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Mitochondrial DNA Mutations Cause Various Diseases

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Mitochondrial DNA Mutations Cause Various Diseases 2013 Neurobiology of Disease in Children Symposium: Mitochondrial Disease, October 30, 2013 Defects of Mitochondrial DNA Replication William C. Copeland Laboratory of Molecular Genetics Mitochondrial DNA mutations cause various diseases * Alpers Disease * Leigh Disease or Syndrome * Barth syndrome * LHON * Beta-oxidation Defects * LIC (Lethal Infantile Cardiomyopathy) * Carnitine-Acyl-Carnitine * Luft Disease Deficiency * MAD * Carnitine Deficiency * MCAD * Co-Enzyme Q10 Deficiency * MELAS * Complex I Deficiency * MERRF * Complex II Deficiency * Mitochondrial Cytopathy * Complex III Deficiency * Mitochondrial DNA Depletion * Complex IV Deficiency * Mitochondrial Encephalopathy * Complex V Deficiency * Mitochondrial Myopathy * COX Deficiency * MNGIE * CPEO * NARP * CPT I Deficiency * Pearson Syndrome * CPT II Deficiency * Pyruvate Carboxylase Deficiency * Glutaric Aciduria Type II * Pyruvate Dehydrogenase Deficiency * KSS * Respiratory Chain * Lactic Acidosis * SCAD * LCAD * SCHAD * LCHAD * VLCAD Origins of mtDNA mutations Damage to DNA •Environmental factors •Endogenous oxidative stress Spontaneous errors •DNA replication •Translesion synthesis •DNA repair re-synthesis Mitochondrial DNA replication p32 - RNaseH 16 Human DNA Polymerases Polymerase Family Chromosome Mol. Wt. (kDa) Function/Comments α (alpha) B Xq21.3-q22.1 165 Initiates replication β (beta) X 8p12-p11 39 BER, other functions γ (gamma) A 15q25 140 Mitochondrial replication & repair δ (delta) B 19q13.3-.4 125 Replication, BER, NER, MMR ε (epsilon) B 12q24.3 255 Replication, checkpoint control ζ (zeta) B 6q22 344 yREV3 homolog, lesion bypass η (eta) Y 6p21.1 78 Lesion bypass, XPV, skin cancer susceptibility θ (theta) A 3q13.31 300 crosslink repair, Dm308, lesion bypass ι (iota) Y 18q21.1 80 Lesion bypass? BER? κ (kappa) Y 5q13.1 99 Lesion bypass, mutator when overexpressed λ (lambda) X 10q23 64 pol β homolog, meiosis? NHEJ µ (mu) X 7p13 55 TdT homolog, NHEJ n (nu) A 4p16.3 100 lesion bypass, crosslink repair? σ (sigma) X 5p15 60 TRF4 Rev1 Y 2q11.1-.2 125 lesion bypass TdT X 10q23-24 57 Terminal transferase Human DNA Polymerase γ Pol γ is a trimeric complex composed of two gene products: 140 kDa and two p55 kDa polypeptides POLG encoding p140: Catalytic subunit • DNA polymerase activity • 3’-5’ exonuclease activity • 5’-dRP lyase activity POLG2 encoding p55 dimer: Accessory subunit • Processivity factor • DNA binding factor p32 - RNaseH The p55 accessory subunit increases the processivity of the DNA polymerase by several hundred fold, stimulates DNA synthesis, and restores salt-tolerance through enhanced DNA binding. DNA polymerase γ participates in both mitochondrial DNA replication and repair. ~90% of mutations detected in vivo are reproduced in vitro with recombinant DNA polymerase γ Proteins involved in mitochondrial DNA replication 5 ' mtSSB p140 - POLG mtSSB p72 - Helicase p55 - POLG2 mtSSB p32 - RNaseH Polγ Twinkle 5 ' 3 ' Helicase 5 ' 3 ' p55 p15 - mtSSB NDP RRM2B TP TK1 thymine thymidine dTMP dTDP dTTP DNC SUCLA2 DNA replication SUCLG1 MGME1 TK2 NDPK