both in the Epidermal and in the Dermal Compartment of Adult Human Skin Nicholas Hunzelmann, Martin Hafner, Sabine.

Mutation of a Nuclear Respiratory Factor 2 Binding Site in the 5′ Untranslated Region of the ADSL Gene in Three Patients with Adenylosuccinate Lyase Deficiency

Yan Jiang, Mingyi Liu, Charlotte A. Spencer, David H. Price

GRACILE Syndrome, a Lethal Metabolic Disorder with Iron Overload, Is Caused by a Point Mutation in BCS1L Ilona Visapää, Vineta Fellman, Jouni Vesa, Ayan.

IFN-γ Upregulates Expression of the Mouse Complement C1rA Gene in Keratinocytes via IFN-Regulatory Factor-1 Sung June Byun, Ik-Soo Jeon, Hyangkyu Lee,

Shamima Rahman, Jan-Willem Taanman, J

Structural and Functional Mutations of the Perlecan Gene Cause Schwartz-Jampel Syndrome, with Myotonic Myopathy and Chondrodysplasia Eri Arikawa-Hirasawa,

Mutations of the Mitochondrial-tRNA Modifier MTO1 Cause Hypertrophic Cardiomyopathy and Lactic Acidosis Daniele Ghezzi, Enrico Baruffini, Tobias B. Haack,

Direct Activation of Gastric H,K-ATPase by N-Terminal Protein Kinase C Phosphorylation. Comparison of the Acute Regulation Mechanisms of H,K-ATPase and.

CLPB Variants Associated with Autosomal-Recessive Mitochondrial Disorder with Cataract, Neutropenia, Epilepsy, and Methylglutaconic Aciduria Carol Saunders,

The mRNA for Protease Nexin-1 is Expressed in Human Dermal Papilla Cells and its Level is Affected by Androgen Tadashige Sonoda, Yuji Asada, Sotaro Kurata,

Volume 115, Issue 4, Pages (October 1998)

Membrane Type 1 Matrix Metalloproteinase Regulates Cellular Invasiveness and Survival in Cutaneous Epidermal Cells Usha Nagavarapu, Kenneth Relloma,

Volume 65, Issue 4, Pages (April 2004)

IGF-II-Mediated COX-2 Gene Expression in Human Keratinocytes Through Extracellular Signal-Regulated Kinase Pathway Hye Jung Kim, Tae-Yoon Kim Journal.

Active Influx Transport is Mediated by Members of the Organic Anion Transporting Polypeptide Family in Human Epidermal Keratinocytes Ruth Schiffer, Mark.

Yongli Bai, Chun Yang, Kathrin Hu, Chris Elly, Yun-Cai Liu

Cell-Density-Dependent Regulation of Expression and Glycosylation of Dopachrome Tautomerase/Tyrosinase-Related Protein-2 Thomas J. Hornyak, Daniel J.

Volume 68, Issue 4, Pages (October 2005)

Evidence That Translation Reinitiation Leads to a Partially Functional Menkes Protein Containing Two Copper-Binding Sites Marianne Paulsen, Connie Lund,

An RMND1 Mutation Causes Encephalopathy Associated with Multiple Oxidative Phosphorylation Complex Deficiencies and a Mitochondrial Translation Defect

Volume 123, Issue 2, Pages (October 2005)

Volume 54, Issue 2, Pages (August 1998)

A Homozygous Nonsense Mutation in Type XVII Collagen Gene (COL17A1) Uncovers an Alternatively Spliced mRNA Accounting for an Unusually Mild Form of Non-Herlitz.

Inhibitory Effect of β-Thujaplicin on Ultraviolet B-Induced Apoptosis in Mouse Keratinocytes Takako Baba, Hajime Nakano, Katsuto Tamai, Daisuke Sawamura,

Upregulation of Tenascin-C Expression by IL-13 in Human Dermal Fibroblasts via the Phosphoinositide 3-kinase/Akt and the Protein Kinase C Signaling Pathways

Noritaka Oyama, Keiji Iwatsuki, Yoshimi Homma, Fumio Kaneko

Three-Dimensional Migration of Human Adult Dermal Fibroblasts from Collagen Lattices into Fibrin/Fibronectin Gels Requires Syndecan-4 Proteoglycan Fubao.

