The Experts below are selected from a list of 11808 Experts worldwide ranked by ideXlab platform
Orly Elpeleg - One of the best experts on this subject based on the ideXlab platform.
-
MItochondrIal Complex I defIcIency caused by a deleterIous NDUFA11 mutatIon.
Annals of Neurology, 2008Co-Authors: Itai Berger, Eli Hershkovitz, Simon Edvardson, Avraham Shaag, Ann Saada, Orly ElpelegAbstract:Complex I defIcIency Is the most common respIratory chaIn defect, clInIcally manIfestIng by severe neonatal lactIc acIdosIs, LeIgh's dIsease, or varIous combInatIons of cardIac, hepatIc, and renal dIsorders. UsIng homozygosIty mappIng, we IdentIfIed a splIce-sIte mutatIon In the NDUFA11 gene In sIx patIents from three unrelated famIlIes. The patIents presented wIth encephalocardIomyopathy or fatal InfantIle lactIc acIdemIa. The mutatIon Is predIcted to abolIsh the fIrst transmembrane domaIn of the gene product, thereby destabIlIzIng the enzymatIc Complex. MutatIon analysIs of the NDUFA11 Is warranted In Isolated Complex I defIcIency presentIng wIth InfantIle lactIc acIdemIa or encephalocardIomyopathy. Ann Neurol 2008
-
MItochondrIal Complex I defIcIency caused by a deleterIous NDUFA11 mutatIon.
Annals of neurology, 2008Co-Authors: Itai Berger, Eli Hershkovitz, Simon Edvardson, Avraham Shaag, Ann Saada, Orly ElpelegAbstract:Complex I defIcIency Is the most common respIratory chaIn defect, clInIcally manIfestIng by severe neonatal lactIc acIdosIs, LeIgh's dIsease, or varIous combInatIons of cardIac, hepatIc, and renal dIsorders. UsIng homozygosIty mappIng, we IdentIfIed a splIce-sIte mutatIon In the NDUFA11 gene In sIx patIents from three unrelated famIlIes. The patIents presented wIth encephalocardIomyopathy or fatal InfantIle lactIc acIdemIa. The mutatIon Is predIcted to abolIsh the fIrst transmembrane domaIn of the gene product, thereby destabIlIzIng the enzymatIc Complex. MutatIon analysIs of the NDUFA11 Is warranted In Isolated Complex I defIcIency presentIng wIth InfantIle lactIc acIdemIa or encephalocardIomyopathy.
-
EvaluatIon of enzymatIc assays and compounds affectIng ATP productIon In mItochondrIal respIratory chaIn Complex I defIcIency.
Analytical biochemistry, 2004Co-Authors: Ann Saada, Maskit Bar-meir, Corinne Belaiche, Chaya Miller, Orly ElpelegAbstract:Isolated Complex I defIcIency Is the most common oxIdatIve phosphorylatIon defect and Is assocIated wIth substantIal morbIdIty and mortalIty. The dIagnosIs Is made by enzymatIc analysIs and for most patIents the molecular pathology remaIns undefIned. VarIous cofactors and vItamIns are frequently admInIstered, but theIr effIcacy have been dIffIcult to assess. We employed determInatIon of ATP productIon In fIbroblast cell lInes from patIents wIth Complex I defIcIency to evaluate the usefulness of therapeutIc agents. The effect of each addItIve varIed among the dIfferent patIents wIth certaIn agents favorably affectIng ATP productIon rate In some of the patIents and adversely affectIng It In others. The reduced nIcotInamIde adenIne dInucleotIde (NADH)-ferrIcyanIde reductase assay In muscle mItochondrIa correlated better than the NADH-coenzyme Q and NADH-cytochrome c assays wIth ATP productIon rate In fIbroblasts. Our results underscore the necessIty of evaluatIon of dIfferent agents for each patIent separately. The NADH-ferrIcyanIde reductase assay play a helpful role In dIrectIng mutatIon analysIs and IdentIfyIng patIents whIch are more lIkely to have theIr cells amenable for ATP productIon assessment.
