RBCC Red Blood Cell Collection

NDUFS1 [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial; 1.6.5.3; 1.6.99.3 (Complex I-75kD; CI-75kD; Flags: Precursor)

UniProt P28331
ID NDUS1_HUMAN Reviewed; 727 AA.
AC P28331; B4DIN9; B4DJA0; B4DPG1; B4DUC1; E7ENF3; Q53TR8; Q8N1C4;
read moreAC Q8TCC9;
DT 01-DEC-1992, integrated into UniProtKB/Swiss-Prot.
DT 07-MAR-2006, sequence version 3.
DT 22-JAN-2014, entry version 154.
DE RecName: Full=NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial;
DE EC=1.6.5.3;
DE EC=1.6.99.3;
DE AltName: Full=Complex I-75kD;
DE Short=CI-75kD;
DE Flags: Precursor;
GN Name=NDUFS1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT PHE-649.
RX PubMed=1935949; DOI=10.1111/j.1432-1033.1991.tb16313.x;
RA Chow W., Ragan I., Robinson B.H.;
RT "Determination of the cDNA sequence for the human mitochondrial 75-kDa
RT Fe-S protein of NADH-coenzyme Q reductase.";
RL Eur. J. Biochem. 201:547-550(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 3; 4 AND 5).
RC TISSUE=Hippocampus, Kidney, and Substantia nigra;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP GLN-241.
RC TISSUE=Brain, and Liver;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PROTEIN SEQUENCE OF 185-200; 247-266; 277-289; 312-325; 361-382;
RP 451-467; 471-499; 519-538; 544-557 AND 625-655, AND MASS SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Vishwanath V., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [7]
RP MASS SPECTROMETRY, AND IDENTIFICATION IN THE NADH-UBIQUINONE
RP OXIDOREDUCTASE COMPLEX.
RX PubMed=12611891; DOI=10.1074/jbc.C300064200;
RA Murray J., Zhang B., Taylor S.W., Oglesbee D., Fahy E., Marusich M.F.,
RA Ghosh S.S., Capaldi R.A.;
RT "The subunit composition of the human NADH dehydrogenase obtained by
RT rapid one-step immunopurification.";
RL J. Biol. Chem. 278:13619-13622(2003).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [9]
RP VARIANTS MT-C1D TRP-241 AND GLY-252.
RX PubMed=11349233; DOI=10.1086/320603;
RA Benit P., Chretien D., Kadhom N., de Lonlay-Debeney P.,
RA Cormier-Daire V., Cabral A., Peudenier S., Rustin P., Munnich A.,
RA Roetig A.;
RT "Large-scale deletion and point mutations of the nuclear NDUFV1 and
RT NDUFS1 genes in mitochondrial complex I deficiency.";
RL Am. J. Hum. Genet. 68:1344-1352(2001).
RN [10]
RP VARIANT GLY-253.
RX PubMed=22499341; DOI=10.1136/jmedgenet-2012-100836;
RA Shamseldin H.E., Alshammari M., Al-Sheddi T., Salih M.A.,
RA Alkhalidi H., Kentab A., Repetto G.M., Hashem M., Alkuraya F.S.;
RT "Genomic analysis of mitochondrial diseases in a consanguineous
RT population reveals novel candidate disease genes.";
RL J. Med. Genet. 49:234-241(2012).
CC -!- FUNCTION: Core subunit of the mitochondrial membrane respiratory
CC chain NADH dehydrogenase (Complex I) that is believed to belong to
CC the minimal assembly required for catalysis. Complex I functions
CC in the transfer of electrons from NADH to the respiratory chain.
CC The immediate electron acceptor for the enzyme is believed to be
