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

Slides:

Advertisements

Similar presentations

Figure 5 ISOX and vorinostat partially restore splicing pattern in DM1 patient-derived fibroblasts. (A) ISOX and vorinostat partially rescue mis-splicing.

Advertisements

Volume 4, Issue 5, Pages (September 2013)

Volume 50, Issue 1, Pages (April 2013)

Volume 16, Issue 3, Pages (September 2012)

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

Marie Sissler, Ligia Elena González-Serrano, Eric Westhof

TRMT5 Mutations Cause a Defect in Post-transcriptional Modification of Mitochondrial tRNA Associated with Multiple Respiratory-Chain Deficiencies Christopher A.

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

Global Mapping of Human RNA-RNA Interactions

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

Sherif Abou Elela, Haller Igel, Manuel Ares Cell

Thiamine Pyrophosphokinase Deficiency in Encephalopathic Children with Defects in the Pyruvate Oxidation Pathway Johannes A. Mayr, Peter Freisinger,

A Truncating Mutation of CEP135 Causes Primary Microcephaly and Disturbed Centrosomal Function Muhammad Sajid Hussain, Shahid Mahmood Baig, Sascha Neumann,

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

Targeted High-Throughput Sequencing Identifies Mutations in atlastin-1 as a Cause of Hereditary Sensory Neuropathy Type I Christian Guelly, Peng-Peng.

Volume 38, Issue 4, Pages (May 2010)

SAGA Is a General Cofactor for RNA Polymerase II Transcription

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

A Nonsense Mutation in DHTKD1 Causes Charcot-Marie-Tooth Disease Type 2 in a Large Chinese Pedigree Wang-yang Xu, Ming-min Gu, Lian-hua Sun, Wen-ting.

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

Exome Sequencing and Functional Analysis Identifies BANF1 Mutation as the Cause of a Hereditary Progeroid Syndrome Xose S. Puente, Victor Quesada, Fernando G.

Mutations in PADI6 Cause Female Infertility Characterized by Early Embryonic Arrest Yao Xu, Yingli Shi, Jing Fu, Min Yu, Ruizhi Feng, Qing Sang, Bo Liang,

Human Senataxin Resolves RNA/DNA Hybrids Formed at Transcriptional Pause Sites to Promote Xrn2-Dependent Termination Konstantina Skourti-Stathaki, Nicholas J.

Volume 23, Issue 5, Pages (May 2018)

Identification and Validation of Genetic Variants that Influence Transcription Factor and Cell Signaling Protein Levels Ronald J. Hause, Amy L. Stark,

Anne L. Sapiro, Patricia Deng, Rui Zhang, Jin Billy Li Cell Reports

Acute Infantile Liver Failure Due to Mutations in the TRMU Gene

A Gene Mutated in Nephronophthisis and Retinitis Pigmentosa Encodes a Novel Protein, Nephroretinin, Conserved in Evolution Edgar Otto, Julia Hoefele,

Volume 38, Issue 4, Pages (May 2010)

PSMB8 Encoding the β5i Proteasome Subunit Is Mutated in Joint Contractures, Muscle Atrophy, Microcytic Anemia, and Panniculitis-Induced Lipodystrophy.

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

Mutations in GTPBP3 Cause a Mitochondrial Translation Defect Associated with Hypertrophic Cardiomyopathy, Lactic Acidosis, and Encephalopathy Robert.

Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability Yair Anikster, Tobias B. Haack, Thierry Vilboux, Ben.

Volume 19, Issue 12, Pages (June 2017)

Volume 8, Issue 6, Pages (September 2014)

A Heterozygous Truncating Mutation in RRM2B Causes Autosomal-Dominant Progressive External Ophthalmoplegia with Multiple mtDNA Deletions Henna Tyynismaa,

Mutations of the Ephrin-B1 Gene Cause Craniofrontonasal Syndrome

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

Biallelic Mutations in PATL2 Cause Female Infertility Characterized by Oocyte Maturation Arrest Biaobang Chen, Zhihua Zhang, Xiaoxi Sun, Yanping Kuang,

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

Codependent Activators Direct Myoblast-Specific MyoD Transcription

Volume 21, Issue 9, Pages (November 2017)

Volume 16, Issue 7, Pages (August 2016)

Volume 14, Issue 3, Pages (September 2011)

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

Posttranscriptional Gene Silencing Is Not Compromised in the Arabidopsis CARPEL FACTORY (DICER-LIKE1) Mutant, a Homolog of Dicer-1 from Drosophila E.Jean.