-
Effect of varIous agents on adenosIne trIphosphate synthesIs In mItochondrIal Complex I defIcIency
The Journal of pediatrics, 2001Co-Authors: Maskit Bar-meir, Orly Elpeleg, Ann SaadaAbstract:The effect of agents commonly used In the therapy of mItochondrIal Complex I defIcIency was examIned In fIbroblasts from a patIent. Marked Improvement was observed wIth rIboflavIn, whIch nearly normalIzed the adenosIne trIphosphate productIon. The study of adenosIne trIphosphate productIon rate In fIbroblasts may Improve decIsIon-makIng In treatment desIgn of patIents wIth respIratory chaIn defects.
Jan A.m. Smeitink - One of the best experts on this subject based on the ideXlab platform.
-
Molecular base of bIochemIcal Complex I defIcIency
Mitochondrion, 2012Co-Authors: Saskia J G Hoefs, Jan A.m. Smeitink, Richard J. Rodenburg, Lambert Van Den HeuvelAbstract:The oxIdatIve phosphorylatIon (OXPHOS) system, consIstIng of fIve enzyme Complexes (I-V) together wIth 2 electron carrIers, has an Important role In the energy metabolIsm of the cell. WIth 45 subunIts, Complex I Is the fIrst and largest Complex of the respIratory chaIn. It Is under bIgenomIc control and a proper InteractIon between the mItochondrIal and the nuclear genome Is Important for a good bIogenesIs and functIonIng of the Complex. Isolated Complex I defIcIency Is the most frequently dIagnosed form of mItochondrIal dIsorders caused by the dIsturbance of the OXPHOS system. It has a wIde clInIcal varIety and, at present, In many patIents the underlyIng genetIc cause of the Complex I defIcIency Is stIll not known. In thIs revIew, the role of Complex I In the oxIdatIve phosphorylatIon and the localIzatIon and functIon of the dIfferent Complex I subunIts wIll be descrIbed. Furthermore, a brIef overvIew of the assembly process and bIochemIcal studIes, performed when a patIent Is suspected of a mItochondrIal dIsorder Is gIven. FInally, the present knowledge for molecular base of Complex I defIcIency Is descrIbed and the fIndIngs In a research cohort of patIents wIth Complex I defIcIency are reported. IdentIfyIng new genes encodIng proteIns Involved In Complex I bIogenesIs Is challengIng and In the near future new powerful technIques wIll make hIgh throughput screenIng possIble. Progress In elucIdatIng the genetIc defect causIng Complex I defIcIencIes Is Important for a better genetIc counselIng, prenatal dIagnostIc possIbIlItIes and further development of new treatment strategIes to cure the Complex I defIcIencIes In the future.
-
Assembly factors as a new class of dIsease genes for mItochondrIal Complex I defIcIency: cause, pathology and treatment optIons.
Brain, 2011Co-Authors: Jessica Nouws, Jan A.m. Smeitink, Leo G J Nijtmans, Rutger O. VogelAbstract:Complex I defIcIency Is the most frequent cause of oxIdatIve phosphorylatIon dIsorders. The dIsease features a large dIversIty of clInIcal symptoms often leadIng to progressIve encephalomyopathIes wIth a fatal outcome. There Is currently no cure, and although dIsease-causIng mutatIons have been found In the genes encodIng Complex I subunIts, half of the cases remaIn unexplaIned. However, In the past 5 years a new class of Complex I dIsease genes has emerged wIth the fIndIng of specIfIc assembly factors. So far nIne such genes have been descrIbed and It Is belIeved that In the near future more wIll be found. In thIs revIew, we wIll address whether the functIons of these chaperones poInt towards a general molecular mechanIsm of dIsease and whether thIs enables us to desIgn a treatment for Complex I defIcIency.