CC ubiquinone (By similarity). This is the largest subunit of complex
CC I and it is a component of the iron-sulfur (IP) fragment of the
CC enzyme. It may form part of the active site crevice where NADH is
CC oxidized.
CC -!- CATALYTIC ACTIVITY: NADH + ubiquinone + 5 H(+)(In) = NAD(+) +
CC ubiquinol + 4 H(+)(Out).
CC -!- CATALYTIC ACTIVITY: NADH + acceptor = NAD(+) + reduced acceptor.
CC -!- COFACTOR: Binds 1 2Fe-2S cluster per subunit (By similarity).
CC -!- COFACTOR: Binds 2 4Fe-4S clusters per subunit (By similarity).
CC -!- SUBUNIT: Complex I is composed of 45 different subunits.
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1;
CC IsoId=P28331-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P28331-2; Sequence=VSP_042682;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=P28331-3; Sequence=VSP_043728, VSP_043729;
CC Note=No experimental confirmation available;
CC Name=4;
CC IsoId=P28331-4; Sequence=VSP_043727;
CC Note=No experimental confirmation available;
CC Name=5;
CC IsoId=P28331-5; Sequence=VSP_045864;
CC Note=No experimental confirmation available;
CC -!- DISEASE: Mitochondrial complex I deficiency (MT-C1D) [MIM:252010]:
CC A disorder of the mitochondrial respiratory chain that causes a
CC wide range of clinical manifestations from lethal neonatal disease
CC to adult-onset neurodegenerative disorders. Phenotypes include
CC macrocephaly with progressive leukodystrophy, non-specific
CC encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh
CC syndrome, Leber hereditary optic neuropathy, and some forms of
CC Parkinson disease. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the complex I 75 kDa subunit family.
CC -!- SIMILARITY: Contains 1 2Fe-2S ferredoxin-type domain.
CC -!- SIMILARITY: Contains 1 4Fe-4S Mo/W bis-MGD-type domain.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/NDUFS1";
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DR EMBL; X61100; CAA43412.1; -; mRNA.
DR EMBL; AK295705; BAG58551.1; -; mRNA.
DR EMBL; AK295987; BAG58762.1; -; mRNA.
DR EMBL; AK298320; BAG60573.1; -; mRNA.
DR EMBL; AK300585; BAG62283.1; -; mRNA.
DR EMBL; AC007383; AAY15061.1; -; Genomic_DNA.
DR EMBL; CH471063; EAW70379.1; -; Genomic_DNA.
DR EMBL; BC022368; AAH22368.1; -; mRNA.
DR EMBL; BC030833; AAH30833.1; -; mRNA.
DR PIR; S17854; S17854.
DR RefSeq; NP_001186910.1; NM_001199981.1.
DR RefSeq; NP_001186911.1; NM_001199982.1.
DR RefSeq; NP_001186912.1; NM_001199983.1.
DR RefSeq; NP_001186913.1; NM_001199984.1.
DR RefSeq; NP_004997.4; NM_005006.6.
DR UniGene; Hs.471207; -.
DR UniGene; Hs.598436; -.
DR ProteinModelPortal; P28331; -.
DR SMR; P28331; 31-636.
DR IntAct; P28331; 11.
DR MINT; MINT-3011123; -.
DR STRING; 9606.ENSP00000233190; -.
DR ChEMBL; CHEMBL2363065; -.
DR DrugBank; DB00157; NADH.
DR PhosphoSite; P28331; -.
DR DMDM; 92090799; -.
DR REPRODUCTION-2DPAGE; IPI00604664; -.
DR REPRODUCTION-2DPAGE; P28331; -.
DR UCD-2DPAGE; P28331; -.
DR PaxDb; P28331; -.
DR PeptideAtlas; P28331; -.
DR PRIDE; P28331; -.
DR Ensembl; ENST00000233190; ENSP00000233190; ENSG00000023228.