PEO1 thymidine dTMP dTDP dTTP POLG2 deoxycytidine dCTP dCDP dCTP dGuoK POLG deoxyguanine dGMP dGDP dGTP MtDNA deoxyadenine dAMP dADP NDPK dATP SUCLA2 OXPHOS SUCLG1 ADP ATP OPA1 MPV17? ANT1 ADP ATP Copeland, Ann. Rev. Med 2008 Human POLG gene 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Mitochondria targeting sequence I II III A B C Exonuclease Thumb Spacer Thumb Palm Fingers Palm 25 170 440 475 785 855 910 1104 1239 p55 binding Exonuclease domain Linker region Polymerase domain Crystal structure of the human pol γ holoenzyme Human POLG gene 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Exonuclease domain Linker region Polymerase domain Mitochondria targeting sequence I II III A B C Exonuclease Thumb Spacer Thumb Palm Fingers Palm 25 170 440 475 785 855 910 1104 1239 p55 binding R3P L304R A467T Y955C 2001 Van Goethem et al., Nat. Genet. Mutation of POLG is associated with Progressive External Ophthalmoplegia characterized by mtDNA deletions Mutations in DNA polymerase γ, POLG Human POLG gene 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Q879H E873X E1136K R869Q T885S A767D H1134R E1143G* H277C L304R L304R G517V K561M A862T L886P T251I S305R G763R G888S H1110Y E1143G* Q497H R853Q L244P H569Q L752P E895G R309H A467T R1096H 3482+2(T>C)splice R574W F749S R852C T914P R1096C W235X T326fs387X A467T M1163R P587L T851A K925fsX R1047W R232G P648R W748S R1187W L428P T849X D930N R232H P589L W748S W1020X L83P R943C L1173fs X R227P W347fs356X L605R G848S A957P G11D Q68X R227W G737R K1191N R374X R627W 2485∆12bp R964C G11D 2157 splice R964C K1191R C224Y C418R R627Q 2480 splice Mitochondria A143V R417T Q715X R807C L965X Y1210fs1216X R627Q L966R 3643 splice targeting sequence I II III A B C Exonuclease Thumb Spacer Thumb Palm Fingers Palm F961S R3P L424X L623W A804T R227W R807P A957S G1205A Q43R G426S R617C P648R T251I Y831C* Y955C D1196N Q45R M430L M603L R953C G268A R709X G848S D1184N ∆(CAG)n G431V R597W R1047W R1187W R275X G746S R853W R1047Q S433C S1176L H110Y L304R P587L V855A R943H G1051R T452X K755E F1164I A862T Q308H R579W H932Y G1076V R1138C D136E L463F G763R N864S R309L R574W G923D I1079L R1128H A467T 2354Gins A889T V1106I W312R R562Q W918R S1095R G380D N468D A1105T S511N R1096C S1104C Exonuclease domain Polymerase domain - adPEO+ (Progressive External Ophthalmoplegia) -Alpers and other Infantile Hepatocerebral Syndromes - NRTI toxicity with mtDNA depletion - arPEO+ -Male infertility / - Ataxia-Neuropathy Syndrome, MIRAS / SANDO / SCAE - PEO, sporadic - testicular cancer / Idiopathic Parkinson - Single Nucleotide Polymorphism (*) - Other http://tools.niehs.nih.gov/polg/ Major clinical syndromes associated with POLG mutations Age of Onset Syndrome Myocerebrohepatopathy spectrum Neonatal/Infancy (MCHS) Alpers-Huttenlocher syndrome Infancy/Childhood (AHS) Ataxia neuropathy spectrum (ANS) Myoclonus, epilepsy, myopathy, Adolescent/young adult sensory ataxia (MEMSA) Progressive external ophthalmoplegia (PEO) with or without sensory ataxic neuropathy and dysarthria (SANDO) Mutations in DNA polymerase γ, POLG Human POLG gene 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Q879H E873X E1136K R869Q T885S A767D H1134R E1143G* H277C L304R L304R G517V K561M A862T L886P T251I S305R G763R G888S H1110Y E1143G* Q497H R853Q