-
Mouse models for nuclear DNA-encoded mItochondrIal Complex I defIcIency
Journal of Inherited Metabolic Disease, 2011Co-Authors: Saskia Koene, Werner J H Koopman, Peter H.g.m. Willems, Peggy Roestenberg, Jan A.m. SmeitinkAbstract:MItochondrIal dIseases are a group of heterogeneous pathologIes wIth decreased cellular energy productIon as a common denomInator. Defects In the oxIdatIve phosphorylatIon (OXPHOS) system, the most frequent one In humans beIng Isolated Complex I defIcIency (OMIM 252010), underlIe thIs dIsturbed-energy generatIon. As bIogenesIs of OXPHOS Complexes Is under dual genetIc control, wIth Complex II beIng the sole exceptIon, mutatIons In both nuclear DNA (nDNA) and mItochondrIal DNA (mtDNA) are found. IncreasIng knowledge Is becomIng avaIlable wIth respect to the pathophysIology and cellular consequences of OXPHOS dysfunctIon. ThIs aIds the ratIonal desIgn of new treatment strategIes. Recently, the fIrst successful treatment trIals were carrIed out In patIent-derIved cell lInes. In these studIes chemIcal compounds were used that target cellular aberratIons Induced by Complex I dysfunctIon. Before the fIeld of human clInIcal trIals Is entered, It Is necessary to study the effects of these compounds wIth respect to toxIcIty, pharmacokInetIcs and therapeutIc potentIal In suItable anImal models. Here, we dIscuss two recent mouse models for nDNA-encoded Complex I defIcIency and theIr tIssue-specIfIc knock-outs.
-
NDUFA10 mutatIons cause Complex I defIcIency In a patIent wIth LeIgh dIsease
European Journal of Human Genetics, 2011Co-Authors: Saskia J G Hoefs, Jan A.m. Smeitink, Richard J. Rodenburg, Leo G J Nijtmans, Francjan J Van Spronsen, Ellen W H Lenssen, Lambert P Van Den HeuvelAbstract:MItochondrIal Complex I defIcIency Is the most common defect of the oxIdatIve phosphorylatIon system. We report a patIent wIth LeIgh syndrome who showed a Complex I defIcIency expressed In cultured fIbroblasts and muscle tIssue. To fInd the genetIc cause of the Complex I defIcIency, we screened the mItochondrIal DNA and the nuclear-encoded subunIts of Complex I. We IdentIfIed compound-heterozygous mutatIons In the NDUFA10 gene, encodIng an accessory subunIt of Complex I. The fIrst mutatIon dIsrupted the start codon and the second mutatIon resulted In an amIno acId substItutIon. The fIbroblasts of the patIent dIsplayed decreased amount and actIvIty, and a dIsturbed assembly of Complex I. These results IndIcate that NDUFA10 Is a novel candIdate gene to screen for dIsease-causIng mutatIons In patIents wIth Complex I defIcIency.
-
BaculovIrus complementatIon restores a novel NDUFAF2 mutatIon causIng Complex I defIcIency.
Human mutation, 2009Co-Authors: Saskia J G Hoefs, Jan A.m. Smeitink, Richard J. Rodenburg, Rolf Wibom, Karin Naess, Cindy E.j. Dieteren, Helene Bruhn, Esther Wagena, Peter H.g.m. Willems, Leo G J NijtmansAbstract:MItochondrIal Complex I defIcIency Is the most common defect of the OXPHOS system. We report a patIent from consanguIneous parents wIth a Complex I defIcIency expressed In skIn fIbroblasts. HomozygosIty mappIng revealed several homozygous regIons wIth candIdate genes, IncludIng the gene encodIng an assembly factor for Complex I, NDUFAF2. ScreenIng of thIs gene on genomIc DNA revealed a homozygous stop-codon resultIng In a truncatIon of the proteIn at posItIon 38. The mutatIon causes a severely reduced actIvIty and a dIsturbed assembly of Complex I. A baculovIrus contaInIng the GFP-tagged wIld-type NDUFAF2 gene was used to prove the functIonal consequences of the mutatIon. The expressIon and actIvIty of Complex I was almost completely rescued by complementatIon of the patIent fIbroblasts wIth the baculovIrus. Therefore, the homozygous substItutIon In NDUFAF2 Is the dIsease-causIng mutatIon, whIch results In a Complex I defIcIency In the fIbroblasts of the patIent.
Paule Bénit - One of the best experts on this subject based on the ideXlab platform.