DR Ensembl; ENST00000423725; ENSP00000397760; ENSG00000023228.
DR Ensembl; ENST00000432169; ENSP00000409689; ENSG00000023228.
DR Ensembl; ENST00000440274; ENSP00000409766; ENSG00000023228.
DR Ensembl; ENST00000449699; ENSP00000399912; ENSG00000023228.
DR Ensembl; ENST00000455934; ENSP00000392709; ENSG00000023228.
DR GeneID; 4719; -.
DR KEGG; hsa:4719; -.
DR UCSC; uc010zir.2; human.
DR CTD; 4719; -.
DR GeneCards; GC02M206986; -.
DR HGNC; HGNC:7707; NDUFS1.
DR MIM; 157655; gene.
DR MIM; 252010; phenotype.
DR neXtProt; NX_P28331; -.
DR Orphanet; 2609; Isolated NADH-CoQ reductase deficiency.
DR Orphanet; 255241; Leigh syndrome with leukodystrophy.
DR PharmGKB; PA31518; -.
DR eggNOG; COG1034; -.
DR HOGENOM; HOG000031442; -.
DR HOVERGEN; HBG003482; -.
DR InParanoid; P28331; -.
DR KO; K03934; -.
DR OMA; MPVMKGM; -.
DR OrthoDB; EOG783MTP; -.
DR PhylomeDB; P28331; -.
DR Reactome; REACT_111217; Metabolism.
DR ChiTaRS; NDUFS1; human.
DR GeneWiki; NDUFS1; -.
DR GenomeRNAi; 4719; -.
DR NextBio; 18202; -.
DR PMAP-CutDB; P28331; -.
DR PRO; PR:P28331; -.
DR ArrayExpress; P28331; -.
DR Bgee; P28331; -.
DR CleanEx; HS_NDUFS1; -.
DR Genevestigator; P28331; -.
DR GO; GO:0005758; C:mitochondrial intermembrane space; IDA:UniProtKB.
DR GO; GO:0005747; C:mitochondrial respiratory chain complex I; IDA:UniProtKB.
DR GO; GO:0051537; F:2 iron, 2 sulfur cluster binding; IEA:UniProtKB-KW.
DR GO; GO:0051539; F:4 iron, 4 sulfur cluster binding; IEA:UniProtKB-KW.
DR GO; GO:0009055; F:electron carrier activity; NAS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0008137; F:NADH dehydrogenase (ubiquinone) activity; NAS:UniProtKB.
DR GO; GO:0008637; P:apoptotic mitochondrial changes; IDA:UniProtKB.
DR GO; GO:0046034; P:ATP metabolic process; IMP:UniProtKB.
DR GO; GO:0006120; P:mitochondrial electron transport, NADH to ubiquinone; NAS:UniProtKB.
DR GO; GO:0072593; P:reactive oxygen species metabolic process; IMP:UniProtKB.
DR GO; GO:0051881; P:regulation of mitochondrial membrane potential; IMP:UniProtKB.
DR Gene3D; 3.10.20.30; -; 1.
DR InterPro; IPR001041; 2Fe-2S_ferredoxin-type.
DR InterPro; IPR012675; Beta-grasp_dom.
DR InterPro; IPR006656; Mopterin_OxRdtase.
DR InterPro; IPR006963; Mopterin_OxRdtase_4Fe-4S_dom.
DR InterPro; IPR000283; NADH_UbQ_OxRdtase_75kDa_su_CS.
DR InterPro; IPR010228; NADH_UbQ_OxRdtase_Gsu.
DR InterPro; IPR019574; NADH_UbQ_OxRdtase_Gsu_4Fe4S-bd.
DR InterPro; IPR015405; NuoG_C.
DR Pfam; PF09326; DUF1982; 1.
DR Pfam; PF00384; Molybdopterin; 1.
DR Pfam; PF10588; NADH-G_4Fe-4S_3; 1.
DR SMART; SM00929; NADH-G_4Fe-4S_3; 1.
DR SUPFAM; SSF54292; SSF54292; 1.
DR TIGRFAMs; TIGR01973; NuoG; 1.
DR PROSITE; PS00197; 2FE2S_FER_1; FALSE_NEG.
DR PROSITE; PS51085; 2FE2S_FER_2; 1.
DR PROSITE; PS51669; 4FE4S_MOW_BIS_MGD; 1.
DR PROSITE; PS00641; COMPLEX1_75K_1; 1.
DR PROSITE; PS00642; COMPLEX1_75K_2; 1.
DR PROSITE; PS00643; COMPLEX1_75K_3; 1.
PE 1: Evidence at protein level;
KW 2Fe-2S; 4Fe-4S; Acetylation; Alternative splicing; Complete proteome;
KW Direct protein sequencing; Disease mutation; Electron transport; Iron;
