Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood F.-Nora Vögtle,

Slides:

Advertisements

Similar presentations

Previous Estimates of Mitochondrial DNA Mutation Level Variance Did Not Account for Sampling Error: Comparing the mtDNA Genetic Bottleneck in Mice and.

Advertisements

Effects of Growth Factors and Basement Membrane Proteins on the Phenotype of U- 373 MG Glioblastoma Cells as Determined by the Expression of Intermediate.

Deficiency of GDP-Man:GlcNAc2-PP-Dolichol Mannosyltransferase Causes Congenital Disorder of Glycosylation Type Ik Markus Schwarz, Christian Thiel, Jürgen.

Figure 4 K19del mutation alters CHP1 association into functional complexes, impairs NHE1 membrane targeting, and potentially compromises protein conformational.

The H Syndrome Is Caused by Mutations in the Nucleoside Transporter hENT3 Vered Molho-Pessach, Israela Lerer, Dvorah Abeliovich, Ziad Agha, Abdulasalam.

Volume 41, Issue 2, Pages (January 2011)

Merei Huigsloot, Leo G. Nijtmans, Radek Szklarczyk, Marieke J. H

Volume 7, Issue 1, Pages (July 2004)

Bethany S. Strunk, Megan N. Novak, Crystal L. Young, Katrin Karbstein

Volume 15, Issue 3, Pages (March 2012)

Volume 23, Issue 4, Pages (April 2015)

The Protein Import Motor of Mitochondria

Volume 139, Issue 2, Pages (October 2009)

Mutations in SLC33A1 Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin Peter.

Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis Francesca Mattioli,

Volume 19, Issue 3, Pages (March 2014)

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

Mutations in CYC1, Encoding Cytochrome c1 Subunit of Respiratory Chain Complex III, Cause Insulin-Responsive Hyperglycemia Pauline Gaignard, Minal Menezes,

TAT-mediated Delivery of LAD Restores Pyruvate Dehydrogenase Complex Activity in the Mitochondria of Patients with LAD Deficiency Matan Rapoport, Ann.

Hypomorphic Pathogenic Variants in TAF13 Are Associated with Autosomal-Recessive Intellectual Disability and Microcephaly Hasan Tawamie, Igor Martianov,

Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy Jessica X. Chong,

Mutations of POLR3A Encoding a Catalytic Subunit of RNA Polymerase Pol III Cause a Recessive Hypomyelinating Leukodystrophy Geneviève Bernard, Eliane.

Volume 3, Issue 5, Pages (May 2013)

Development and Dynamic Regulation of Mitochondrial Network in Human Midbrain Dopaminergic Neurons Differentiated from iPSCs Du Fang, Yu Qing, Shijun.

A Truncating Mutation of TRAPPC9 Is Associated with Autosomal-Recessive Intellectual Disability and Postnatal Microcephaly Ganeshwaran H. Mochida, Muhammad.

A Founder Mutation in PET100 Causes Isolated Complex IV Deficiency in Lebanese Individuals with Leigh Syndrome Sze Chern Lim, Katherine R. Smith, David A.

A Mutation in the Fibroblast Growth Factor 14 Gene Is Associated with Autosomal Dominant Cerebral Ataxia John C. van Swieten, Esther Brusse, Bianca M.

Merei Huigsloot, Leo G. Nijtmans, Radek Szklarczyk, Marieke J. H

Volume 87, Issue 2, Pages (July 2015)

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

Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy Marisa I. Mendes, Mariana.

Hung-Chun Yu, Jennifer L

Aldolase Is Essential for Energy Production and Bridging Adhesin-Actin Cytoskeletal Interactions during Parasite Invasion of Host Cells G. Lucas Starnes,

Volume 21, Issue 6, Pages (June 2015)

EB3 Regulates Microtubule Dynamics at the Cell Cortex and Is Required for Myoblast Elongation and Fusion Anne Straube, Andreas Merdes Current Biology

Infrared Radiation Affects the Mitochondrial Pathway of Apoptosis in Human Fibroblasts Sandra Frank, Lisa Oliver, Corinne Lebreton-De Coster, Carole Moreau,

Temperature-Sensitive RB Mutations Linked to Incomplete Penetrance of Familial Retinoblastoma in 12 Families Gregory A. Otterson, Sanjay Modi, Kari Nguyen,

Simon Edvardson, Claudia M. Nicolae, Pankaj B

Mutations in Iron-Sulfur Cluster Scaffold Genes NFU1 and BOLA3 Cause a Fatal Deficiency of Multiple Respiratory Chain and 2-Oxoacid Dehydrogenase Enzymes

ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy Tobias B. Haack, Robert Kopajtich, Peter Freisinger,

Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies

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

NDUFB8 Mutations Cause Mitochondrial Complex I Deficiency in Individuals with Leigh- like Encephalomyopathy Dorota Piekutowska-Abramczuk, Zahra Assouline,

Volume 19, Issue 3, Pages (March 2014)

Volume 3, Issue 2, Pages (August 2002)

Periklis Makrythanasis, Mitsuhiro Kato, Maha S

Volume 15, Issue 3, Pages (March 2012)

Volume 10, Issue 2, Pages (August 2009)

X-Linked Dominant Scapuloperoneal Myopathy Is Due to a Mutation in the Gene Encoding Four-and-a-Half-LIM Protein 1 Catarina M. Quinzii, Tuan H. Vu, K.

Autosomal-Dominant Striatal Degeneration Is Caused by a Mutation in the Phosphodiesterase 8B Gene Silke Appenzeller, Anja Schirmacher, Hartmut Halfter,

Volume 21, Issue 20, Pages (October 2011)

Coordination of Two Genomes by Mitochondrial Translational Plasticity

Volume 3, Issue 2, Pages (August 2002)

Mutations in POLR3A and POLR3B Encoding RNA Polymerase III Subunits Cause an Autosomal-Recessive Hypomyelinating Leukoencephalopathy Hirotomo Saitsu,

Fang Du, Qing Yu, Allen Chen, Doris Chen, Shirley ShiDu Yan

Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas Qilin Zhang, Cheng Peng,

Volume 15, Issue 3, Pages (March 2012)

Volume 20, Issue 6, Pages (December 2014)

Volume 44, Issue 5, Pages (December 2011)

A Homozygous Mutation in KCTD7 Links Neuronal Ceroid Lipofuscinosis to the Ubiquitin-Proteasome System John F. Staropoli, Amel Karaa, Elaine T. Lim,

A Novel Claudin 16 Mutation Associated with Childhood Hypercalciuria Abolishes Binding to ZO-1 and Results in Lysosomal Mistargeting Dominik Müller,

Gene Augmentation and Readthrough Rescue Channelopathy in an iPSC-RPE Model of Congenital Blindness Pawan K. Shahi, Dalton Hermans, Divya Sinha, Simran.

Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L

Hannah R. Elliott, David C. Samuels, James A. Eden, Caroline L

Volume 20, Issue 4, Pages (October 2014)

Functional Characterization of Missense Mutations in ATP7B: Wilson Disease Mutation or Normal Variant? John R. Forbes, Diane W. Cox The American Journal.

A Truncating Mutation of TRAPPC9 Is Associated with Autosomal-Recessive Intellectual Disability and Postnatal Microcephaly Ganeshwaran H. Mochida, Muhammad.

Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis Francesca Mattioli,

Protein Phosphorylation and Prevention of Cytochrome Oxidase Inhibition by ATP: Coupled Mechanisms of Energy Metabolism Regulation Rebeca Acin-Perez,

A Founder Mutation in PET100 Causes Isolated Complex IV Deficiency in Lebanese Individuals with Leigh Syndrome Sze Chern Lim, Katherine R. Smith, David A.

Presentation transcript:

Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood F.-Nora Vögtle, Björn Brändl, Austin Larson, Manuela Pendziwiat, Marisa W. Friederich, Susan M. White, Alice Basinger, Cansu Kücükköse, Hiltrud Muhle, Johanna A. Jähn, Oliver Keminer, Katherine L. Helbig, Carolyn F. Delto, Lisa Myketin, Dirk Mossmann, Nils Burger, Noriko Miyake, Audrey Burnett, Andreas van Baalen, Mark A. Lovell, Naomichi Matsumoto, Maie Walsh, Hung-Chun Yu, Deepali N. Shinde, Ulrich Stephani, Johan L.K. Van Hove, Franz-Josef Müller, Ingo Helbig The American Journal of Human Genetics Volume 102, Issue 4, Pages 557-573 (April 2018) DOI: 10.1016/j.ajhg.2018.02.014 Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 1 Genetics and MRI of Individuals Carrying PMPCB Variants (A) Pedigrees of all families with PMPCB pathogenic variants. Black symbols designate affected individuals. (B) Sagittal T1 MRI images of individual A:II-1 at 13 months (a), individual B:II-2 at 4 years (b), individual C:II-1 at 3 years (c), and individual D:II-1 at 3 years 3 months (d) demonstrating cerebellar atrophy in all four individuals. T2 transverse images of individual D:II-1 at 1 year (e) and 4 years 7 months (g) and individual D:II-2 at 9 months (f) and 3 years, 3 months (h), demonstrating progressive cerebral atrophy. (C) Model of the crystal structure of the yeast MPP heterodimer (Mas1, blue; Mas2, gray) with the bound presequence peptide (green) in front (left) and back (right) view. The active site (yellow) and the positions of the mutations (red) are shown in stick representation. The American Journal of Human Genetics 2018 102, 557-573DOI: (10.1016/j.ajhg.2018.02.014) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 2 Analysis of Mitochondria Isolated from PMPCB iPSCs and Dermal Fibroblasts (A) Morphology and ICC-based characterization of hiPSC clone D:II-2.11 derived from affected individual D:II-2. BF, bright field. (B) Protein steady-state levels of mitochondria isolated from three different PMPCB iPSC cell clones (D:II-2.4, D:II-2.9, D:II-2.11) and controls (Ctrl.). i, intermediate; m, mature. (C) Quantifications of protein steady-state levels from (B). Values represent mean ± SEM (error bars; n = 3). (D) Protein steady-state analysis of mitochondria isolated from fibroblasts of family D with affected individual D:II-2 and individual A:II-1 and controls (Ctrl. 1–3). (E) Processing of radiolabeled Frataxin (FXN) precursor in mitochondrial extract from affected individual D:II-2 (D:II-2.4) and control (Ctrl., C2.2) iPSC line. α-GRP75, loading control. (F) Formation of ISD complex in mitochondria isolated from control (C1, C2.2, C2.5) and affected individual (D:II-2.4, D:II-2.9, D:II-2.11) hiPSC lines. The American Journal of Human Genetics 2018 102, 557-573DOI: (10.1016/j.ajhg.2018.02.014) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 3 Analysis of PMPCB Mutations in Yeast (A) Growth of Mas1 wild-type, Mas1Arg144Cys, and Mas1Thr170Pro mutant yeast strains under fermentative and respiratory conditions. (B) Import of radiolabelled precursors upon in organello heat shock into mitochondria isolated from wild-type and Mas1 mutant cells. p, precursor; i, intermediate; m, mature. (C) Western blot analysis of steady-state protein levels in Mas1 wild-type, Mas1Arg144Cys, and Mas1Thr170Pro mutant mitochondria isolated after in vivo heat shock. The American Journal of Human Genetics 2018 102, 557-573DOI: (10.1016/j.ajhg.2018.02.014) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 4 Characterization of Mitochondrial Functions in Mas1 Mutant Yeast Cells (A) BN-PAGE analysis of respiratory chain complexes in Mas1 wild-type and mutant mitochondria isolated after cell growth at 23°C. (B) Analysis as in (A), mitochondria were isolated after in vivo heat shock. (C) Membrane potential measurement in mitochondria isolated from Mas1, Mas1Arg144Cys, and Mas1Thr170Pro cells after growth at permissive temperature (− heat shock; values represent mean ± SEM, n = 4) or in vivo heat shock (+ heat shock; values represent mean ± SEM, n = 3). (D) ISD complex formation in Mas1 wild-type and mutant mitochondria isolated at 23°C (− heat shock) or after in vivo heat shock. The American Journal of Human Genetics 2018 102, 557-573DOI: (10.1016/j.ajhg.2018.02.014) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 5 Analysis of Enzymatic Activity of Fe-S-Cluster-Containing Proteins and Protein Complexes in PMPCB Tissues (A) Isolated mitochondrial membrane fractions of individual A:II-1 and control (Ctrl.) muscle samples were analyzed by BN-PAGE followed by in-gel activity staining for respiratory chain complex I, II, IV, and V. (B) Assembly of respiratory chain complex I by BN-PAGE analysis in isolated mitochondrial membrane fractions obtained from affected individual A:II-1 and control fibroblasts. holocomplex, fully assembled complex I; ∗, lower molecular weight subcomplexes. (C) Enzymatic activity of mitochondrial and cytosolic aconitase in fibroblasts of individual A:II-1 and control. Values represent mean ± SD (error bars; control n = 9, A:II-1 n = 5). (D) Mitochondrial and cytosolic aconitase activity in muscle homogenates from individual A:II-1 and controls. Data are represented as mean ± SD (error bars; control n = 11, A:II-1 average of two measurements). The American Journal of Human Genetics 2018 102, 557-573DOI: (10.1016/j.ajhg.2018.02.014) Copyright © 2018 American Society of Human Genetics Terms and Conditions