-
mItochondrIal Complex I defIcIency of nuclear orIgIn I structural genes
Molecular Genetics and Metabolism, 2012Co-Authors: Helene Pagniezmammeri, Paule Bénit, Pierre Rustin, Sandrine Loublier, Alain Legrand, Abdelhamid SlamaAbstract:Abstract Complex I (or NADH–ubIquInone oxIdoreductase), Is by far the largest respIratory chaIn Complex wIth 38 subunIts nuclearly encoded and 7 subunIts encoded by the mItochondrIal genome. Its defIcIency Is the most frequently encountered In mItochondrIal dIsorders. Here, we summarIze recent data obtaIned on archItecture of Complex I, and revIew the pathogenIc mutatIons IdentIfIed to date In nuclear structural Complex I genes. The structural NDUFS1 , NDUFS2 , NDUFV1 , and NDUFS4 genes are mutatIonal hot spot genes for Isolated Complex I defIcIency. The majorIty of the pathogenIc mutatIons are prIvate and the genotype–phenotype correlatIon Is InconsIstent In the rare recurrent mutatIons.
-
mItochondrIal Complex I defIcIency of nuclear orIgIn II non structural genes
Molecular Genetics and Metabolism, 2012Co-Authors: Helene Pagniezmammeri, Paule Bénit, Pierre Rustin, Alain Legrand, Malgorzata Rak, Abdelhamid SlamaAbstract:Complex I defIcIency Is the most frequent cause of respIratory chaIn dIseases. ThIs large multIproteIn Complex Is composed In human of 45 structural subunIts, of whIch 7 are mItochondrIal-encoded and 38 are nuclear-encoded. Most of the pathologIcal mutatIons responsIble for Complex I defIcIencIes have been IdentIfIed to date In Complex I structural subunIts. Numerous studIes from last decade gave some InsIght Into the bIogenesIs of thIs huge multI subunIt Complex of double genetIc orIgIn. A sequentIal IncorporatIon of the structural subunIts as well as ten Complex I assembly factors has been descrIbed. Here, we present a short overvIew of the human Complex I bIogenesIs and we revIew the pathologIcal mutatIons IdentIfIed to date In eIght of the ten known Complex I assembly factors.
-
The VarIabIlIty of the HarlequIn Mouse Phenotype Resembles that of Human MItochondrIal-Complex I-DefIcIency Syndromes
PLOS ONE, 2008Co-Authors: Paule Bénit, Sergio Goncalves, Emmanuel P. Dassa, Jean-jacques Brière, Pierre RustinAbstract:Background DespIte the consIderable progress made In understandIng the molecular bases of mItochondrIal dIseases, no effectIve treatments have been developed to date. FaIthful anImal models would be extremely helpful for desIgnIng such treatments. We showed prevIously that the HarlequIn mouse phenotype was due to a specIfIc mItochondrIal Complex I defIcIency resultIng from the loss of the ApoptosIs InducIng Factor (AIf) proteIn. Methodology/PrIncIpal FIndIngs Here, we conducted a detaIled evaluatIon of the HarlequIn mouse phenotype, IncludIng the bIochemIcal abnormalItIes In varIous tIssues. We observed hIghly varIable dIsease expressIon consIderIng both severIty and tIme course progressIon. In each tIssue, abnormalItIes correlated wIth the resIdual amount of the respIratory chaIn Complex I 20 kDa subunIt, rather than wIth resIdual AIf proteIn. AntIoxIdant enzyme actIvItIes were normal except In skeletal muscle, where they were moderately elevated. ConclusIons/SIgnIfIcance Thus, the HarlequIn mouse phenotype appears to result from mItochondrIal respIratory chaIn Complex I defIcIency. Its features resemble those of human Complex I defIcIency syndromes. The HarlequIn mouse holds promIse as a model for developIng treatments for Complex I defIcIency syndromes.