KW Iron-sulfur; Membrane; Metal-binding; Mitochondrion;
KW Mitochondrion inner membrane; NAD; Oxidoreductase; Polymorphism;
KW Reference proteome; Respiratory chain; Transit peptide; Transport;
KW Ubiquinone.
FT TRANSIT 1 23 Mitochondrion (By similarity).
FT CHAIN 24 727 NADH-ubiquinone oxidoreductase 75 kDa
FT subunit, mitochondrial.
FT /FTId=PRO_0000019968.
FT DOMAIN 30 108 2Fe-2S ferredoxin-type.
FT DOMAIN 245 301 4Fe-4S Mo/W bis-MGD-type.
FT METAL 64 64 Iron-sulfur 1 (2Fe-2S) (By similarity).
FT METAL 75 75 Iron-sulfur 1 (2Fe-2S) (By similarity).
FT METAL 78 78 Iron-sulfur 1 (2Fe-2S) (By similarity).
FT METAL 92 92 Iron-sulfur 1 (2Fe-2S) (By similarity).
FT METAL 124 124 Iron-sulfur 2 (4Fe-4S); via pros nitrogen
FT (By similarity).
FT METAL 128 128 Iron-sulfur 2 (4Fe-4S) (By similarity).
FT METAL 131 131 Iron-sulfur 2 (4Fe-4S) (By similarity).
FT METAL 137 137 Iron-sulfur 2 (4Fe-4S) (By similarity).
FT METAL 176 176 Iron-sulfur 3 (4Fe-4S) (By similarity).
FT METAL 179 179 Iron-sulfur 3 (4Fe-4S) (By similarity).
FT METAL 182 182 Iron-sulfur 3 (4Fe-4S) (By similarity).
FT METAL 226 226 Iron-sulfur 3 (4Fe-4S) (By similarity).
FT MOD_RES 84 84 N6-acetyllysine (By similarity).
FT MOD_RES 467 467 N6-acetyllysine (By similarity).
FT MOD_RES 499 499 N6-acetyllysine (By similarity).
FT MOD_RES 709 709 N6-acetyllysine (By similarity).
FT VAR_SEQ 1 57 Missing (in isoform 4).
FT /FTId=VSP_043727.
FT VAR_SEQ 1 2 ML -> MW (in isoform 3).
FT /FTId=VSP_043728.
FT VAR_SEQ 1 1 M -> MRIRGSSGTLSRINM (in isoform 2).
FT /FTId=VSP_042682.
FT VAR_SEQ 3 113 Missing (in isoform 3).
FT /FTId=VSP_043729.
FT VAR_SEQ 52 87 Missing (in isoform 5).
FT /FTId=VSP_045864.
FT VARIANT 241 241 R -> Q (in dbSNP:rs17856901).
FT /FTId=VAR_025511.
FT VARIANT 241 241 R -> W (in MT-C1D).
FT /FTId=VAR_019532.
FT VARIANT 252 252 D -> G (in MT-C1D).
FT /FTId=VAR_019533.
FT VARIANT 253 253 V -> G.
FT /FTId=VAR_069506.
FT VARIANT 649 649 V -> F (in dbSNP:rs1044049).
FT /FTId=VAR_018463.
FT CONFLICT 8 8 K -> R (in Ref. 1; CAA43412).
FT CONFLICT 417 417 R -> W (in Ref. 1; CAA43412).
FT CONFLICT 572 572 H -> L (in Ref. 2; BAG58551).
FT CONFLICT 691 691 I -> L (in Ref. 1; CAA43412).
SQ SEQUENCE 727 AA; 79468 MW; 9C35F4B8294771FB CRC64;
MLRIPVRKAL VGLSKSPKGC VRTTATAASN LIEVFVDGQS VMVEPGTTVL QACEKVGMQI
PRFCYHERLS VAGNCRMCLV EIEKAPKVVA ACAMPVMKGW NILTNSEKSK KAREGVMEFL
LANHPLDCPI CDQGGECDLQ DQSMMFGNDR SRFLEGKRAV EDKNIGPLVK TIMTRCIQCT
RCIRFASEIA GVDDLGTTGR GNDMQVGTYI EKMFMSELSG NIIDICPVGA LTSKPYAFTA
RPWETRKTES IDVMDAVGSN IVVSTRTGEV MRILPRMHED INEEWISDKT RFAYDGLKRQ
RLTEPMVRNE KGLLTYTSWE DALSRVAGML QSFQGKDVAA IAGGLVDAEA LVALKDLLNR
VDSDTLCTEE VFPTAGAGTD LRSNYLLNTT IAGVEEADVV LLVGTNPRFE APLFNARIRK
SWLHNDLKVA LIGSPVDLTY TYDHLGDSPK ILQDIASGSH PFSQVLKEAK KPMVVLGSSA
LQRNDGAAIL AAVSSIAQKI RMTSGVTGDW KVMNILHRIA SQVAALDLGY KPGVEAIRKN
PPKVLFLLGA DGGCITRQDL PKDCFIIYQG HHGDVGAPIA DVILPGAAYT EKSATYVNTE
GRAQQTKVAV TPPGLAREDW KIIRALSEIA GMTLPYDTLD QVRNRLEEVS PNLVRYDDIE
GANYFQQANE LSKLVNQQLL ADPLVPPQLT IKDFYMTDSI SRASQTMAKC VKAVTEGAQA
VEEPSIC
//