L244P H569Q L752P E895G R309H A467T R1096H 3482+2(T>C)splice R574W F749S R852C T914P R1096C W235X T326fs387X A467T M1163R P587L T851A K925fsX R1047W R232G P648R W748S R1187W L428P T849X D930N R232H P589L W748S W1020X L83P R943C L1173fs X R227P W347fs356X L605R G848S A957P G11D Q68X R227W G737R K1191N R374X R627W 2485∆12bp R964C G11D 2157 splice R964C K1191R C224Y C418R R627Q 2480 splice Mitochondria A143V R417T Q715X R807C L965X Y1210fs1216X R627Q L966R 3643 splice targeting sequence I II III A B C Exonuclease Thumb Spacer Thumb Palm Fingers Palm F961S R3P L424X L623W A804T R227W R807P A957S G1205A Q43R G426S R617C P648R T251I Y831C* Y955C D1196N Q45R M430L M603L R953C G268A R709X G848S D1184N ∆(CAG)n G431V R597W R1047W R1187W R275X G746S R853W R1047Q S433C S1176L H110Y L304R P587L V855A R943H G1051R T452X K755E F1164I A862T Q308H R579W H932Y G1076V R1138C D136E L463F G763R N864S R309L R574W G923D I1079L R1128H A467T 2354Gins A889T V1106I W312R R562Q W918R S1095R G380D N468D A1105T S511N R1096C S1104C Exonuclease domain Polymerase domain - adPEO+ (Progressive External Ophthalmoplegia) -Alpers and other Infantile Hepatocerebral Syndromes - NRTI toxicity with mtDNA depletion - arPEO+ -Male infertility / - Ataxia-Neuropathy Syndrome, MIRAS / SANDO / SCAE - PEO, sporadic - testicular cancer / Idiopathic Parkinson - Single Nucleotide Polymorphism (*) - Other http://tools.niehs.nih.gov/polg/ Studying mitochondrial DNA replication in yeast Easily screen for mitochondrial Conserved regions with human POLG dysfunction Yeast genetics Heteroallelic Monoallelic Strand et al., 20030 WT MIP1 ΔWT MIP1 Assay for mtDNA mutants X mut mip1 mut mip1 • mtDNA depletion • mtDNA point mutations • mtDNA deletions Monoallelic mutants that increase petite colony formation frequency Table 2. Monoallelic mip1 mutations that increased petite frequency Genotypea % Petite Wildtype 10 Exo- 46 L260R 40 Q264H 100 R265L 35 R607C 100 R607P 67 G651S 100 T654A 100 R656W 100 R656Q 100 N667S 100 G691S 18 H734Y 100 A759P 100 G832V 100 R853C 100 R853H 100 S861C 100 V863I 100 D941N 33 a All strains contain plasmid pFL39 with a mutation causing the indicated amino acid change and contain chromosomal mip1 deletion Stumpf et al. HMG 2010, What causes mitochondrial dysfunction in mip1 mutants? • MtDNA depletion • Point mutagenesis • Deletions mip1 disease mutations increase mtDNA mutagenesis (heteroallelic: wt/mut) Stumpf et al. HMG 2010, Homozygous POLG exo-/- mice have premature aging phenotypes But POLG exo+/- heterozygous mice appear normal +/- exo exo-/- Homozygous POLG exo-/- mice display a 2000-fold increase in point mutations Heterozygous POLG exo+/- display a 500-fold increase in point mutations Trifunovic et al., 2004; Kujoth et al., 2005 Vermulst et al. 2007 Exonuclease domain mip1 mutations cause very little increase in mutant frequency Heteroallelic strains Monoallelic strains 600 80 70 500 60 400 50 300 40 30 200 20 100 10 0 0 Mutant Frequency relative to wild-type Mutant Frequency Relative to wildtype wild- exo- G224A L210P L260R Q264H R265L R265H wild- exo G224D G224A L210P L260R R265L R265H type type Stumpf et al., 2010, Hu et al., 1995, Baruffini et al., 2006 What about deletions? • What is the role
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