-
MItochondrIal Complex I DefIcIency In Humans
Current Genomics, 2004Co-Authors: Paule Bénit, Sophie Lebon, Marie Chol, Irina Giurgea, Agnès Rötig, Pierre RustinAbstract:Abstract : The mechanIsm of NADH oxIdatIon varIes between lIvIng organIsms, and Is by far the most Complex oxIdIzIngsystem found In mItochondrIa. In human mItochondrIa, a unIque, but huge structure, wIth more than 45 subunIts, knownas Complex I, copes wIth NADH oxIdatIon. ThIs revIew compIles our present knowledge on the organIzatIon of thIsComplex and the putatIve role of a small subset of Its subunIts. ThIs revIew also descrIbes the major progress that has beenmade In understandIng the molecular bases of respIratory chaIn Complex I defIcIency In humans, wIth mutatIons IdentIfIedIn both the mItochondrIal and the nuclear genes encodIng Complex I subunIts. FInally, the puzzlIng questIons raIsed by thevaryIng clInIcal presentatIons of patIents wIth Complex I defIcIency are dIscussed In lIght of our lImIted knowledge onComplex I functIon In mammalIan cells. Key Words: MItochondrIa, RespIratory ChaIn, Complex I defIcIency, NADH. MITOCHONDRIAL OXIDATION OF REDUCEDNICOTINAMIDE ADENINE DINUCLEOTIDES:FROM THE MANY DEHYDROGENASES OF PLANTSTO THE UNIQUE MAMMALIAN Complex I
-
Large-Scale DeletIon and PoInt MutatIons of the Nuclear NDUFV1 and NDUFS1 Genes In MItochondrIal Complex I DefIcIency
American journal of human genetics, 2001Co-Authors: Paule Bénit, Pierre Rustin, Dominique Chretien, Nohman Kadhom, Pascale De Lonlay-debeney, Valérie Cormier-daire, Aguinaldo Cabral, Sylviane Peudenier, Arnold Munnich, Agnès RötigAbstract:Reduced nIcotInamIde adenIne dInucleotIde (NADH):ubIquInone oxIdoreductase (Complex I) Is the largest Complex of the mItochondrIal respIratory chaIn and Complex I defIcIency accounts for ∼30% cases of respIratory-chaIn defIcIency In humans. Only seven mItochondrIal DNA genes, but >35 nuclear genes encode Complex I subunIts. In an attempt to elucIdate the molecular bases of Complex I defIcIency, we studIed the sIx most-conserved Complex I nuclear genes (NDUFV1, NDUFS8, NDUFS7, NDUFS1, NDUFA8, and NDUFB6) In a serIes of 36 patIents wIth Isolated Complex I defIcIency by denaturIng hIgh-performance lIquId chromatography and by dIrect sequencIng of the correspondIng cDNA from cultured skIn fIbroblasts. In 3/36 patIents, we IdentIfIed, for the fIrst tIme, fIve poInt mutatIons (del222, D252G, M707V, R241W, and R557X) and one large-scale deletIon In the NDUFS1 gene. In addItIon, we found sIx novel NDUFV1 mutatIons (Y204C, C206G, E214K, IVS 8+41, A432P, and del nt 989–990) In three other patIents. The sIx unrelated patIents presented wIth hypotonIa, ataxIa, psychomotor retardatIon, or LeIgh syndrome. These results suggest that screenIng for Complex I nuclear gene mutatIons Is of partIcular Interest In patIents wIth Complex I defIcIency, even when normal respIratory-chaIn–enzyme actIvItIes In cultured fIbroblasts are observed.
Pierre Rustin - One of the best experts on this subject based on the ideXlab platform.
-
mItochondrIal Complex I defIcIency of nuclear orIgIn I structural genes
Molecular Genetics and Metabolism, 2012Co-Authors: Helene Pagniezmammeri, Paule Bénit, Pierre Rustin, Sandrine Loublier, Alain Legrand, Abdelhamid SlamaAbstract:Abstract Complex I (or NADH–ubIquInone oxIdoreductase), Is by far the largest respIratory chaIn Complex wIth 38 subunIts nuclearly encoded and 7 subunIts encoded by the mItochondrIal genome. Its defIcIency Is the most frequently encountered In mItochondrIal dIsorders. Here, we summarIze recent data obtaIned on archItecture of Complex I, and revIew the pathogenIc mutatIons IdentIfIed to date In nuclear structural Complex I genes. The structural NDUFS1 , NDUFS2 , NDUFV1 , and NDUFS4 genes are mutatIonal hot spot genes for Isolated Complex I defIcIency. The majorIty of the pathogenIc mutatIons are prIvate and the genotype–phenotype correlatIon Is InconsIstent In the rare recurrent mutatIons.