MIM 157655
*RECORD*
*FIELD* NO
157655
*FIELD* TI
*157655 NADH-UBIQUINONE OXIDOREDUCTASE Fe-S PROTEIN 1; NDUFS1
;;COMPLEX I, MITOCHONDRIAL RESPIRATORY CHAIN, 75-KD SUBUNIT
read more*FIELD* TX

DESCRIPTION

The multisubunit NADH:ubiquinone oxidoreductase (complex I; EC 1.6.5.3)
is the first enzyme complex in the electron transport chain of
mitochondria. By use of chaotropic agents, complex I can be fragmented
into 3 different fractions: a flavoprotein fraction, an iron-sulfur
protein (IP) fraction, and a hydrophobic protein (HP) fraction. The IP
fraction contains NDUFS1, NDUFS2 (602985), NDUFS3 (603846), NDUFS4
(602694), NDUFS5 (603847), NDUFS6 (603848), and NDUFA5 (601677) (Loeffen
et al., 1998). The 75-kD Fe-S protein of the mitochondrial NADH-CoQ
reductase is an integral part of the respiratory chain and is one of
several Fe-S proteins operating within complex I of the mitochondrial
respiratory chain assembly (Ragan, 1987). Functionally, this enzyme is
thought to be the first of the Fe-S proteins to accept electrons from an
NADH-flavoprotein reductase within the complex.

CLONING

By screening a human hepatoma cDNA expression library with antibodies
against complex I, Chow et al. (1991) isolated a partial cDNA encoding a
protein similar to the bovine 75-kD Fe-S protein. The authors used PCR
to isolate additional kidney cDNAs corresponding to the entire coding
region of the human gene. The predicted human 75-kD Fe-S protein
contains 727 amino acids including a 23-amino acid presequence and is
97% identical to the bovine homolog. Various cysteine-rich motifs
similar to those found in rubredoxins, in the Reiske Fe-S protein in
Neurospora, and in 4Fe-4S ferredoxins are present in the protein
sequence. Northern blot analysis revealed that the gene encoding the
75-kD Fe-S protein is expressed as a 2.6-kb mRNA in skin fibroblasts.

GENE FUNCTION

Ricci et al. (2004) identified NDUFS1 as a critical caspase substrate in
mitochondria. Cells expressing a noncleavable mutant of NDUFS1 sustained
mitochondrial transmembrane potential and ATP levels during apoptosis,
and reactive oxygen species production in response to apoptotic stimuli
was dampened. While cytochrome c release and DNA fragmentation were
unaffected by the noncleavable NDUFS1 mutant, mitochondrial morphology
of dying cells was maintained and loss of plasma membrane integrity was
delayed. Ricci et al. (2004) concluded that caspase cleavage of NDUFS1
is required for several mitochondrial changes associated with apoptosis.

MAPPING

Duncan et al. (1992) showed by isotopic in situ hybridization that the
gene encoding the 75-kD Fe-S protein, NDUFS1, is located in the 2q33-q34
region.

MOLECULAR GENETICS

In 3 of 36 patients with isolated mitochondrial complex I deficiency
(252010), Benit et al. (2001) identified 5 different point mutations and
1 large-scale deletion in the NDUFS1 gene (see, e.g.,
157655.0001-157655.0003).

In 4 patients from 3 families with severe mitochondrial complex I
deficiency and very low complex I activity (less than 30% of normal),
Hoefs et al. (2010) identified 5 different biallelic mutations in the
NDUFS1 gene (see, e.g., 157655.0006-157655.0008). Patient cells also
showed decreased amounts of assembled complex I and accumulation of
subcomplexes, indicating disturbance in the assembly or stability of
complex I. All patients had a severe, progressive disease course
resulting in death in childhood due to neurologic disability. Brain MRI
performed in 2 patients showed severe and progressive white matter
abnormalities. Hoefs et al. (2010) suggested that patients with very low
complex I deficiency should be specifically screened for NDUFS1
mutations.