Xin Xie, Tomas Venit, Nizar Drou, Piergiorgio Percipalle

Volume 13, Issue 10, Pages (December 2015)

Functional Genomic Analysis of Human Mitochondrial RNA Processing

Volume 10, Issue 2, Pages (August 2009)

Figure 3 In silico modelling of the human mt-AlaRS Arg580 residue and p.Arg580Trp variant. (A) Multiple sequence ... Figure 3 In silico modelling of the.

Maternally Inherited Stable Intronic Sequence RNA Triggers a Self-Reinforcing Feedback Loop during Development Mandy Li-Ian Tay, Jun Wei Pek Current.

Tobias B. Haack, Christian Staufner, Marlies G. Köpke, Beate K

Volume 17, Issue 3, Pages (March 2013)

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

Volume 8, Issue 6, Pages (September 2014)

Matthis Synofzik, Tobias B

Volume 9, Pages (November 2018)

Exome Sequencing Identifies CCDC8 Mutations in 3-M Syndrome, Suggesting that CCDC8 Contributes in a Pathway with CUL7 and OBSL1 to Control Human Growth

Arun Kumar, Satish C. Girimaji, Mahesh R. Duvvari, Susan H. Blanton

Bi-allelic Truncating Mutations in TANGO2 Cause Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy Laura S. Kremer, Felix Distelmaier,

DHTKD1 Mutations Cause 2-Aminoadipic and 2-Oxoadipic Aciduria

Mutations in NEXN, a Z-Disc Gene, Are Associated with Hypertrophic Cardiomyopathy Hu Wang, Zhaohui Li, Jizheng Wang, Kai Sun, Qiqiong Cui, Lei Song, Yubao.

Mutations in PTPRQ Are a Cause of Autosomal-Recessive Nonsyndromic Hearing Impairment DFNB84 and Associated with Vestibular Dysfunction Margit Schraders,

Gloria Brea-Calvo, Tobias B

Hannah Kennedy, Tobias B. Haack, Verity Hartill, Lavinija Mataković, E

Ciliary Abnormalities Due to Defects in the Retrograde Transport Protein DYNC2H1 in Short-Rib Polydactyly Syndrome Amy E. Merrill, Barry Merriman, Claire.

Matthis Synofzik, Tobias B

Identification of a New Splice Form of the EDA1 Gene Permits Detection of Nearly All X- Linked Hypohidrotic Ectodermal Dysplasia Mutations Alex W. Monreal,

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

Presentation transcript:

ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy Tobias B. Haack, Robert Kopajtich, Peter Freisinger, Thomas Wieland, Joanna Rorbach, Thomas J. Nicholls, Enrico Baruffini, Anett Walther, Katharina Danhauser, Franz A. Zimmermann, Ralf A. Husain, Jessica Schum, Helen Mundy, Ileana Ferrero, Tim M. Strom, Thomas Meitinger, Robert W. Taylor, Michal Minczuk, Johannes A. Mayr, Holger Prokisch The American Journal of Human Genetics Volume 93, Issue 2, Pages 211-223 (August 2013) DOI: 10.1016/j.ajhg.2013.06.006 Copyright © 2013 The Authors Terms and Conditions