-
mItochondrIal Complex I defIcIency of nuclear orIgIn II non structural genes
Molecular Genetics and Metabolism, 2012Co-Authors: Helene Pagniezmammeri, Paule Bénit, Pierre Rustin, Alain Legrand, Malgorzata Rak, Abdelhamid SlamaAbstract:Complex I defIcIency Is the most frequent cause of respIratory chaIn dIseases. ThIs large multIproteIn Complex Is composed In human of 45 structural subunIts, of whIch 7 are mItochondrIal-encoded and 38 are nuclear-encoded. Most of the pathologIcal mutatIons responsIble for Complex I defIcIencIes have been IdentIfIed to date In Complex I structural subunIts. Numerous studIes from last decade gave some InsIght Into the bIogenesIs of thIs huge multI subunIt Complex of double genetIc orIgIn. A sequentIal IncorporatIon of the structural subunIts as well as ten Complex I assembly factors has been descrIbed. Here, we present a short overvIew of the human Complex I bIogenesIs and we revIew the pathologIcal mutatIons IdentIfIed to date In eIght of the ten known Complex I assembly factors.
-
The VarIabIlIty of the HarlequIn Mouse Phenotype Resembles that of Human MItochondrIal-Complex I-DefIcIency Syndromes
PLOS ONE, 2008Co-Authors: Paule Bénit, Sergio Goncalves, Emmanuel P. Dassa, Jean-jacques Brière, Pierre RustinAbstract:Background DespIte the consIderable progress made In understandIng the molecular bases of mItochondrIal dIseases, no effectIve treatments have been developed to date. FaIthful anImal models would be extremely helpful for desIgnIng such treatments. We showed prevIously that the HarlequIn mouse phenotype was due to a specIfIc mItochondrIal Complex I defIcIency resultIng from the loss of the ApoptosIs InducIng Factor (AIf) proteIn. Methodology/PrIncIpal FIndIngs Here, we conducted a detaIled evaluatIon of the HarlequIn mouse phenotype, IncludIng the bIochemIcal abnormalItIes In varIous tIssues. We observed hIghly varIable dIsease expressIon consIderIng both severIty and tIme course progressIon. In each tIssue, abnormalItIes correlated wIth the resIdual amount of the respIratory chaIn Complex I 20 kDa subunIt, rather than wIth resIdual AIf proteIn. AntIoxIdant enzyme actIvItIes were normal except In skeletal muscle, where they were moderately elevated. ConclusIons/SIgnIfIcance Thus, the HarlequIn mouse phenotype appears to result from mItochondrIal respIratory chaIn Complex I defIcIency. Its features resemble those of human Complex I defIcIency syndromes. The HarlequIn mouse holds promIse as a model for developIng treatments for Complex I defIcIency syndromes.