*FIELD* AV
.0001
MITOCHONDRIAL COMPLEX I DEFICIENCY
NDUFS1, 3-BP DEL, 664CAT

In a patient with mitochondrial complex I deficiency (252010), Benit et
al. (2001) identified compound heterozygosity for 2 mutations in the
NDUFS1 gene: a 3-bp deletion (664delCAT), resulting in the in-frame
deletion of ile222, and a 755A-G transition, resulting in an
asp252-to-gly substitution (D252G; 157655.0002). The proband had
unrelated healthy parents and was normal until age 4 months, when he
developed psychomotor retardation with hypotonia. At age 7 months, he
presented with nystagmus and bilateral optic atrophy. Leukodystrophy,
lactic acidosis, and hyperlactatorachia were noted. He died at age 10
months. An older sister with similar findings died at age 7 months, and
an older brother developed 2 episodes of ataxia and mild psychomotor
retardation at age 2 years.

.0002
MITOCHONDRIAL COMPLEX I DEFICIENCY
NDUFS1, ASP252GLY

See 157655.0001 and Benit et al. (2001).

.0003
MITOCHONDRIAL COMPLEX I DEFICIENCY
NDUFS1, ARG241TRP

In a child with mitochondrial complex I deficiency (252010), Benit et
al. (2001) identified a 721C-T transition in the NDUFS1 gene, resulting
in an arg241-to-trp (R241W) substitution. The patient was the offspring
of healthy unrelated parents and was normal until age 2 months, when he
presented with growth retardation, axial hypotonia, hepatomegaly, and
persistent hyperlactatemia. Magnetic resonance imaging showed
hyperintensity of basal ganglia. The child later developed macrocytic
anemia and dystonia. He died suddenly at age 5 months. His older sister
presented with growth retardation, macrocytic anemia, and metabolic
acidosis at age 3 months and died shortly thereafter in an acute episode
of hyperlactatemia.

.0004
MITOCHONDRIAL COMPLEX I DEFICIENCY
NDUFS1, LEU231VAL

In a Spanish child with mitochondrial complex I deficiency (252010) and
features of Leigh syndrome (256000), Martin et al. (2005) identified a
homozygous 691C-G transversion in the NDUFS1 gene, resulting in a
leu231-to-val (L231V) substitution in a highly conserved region near the
C terminus of the protein thought to be involved in the ligation of
iron-sulfur clusters. The parents were heterozygous for the mutation.
The mutation was not identified in 200 control chromosomes.

.0005
MITOCHONDRIAL COMPLEX I DEFICIENCY
NDUFS1, THR595ALA

In 2 sibs, born of consanguineous parents, with complex I deficiency
(252010), Ferreira et al. (2011) identified a homozygous 1783A-G
transition in the NDUFS1 gene, resulting in a thr595-to-ala (T595A)
substitution in a highly conserved residue. Each unaffected parent was
heterozygous for the mutation, which was not found in 200 control
chromosomes. The patients had a neurodegenerative disorder of the white
matter beginning around the first year of life. One showed loss of early
developmental milestones and the other showed early delayed psychomotor
development and irritability. Both had dystonic posturing, difficulty
swallowing, and increased lactate in bodily fluids. Although there were
episodes of deterioration, there was also some improvement in symptoms
with age. Brain MRI showed progressive cavitating leukoencephalopathy
with multiple cystic lesions in the white matter. Muscle biopsy of 1 sib
showed significantly decreased complex I activity (45% of controls) and
a decreased amount of complex I subunits. Reduced fully assembled
complex I was seen in mitochondria isolated from fibroblasts from the
other sib, but only under stress conditions. Modeling of the mutation in
yeast showed that reduced complex I activity was due mainly to decreased
accumulation of fully assembled active complex I in the membrane and not
to diminished activity of the mutant enzyme.

.0006
MITOCHONDRIAL COMPLEX I DEFICIENCY
NDUFS1, ASP619ASN

In a girl with mitochondrial complex I deficiency (252010), Hoefs et al.
(2010) identified compound heterozygosity for 2 mutations in the NDUFS1
gene: a c.1855G-A transition resulting in an asp619-to-asn (D619N)
substitution at a highly conserved residue in the molybdopterin
oxidoreductase domain, and a c.1669C-T transition resulting in an
arg557-to-ter (R557X; 157655.0002) substitution. Each unaffected parent
carried 1 of the mutations, which were not found in 100 controls. She
had normal development in the first months of life, but showed crying
and regression of motor skills at age 8 months. Brain MRI showed
progressive leukodystrophic lesions with rarefaction and atrophy of the
corpus callosum. The disease course was progressive, and she developed
spasticity, microcephaly, mental retardation, and neuropathy. She died
at age 12 years. Patient fibroblasts showed extremely low complex I
activity (27% of controls), as well as decreased assembly of complex I
and accumulation of subcomplexes.