Ketoconazole Suppresses Prostaglandin E2-Induced Cyclooxygenase-2 Expression in Human Epidermoid Carcinoma A-431 Cells Naoko Kanda, Dr., Shinichi Watanabe

A Novel Homozygous Mutation Affecting Integrin α6 in a Case of Junctional Epidermolysis Bullosa with Pyloric Atresia Detected In Utero by Ultrasound Examination

Halofuginone, an Inhibitor of Type-I Collagen Synthesis and Skin Sclerosis, Blocks Transforming-Growth-Factor-β-Mediated Smad3 Activation in Fibroblasts

Glucosamine sulfate modulates the levels of aggrecan and matrix metalloproteinase-3 synthesized by cultured human osteoarthritis articular chondrocytes

Deletion of the Cytoplasmatic Domain of BP180/Collagen XVII Causes a Phenotype with Predominant Features of Epidermolysis Bullosa Simplex Marcel Huber,

2-Methyl-3-Hydroxybutyryl-CoA Dehydrogenase Deficiency Is Caused by Mutations in the HADH2 Gene Rob Ofman, P.N. Jos Ruiter, Marike Feenstra, Marinus.

Cowden Syndrome–Affected Patients with PTEN Promoter Mutations Demonstrate Abnormal Protein Translation Rosemary E. Teresi, Kevin M. Zbuk, Marcus G.

Mutations in C12orf65 in Patients with Encephalomyopathy and a Mitochondrial Translation Defect Hana Antonicka, Elsebet Østergaard, Florin Sasarman,

PEX3 Is the Causal Gene Responsible for Peroxisome Membrane Assembly–Defective Zellweger Syndrome of Complementation Group G Kamran Ghaedi, Masanori.

Volume 55, Issue 5, Pages (May 1999)

Nature of Mitochondrial DNA Deletions in Substantia Nigra Neurons

Assessing the Functional Characteristics of Synonymous and Nonsynonymous Mutation Candidates by Use of Large DNA Constructs A.M. Eeds, D. Mortlock, R.

A Novel Frameshift Mutation in Exon 23 of ATP7A (MNK) Results in Occipital Horn Syndrome and Not in Menkes Disease Susan L. Dagenais, Ayla N. Adam, Jeffrey.

Volume 17, Issue 3, Pages (March 2013)

A Novel Gene Expressed in Human Keratinocytes with Long-Term In Vitro Growth Potential is Required for Cell Growth Laure Aurelian, Cynthia C. Smith,

James W. Smyth, Robin M. Shaw Cell Reports

James Gailit, Mary J. Marchese, Richard R. Kew, Barry L. Gruber

Volume 57, Issue 2, Pages (October 2000)

Rita Das, Zhaolan Zhou, Robin Reed Molecular Cell

Volume 59, Issue 3, Pages (March 2001)

Expression of FcRn, the MHC Class I-Related Receptor for IgG, in Human Keratinocytes Karla Cauza, Gabriele Hinterhuber, Ruth Dingelmaier-Hovorka, Karin.

1α,25-Dihydroxyvitamin D3 Stimulates Activator Protein 1 DNA-Binding Activity by a Phosphatidylinositol 3-Kinase/Ras/MEK/Extracellular Signal Regulated.

Sequential effects of high glucose on mesangial cell transforming growth factor-β1 and fibronectin synthesis Jong Hoon Oh, Hunjoo Ha, Mi Ra Yu, Hi Bahl.

Yan Jiang, Mingyi Liu, Charlotte A. Spencer, David H. Price

Identification and Characterization of a Mutation, in the Human UDP-Galactose-4- Epimerase Gene, Associated with Generalized Epimerase-Deficiency Galactosemia

Effects of Hepatocyte Growth Factor on the Expression of Type I Collagen and Matrix Metalloproteinase-1 in Normal and Scleroderma Dermal Fibroblasts

Transcriptional Termination Factors for RNA Polymerase II in Yeast

Volume 123, Issue 2, Pages (October 2005)

Presentation transcript:

An mtDNA Mutation in the Initiation Codon of the Cytochrome C Oxidase Subunit II Gene Results in Lower Levels of the Protein and a Mitochondrial Encephalomyopathy Kim M. Clark, Robert W. Taylor, Margaret A. Johnson, Patrick F. Chinnery, Zofia M.A. Chrzanowska-Lightowlers, Richard M. Andrews, Isobel P. Nelson, Nicholas W. Wood, Phillipa J. Lamont, Michael G. Hanna, Robert N. Lightowlers, Douglass M. Turnbull The American Journal of Human Genetics Volume 64, Issue 5, Pages 1330-1339 (May 1999) DOI: 10.1086/302361 Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 1 Chromatogram from fluorescent M13 sequencing. Sequence shows nt 7578–7597. An arrow represents the heteroplasmic T→C transition at position 7587. The American Journal of Human Genetics 1999 64, 1330-1339DOI: (10.1086/302361) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 2 Schematic illustrating the position of the 7587C mutation within the mitochondrial genome, as well as the associated amino acid change. The initiation codon of COX II is changed to threonine. Initiation of translation could occur either at the next initiation site (AUG), which is “out of frame” and would yield a five-residue polypeptide, or at the next “in-frame” initiation site (AUA), 16 codons downstream. The American Journal of Human Genetics 1999 64, 1330-1339DOI: (10.1086/302361) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 3 Quantification of the 7587C mutation in muscle, cultured fibroblasts, and cultured myoblasts from the index case. PCR and RFLP were done as described in Patients and Methods, and products were electrophoresed through a 3% Metaphor agarose gel. The levels of mutated mtDNA are represented as percentages of total mtDNA and are shown (bottom). To separate the 291-bp and 272-bp bands, it was necessary to run the 94-bp and 19-bp fragments off the bottom of the gel. The American Journal of Human Genetics 1999 64, 1330-1339DOI: (10.1086/302361) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 4 Distribution of the 7587C mutation in single fibers expressing either a COX-positive or -negative phenotype. The levels of mutated mtDNA are represented as percentages of total mtDNA and are shown underneath. To separate the 291-bp and 272-bp bands, it was necessary to run the 19-bp fragment off the bottom of the gel. The American Journal of Human Genetics 1999 64, 1330-1339DOI: (10.1086/302361) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 5 Threshold of the 7587C mutation. Microphotometric enzyme analysis and single-fiber PCR were performed on adjacent 8-μm serial sections as described in Patients and Methods. Values for COX activity are represented as ΔA450nm × 10−5/s. The American Journal of Human Genetics 1999 64, 1330-1339DOI: (10.1086/302361) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 6 Mitochondrial protein synthesis in fibroblasts. Fibroblasts were cultured in the presence of 10 μg emetine/ml and were pulse labeled for 30 min (lanes 1 and 2) or 2 h (lanes 3 and 4) with 500 μCi 35S methionine/cysteine. Products were separated through a 1.2% polyacrylamide gel as described in Patients and Methods. Products were labeled according to molecular weight and findings from products from previously reported in vivo translation assays (Chomyn 1996). ND = NADH ubiquinone oxido-reductase; cyt b = apo cytochrome-b; and ATPase = ATP synthase. The American Journal of Human Genetics 1999 64, 1330-1339DOI: (10.1086/302361) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 7 Immunoblotting of whole-cell lysate. Equal amounts (15 μg) of protein were subjected to SDS PAGE and were blotted onto a polyvinylidene difluoride membrane as described in Patients and Methods. A, Incubation with a monoclonal COX II antibody, demonstrating absence of COX II in patient II-2 fibroblasts. B, Incubation with a polyclonal antibody to COX IV. Patient II-2 fibroblasts contain half the amount of COX IV, compared with that in the control. C, Incubation with a polyclonal antibody to crotonase, demonstrating that the results shown in A are not due to a variation in protein loading. The more intense signal obtained from patient II-2 fibroblasts suggests that there is either up-regulation of crotonase or slightly more protein in this lane compared with that in the control fibroblasts. High-molecular-weight species represent nonspecific proteins recognized by the crotonase antisera. Molecular-weight markers were included on the gel to check product sizes. The American Journal of Human Genetics 1999 64, 1330-1339DOI: (10.1086/302361) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 8 Northern blot hybridization analysis. Equal amounts (18 μg) of RNA were separated onto a 1.2% agarose gel containing 2.5% formaldehyde and were transferred to a nitrocellulose membrane, and mitochondrial and nuclear probes were constructed and radiolabeled as described in Patients and Methods. Hybridization was done with a 280-bp COX II probe, a 1.2-kb β-actin probe, and a 380-bp ND4-specific probe. The steady-state level of COX II mRNA in patient II-2 is one-third of that in controls. The American Journal of Human Genetics 1999 64, 1330-1339DOI: (10.1086/302361) Copyright © 1999 The American Society of Human Genetics Terms and Conditions