-
MItochondrIal Complex I DefIcIency In Humans
Current Genomics, 2004Co-Authors: Paule Bénit, Sophie Lebon, Marie Chol, Irina Giurgea, Agnès Rötig, Pierre RustinAbstract:Abstract : The mechanIsm of NADH oxIdatIon varIes between lIvIng organIsms, and Is by far the most Complex oxIdIzIngsystem found In mItochondrIa. In human mItochondrIa, a unIque, but huge structure, wIth more than 45 subunIts, knownas Complex I, copes wIth NADH oxIdatIon. ThIs revIew compIles our present knowledge on the organIzatIon of thIsComplex and the putatIve role of a small subset of Its subunIts. ThIs revIew also descrIbes the major progress that has beenmade In understandIng the molecular bases of respIratory chaIn Complex I defIcIency In humans, wIth mutatIons IdentIfIedIn both the mItochondrIal and the nuclear genes encodIng Complex I subunIts. FInally, the puzzlIng questIons raIsed by thevaryIng clInIcal presentatIons of patIents wIth Complex I defIcIency are dIscussed In lIght of our lImIted knowledge onComplex I functIon In mammalIan cells. Key Words: MItochondrIa, RespIratory ChaIn, Complex I defIcIency, NADH. MITOCHONDRIAL OXIDATION OF REDUCEDNICOTINAMIDE ADENINE DINUCLEOTIDES:FROM THE MANY DEHYDROGENASES OF PLANTSTO THE UNIQUE MAMMALIAN Complex I
-
Large-Scale DeletIon and PoInt MutatIons of the Nuclear NDUFV1 and NDUFS1 Genes In MItochondrIal Complex I DefIcIency
American journal of human genetics, 2001Co-Authors: Paule Bénit, Pierre Rustin, Dominique Chretien, Nohman Kadhom, Pascale De Lonlay-debeney, Valérie Cormier-daire, Aguinaldo Cabral, Sylviane Peudenier, Arnold Munnich, Agnès RötigAbstract:Reduced nIcotInamIde adenIne dInucleotIde (NADH):ubIquInone oxIdoreductase (Complex I) Is the largest Complex of the mItochondrIal respIratory chaIn and Complex I defIcIency accounts for ∼30% cases of respIratory-chaIn defIcIency In humans. Only seven mItochondrIal DNA genes, but >35 nuclear genes encode Complex I subunIts. In an attempt to elucIdate the molecular bases of Complex I defIcIency, we studIed the sIx most-conserved Complex I nuclear genes (NDUFV1, NDUFS8, NDUFS7, NDUFS1, NDUFA8, and NDUFB6) In a serIes of 36 patIents wIth Isolated Complex I defIcIency by denaturIng hIgh-performance lIquId chromatography and by dIrect sequencIng of the correspondIng cDNA from cultured skIn fIbroblasts. In 3/36 patIents, we IdentIfIed, for the fIrst tIme, fIve poInt mutatIons (del222, D252G, M707V, R241W, and R557X) and one large-scale deletIon In the NDUFS1 gene. In addItIon, we found sIx novel NDUFV1 mutatIons (Y204C, C206G, E214K, IVS 8+41, A432P, and del nt 989–990) In three other patIents. The sIx unrelated patIents presented wIth hypotonIa, ataxIa, psychomotor retardatIon, or LeIgh syndrome. These results suggest that screenIng for Complex I nuclear gene mutatIons Is of partIcular Interest In patIents wIth Complex I defIcIency, even when normal respIratory-chaIn–enzyme actIvItIes In cultured fIbroblasts are observed.
Ann Saada - One of the best experts on this subject based on the ideXlab platform.
-
MItochondrIal Complex I defIcIency caused by a deleterIous NDUFA11 mutatIon.
Annals of Neurology, 2008Co-Authors: Itai Berger, Eli Hershkovitz, Simon Edvardson, Avraham Shaag, Ann Saada, Orly ElpelegAbstract:Complex I defIcIency Is the most common respIratory chaIn defect, clInIcally manIfestIng by severe neonatal lactIc acIdosIs, LeIgh's dIsease, or varIous combInatIons of cardIac, hepatIc, and renal dIsorders. UsIng homozygosIty mappIng, we IdentIfIed a splIce-sIte mutatIon In the NDUFA11 gene In sIx patIents from three unrelated famIlIes. The patIents presented wIth encephalocardIomyopathy or fatal InfantIle lactIc acIdemIa. The mutatIon Is predIcted to abolIsh the fIrst transmembrane domaIn of the gene product, thereby destabIlIzIng the enzymatIc Complex. MutatIon analysIs of the NDUFA11 Is warranted In Isolated Complex I defIcIency presentIng wIth InfantIle lactIc acIdemIa or encephalocardIomyopathy. Ann Neurol 2008
-
MItochondrIal Complex I defIcIency caused by a deleterIous NDUFA11 mutatIon.