.0007
MITOCHONDRIAL COMPLEX I DEFICIENCY
NDUFS1, ARG557TER

See 157655.0001 and Hoefs et al. (2010).

.0008
MITOCHONDRIAL COMPLEX I DEFICIENCY
NDUFS1, ARG408CYS

In a boy, born of consanguineous parents, with complex I deficiency
(252010), Hoefs et al. (2010) identified a homozygous c.1222C-T
transition in the NDUFS1 gene, resulting in an arg408-to-cys (R408C)
substitution at a highly conserved residue in the molybdopterin
oxidoreductase domain. In infancy, the patient showed decreased
spontaneous movements, abnormal breathing pattern, feeding problems, and
hypotonia, resulting in death at age 8 months. One of his brothers had
the same mutation and a similar clinical picture, with increased
lactate, pyruvate, and alanine in both plasma and CSFS, consistent with
mitochondrial dysfunction. Patient fibroblasts showed severely reduced
complex I activity (20% of controls). The mutation was not found in 100
controls.

*FIELD* RF
1. Benit, P.; Chretien, D.; Kadhom, N.; de Lonlay-Debeney, P.; Cormier-Daire,
V.; Cabral, A.; Peudenier, S.; Rustin, P.; Munnich, A.; Rotig, A.
: Large-scale deletion and point mutations of the nuclear NDUFV1 and
NDUFS1 genes in mitochondrial complex I deficiency. Am. J. Hum. Genet. 68:
1344-1352, 2001.

2. Chow, W.; Ragan, I.; Robinson, B. H.: Determination of the cDNA
sequence for the human mitochondrial 75-kDa Fe-S protein of NADH-coenzyme
Q reductase. Europ. J. Biochem. 201: 547-550, 1991.

3. Duncan, A. M. V.; Chow, W.; Robinson, B. H.: Localization of the
human 75-kDal Fe-S protein of NADH-coenzyme Q reductase gene (NDUFS1)
to 2q33-q34. Cytogenet. Cell Genet. 60: 212-213, 1992.

4. Ferreira, M.; Torraco, A.; Rizza, T.; Fattori, F.; Meschini, M.
C.; Castana, C.; Go, N. E.; Nargang, F. E.; Duarte, M.; Piemonte,
F.; Dionisi-Vici, C.; Videira, A.; Vilarinho, L.; Santorelli, F. M.;
Carrozzo, R.; Bertini, E.: Progressive cavitating leukoencephalopathy
associated with respiratory chain complex I deficiency and a novel
mutation in NDUFS1. Neurogenetics 12: 9-17, 2011.

5. Hoefs, S. J. G.; Skjeldal, O. H.; Rodenburg, R. J.; Nedregaard,
B.; van Kaauwen, E. P. M.; Spiekerkotter, U.; von Kleist-Retzow, J.-C.;
Smeitink, J. A. M.; Nijtmans, L. G.; van den Heuvel, L. P.: Novel
mutations in the NDUFS1 gene cause low residual activities in human
complex I deficiencies. Molec. Genet. Metab. 100: 251-256, 2010.

6. Loeffen, J. L. C. M.; Triepels, R. H.; van den Heuvel, L. P.; Schuelke,
M.; Buskens, C. A. F.; Smeets, R. J. P.; Trijbels, J. M. F.; Smeitink,
J. A. M.: cDNA of eight nuclear encoded subunits of NADH:ubiquinone
oxidoreductase: human complex I cDNA characterization completed. Biochem.
Biophys. Res. Commun. 253: 415-422, 1998.

7. Martin, M. A.; Blazquez, A.; Gutierrez-Solana, L. G.; Fernandez-Moreira,
D.; Briones, P.; Andreu, A. L.; Garesse, R.; Campos, Y.; Arenas, J.
: Leigh syndrome associated with mitochondrial complex I deficiency
due to a novel mutation in the NDUFS1 gene. Arch. Neurol. 62: 659-661,
2005.