Figure 1 ELAC2 Mutation Status and Gene Structure (A) Pedigrees of three families with mutations in ELAC2. Individual #57415 (F1: II-3) from unrelated parents was found to have a compound heterozygous mutation. Individuals #61982 (F2: II-5) and #65937 (F3: II-2) born to consanguineous parents (first-degree cousins) carry homozygous missense mutations in ELAC2. (B) Gene structure of ELAC2 with known protein domains of the gene product and localization and conservation of amino acid residues affected by mutations. Intronic regions are not drawn to scale. The American Journal of Human Genetics 2013 93, 211-223DOI: (10.1016/j.ajhg.2013.06.006) Copyright © 2013 The Authors Terms and Conditions

Figure 2 Quantification and Rescue of the Mitochondrial mRNA Processing Defect by qPCR (A) Map of the mitochondrial genome with the annotation of rRNA, tRNA, and mRNA genes among the heavy and light strand. Numbering 1–10 indicates the RNA cleavage sites located 5′ terminal of rRNAs or mRNAs. As an example for the primer design, a scheme of the tRNAArg-ND4L junction is given. (B and C) Quantification of the ten unprocessed mitochondrial tRNA-rRNA or tRNA-mRNA junctions analyzed by qPCR in (C) muscle and (D) fibroblasts before (−) and after (+) transduction with a wild-type ELAC2 expression construct. Values are given as fold change to the average of three different controls. Error bars indicate ±1 standard deviation (SD) from the mean of at least three technical (B) or biological (C) replicates. The American Journal of Human Genetics 2013 93, 211-223DOI: (10.1016/j.ajhg.2013.06.006) Copyright © 2013 The Authors Terms and Conditions

Figure 3 Steady-State Levels Mitochondrial RNAs and RNA-Seq in Mutant Fibroblasts (A and B) Quantification of steady-state levels of (A) 14 mt-tRNAs and (B) 3 mt-mRNAs and 16S mt-rRNA in control and affected individual’s (#57415) fibroblasts by RNA blot analysis. 18S rRNA was used as loading control. (C) Mitochondrial transcriptome analysis by next-generation sequencing (RNA-seq) of fibroblasts RNA from ELAC2 individuals and three controls. Relative sequencing coverage is plotted against the mitochondrial genome (numbering according to RefSeq accession number J01415). Colored lines represent individuals #57415 (blue), #61982 (red), and #65937 (green). The black dotted line indicates the average of three controls. The ten RNase Z cleavage sites analyzed by qPCR (Figure 2) are shown with higher magnification. (D) RNA blot analysis decorated with tRNALeu(UUR)- and tRNAVal-specific probes to detect unprocessed mt-tRNA-mRNA intermediates. The American Journal of Human Genetics 2013 93, 211-223DOI: (10.1016/j.ajhg.2013.06.006) Copyright © 2013 The Authors Terms and Conditions

Figure 4 Mitochondrial Translation and Steady-State Levels of Respiratory Chain Complexes in Mutant Fibroblasts (A and B) Analysis of mitochondrial translation products in fibroblasts from individual #57415 by [35S]methionine pulse labeling (A) and quantification of three experiments (B). Error bars indicate ±1 SD from the mean of three replicates. mtDNA-encoded structural subunits of complex I (ND1, ND2, ND3, ND4, ND4L, ND5, ND6), complex III (cytb), complex IV (MT-COI, MT-COII, MT-COIII), and complex V (ATP6, ATP8) are shown. (C and D) Immunoblot analysis of respiratory chain complex subunits in crude mitochondrial extractions from individual #57415 and control (C) fibroblasts as well as (D) muscle. Porin antibody was used as a loading control in muscle. The American Journal of Human Genetics 2013 93, 211-223DOI: (10.1016/j.ajhg.2013.06.006) Copyright © 2013 The Authors Terms and Conditions

Figure 5 Model of Potential ELAC2 Pathomechanism Suggested model of normal and impaired ELAC2 activity. Under normal conditions minor amounts of unprocessed ELAC2 substrates can be degraded by the RNA surveillance machinery. Reduced ELAC2 activity results in an accumulation of mitochondrial precursor mRNAs, which impair mitochondrial translation. The American Journal of Human Genetics 2013 93, 211-223DOI: (10.1016/j.ajhg.2013.06.006) Copyright © 2013 The Authors Terms and Conditions