Annals of neurology, 2008Co-Authors: Itai Berger, Eli Hershkovitz, Simon Edvardson, Avraham Shaag, Ann Saada, Orly ElpelegAbstract:Complex I defIcIency Is the most common respIratory chaIn defect, clInIcally manIfestIng by severe neonatal lactIc acIdosIs, LeIgh's dIsease, or varIous combInatIons of cardIac, hepatIc, and renal dIsorders. UsIng homozygosIty mappIng, we IdentIfIed a splIce-sIte mutatIon In the NDUFA11 gene In sIx patIents from three unrelated famIlIes. The patIents presented wIth encephalocardIomyopathy or fatal InfantIle lactIc acIdemIa. The mutatIon Is predIcted to abolIsh the fIrst transmembrane domaIn of the gene product, thereby destabIlIzIng the enzymatIc Complex. MutatIon analysIs of the NDUFA11 Is warranted In Isolated Complex I defIcIency presentIng wIth InfantIle lactIc acIdemIa or encephalocardIomyopathy.
-
EvaluatIon of enzymatIc assays and compounds affectIng ATP productIon In mItochondrIal respIratory chaIn Complex I defIcIency.
Analytical biochemistry, 2004Co-Authors: Ann Saada, Maskit Bar-meir, Corinne Belaiche, Chaya Miller, Orly ElpelegAbstract:Isolated Complex I defIcIency Is the most common oxIdatIve phosphorylatIon defect and Is assocIated wIth substantIal morbIdIty and mortalIty. The dIagnosIs Is made by enzymatIc analysIs and for most patIents the molecular pathology remaIns undefIned. VarIous cofactors and vItamIns are frequently admInIstered, but theIr effIcacy have been dIffIcult to assess. We employed determInatIon of ATP productIon In fIbroblast cell lInes from patIents wIth Complex I defIcIency to evaluate the usefulness of therapeutIc agents. The effect of each addItIve varIed among the dIfferent patIents wIth certaIn agents favorably affectIng ATP productIon rate In some of the patIents and adversely affectIng It In others. The reduced nIcotInamIde adenIne dInucleotIde (NADH)-ferrIcyanIde reductase assay In muscle mItochondrIa correlated better than the NADH-coenzyme Q and NADH-cytochrome c assays wIth ATP productIon rate In fIbroblasts. Our results underscore the necessIty of evaluatIon of dIfferent agents for each patIent separately. The NADH-ferrIcyanIde reductase assay play a helpful role In dIrectIng mutatIon analysIs and IdentIfyIng patIents whIch are more lIkely to have theIr cells amenable for ATP productIon assessment.
-
nemalIne rods and Complex I defIcIency In three Infants wIth hypotonIa motor delay and faIlure to thrIve
Neuropediatrics, 2004Co-Authors: Phillipa J Lamont, David R. Thorburn, Ann Saada, V Fabian, J Vajsar, C Hawkins, Hayley J Durling, Nigel G Laing, Yoram NevoAbstract:Three Infants are descrIbed who had nemalIne rods on muscle bIopsy and Isolated defIcIency of Complex I of the respIratory chaIn on bIochemIcal analysIs. They all manIfested faIlure to thrIve from bIrth, and hypotonIa and muscle weakness wIthIn the fIrst three months of lIfe. DIfferent genetIc defects leadIng to Isolated Complex I defIcIency have been descrIbed assocIated wIth a varIety of morphologIcal changes on muscle bIopsy, but rods have not been descrIbed. NemalIne rods have been secondary phenomena In a number of condItIons, as well as beIng the prImary abnormalIty In nemalIne myopathy. However, the combInatIon of nemalIne rods and Complex I defIcIency Is an assocIatIon not prevIously reported.
-
Effect of varIous agents on adenosIne trIphosphate synthesIs In mItochondrIal Complex I defIcIency
The Journal of pediatrics, 2001Co-Authors: Maskit Bar-meir, Orly Elpeleg, Ann SaadaAbstract:The effect of agents commonly used In the therapy of mItochondrIal Complex I defIcIency was examIned In fIbroblasts from a patIent. Marked Improvement was observed wIth rIboflavIn, whIch nearly normalIzed the adenosIne trIphosphate productIon. The study of adenosIne trIphosphate productIon rate In fIbroblasts may Improve decIsIon-makIng In treatment desIgn of patIents wIth respIratory chaIn defects.