8. Ragan, C. I.: Structure of NADH-ubiquinone reductase (complex
I). Curr. Top. Bioenerg. 15: 1-36, 1987.

9. Ricci, J.-E.; Munoz-Pinedo, C.; Fitzgerald, P.; Bailly-Maitre,
B.; Perkins, G. A.; Yadava, N.; Scheffler, I. E.; Ellisman, M. H.;
Green, D. R.: Disruption of mitochondrial function during apoptosis
is mediated by caspase cleavage of the p75 subunit of complex I of
the electron transport chain. Cell 117: 773-786, 2004.

*FIELD* CN
Cassandra L. Kniffin - updated: 5/23/2013
Cassandra L. Kniffin - updated: 6/12/2012
Cassandra L. Kniffin - updated: 8/29/2005
Stylianos E. Antonarakis - updated: 8/6/2004
Victor A. McKusick - updated: 6/20/2001
Rebekah S. Rasooly - updated: 5/26/1999

*FIELD* CD
Victor A. McKusick: 7/1/1993

*FIELD* ED
carol: 06/07/2013
ckniffin: 5/23/2013
ckniffin: 5/8/2013
alopez: 6/18/2012
ckniffin: 6/12/2012
carol: 10/21/2011
carol: 9/21/2005
ckniffin: 8/29/2005
mgross: 8/6/2004
mgross: 3/17/2004
mgross: 6/20/2001
terry: 6/20/2001
alopez: 5/26/1999
carol: 8/19/1998
carol: 6/23/1998
terry: 6/1/1998
alopez: 7/31/1997
mimadm: 5/17/1994
carol: 7/9/1993
carol: 7/6/1993
carol: 7/1/1993

MIM 252010
*RECORD*
*FIELD* NO
252010
*FIELD* TI
#252010 MITOCHONDRIAL COMPLEX I DEFICIENCY
;;NADH:Q(1) OXIDOREDUCTASE DEFICIENCY;;
read moreNADH-COENZYME Q REDUCTASE DEFICIENCY;;
MITOCHONDRIAL NADH DEHYDROGENASE COMPONENT OF COMPLEX I, DEFICIENCY
OF
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
isolated deficiency of mitochondrial respiratory chain complex I can be
caused by mutations in multiple different genes, both nuclear-encoded
and mitochondrial-encoded. Human complex I (NADH-ubiquinone reductase;
EC 1.6.5.3) consists of at least 36 nuclear-encoded and 7
mitochondrial-encoded subunits; mutations in any of these subunits can
cause the disorder (see Genetic Heterogeneity of Complex I Deficiency
below).

DESCRIPTION

Isolated complex I deficiency is the most common enzymatic defect of the
oxidative phosphorylation disorders (McFarland et al., 2004; Kirby et
al., 2004). It causes a wide range of clinical disorders, ranging from
lethal neonatal disease to adult-onset neurodegenerative disorders.
Phenotypes include macrocephaly with progressive leukodystrophy,
nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver
disease, Leigh syndrome (256000), Leber hereditary optic neuropathy
(535000), and some forms of Parkinson disease (see 556500) (Loeffen et
al., 2000; Pitkanen et al., 1996; Robinson, 1998).

- Genetic Heterogeneity of Complex I Deficiency

Mitochondrial complex I deficiency shows extreme genetic heterogeneity
and can be caused by mutation in nuclear-encoded genes or in
mitochondrial-encoded genes. There are no obvious genotype-phenotype
correlations, and inference of the underlying basis from the clinical or
biochemical presentation is difficult, if not impossible (summary by
Haack et al., 2012). However, the majority of cases are caused by
mutations in nuclear-encoded genes (Loeffen et al., 2000; Triepels et
al., 2001).

Complex I deficiency with autosomal recessive inheritance results from
mutation in nuclear-encoded subunit genes, including NDUFV1 (161015),
NDUFV2 (600532), NDUFS1 (157655), NDUFS2 (602985), NDUFS3 (603846),
NDUFS4 (602694), NDUFS6 (603848), NDUFS7 (601825), NDUFS8 (602141),
NDUFA2 (602137), NDUFA11 (612638), NDUFAF3 (612911), NDUFA10 (603835),
NDUFB3 (603839), NDUFB9 (601445), and the complex I assembly genes
B17.2L (609653), HRPAP20 (611776), C20ORF7 (612360), NUBPL (613621), and
NDUFAF1 (606934). The disorder can also be caused by mutation in other
nuclear-encoded genes, including FOXRED1 (613622), ACAD9 (611103; see
611126), and MTFMT (611766; see 256000).

X-linked inheritance is observed with mutations in the NDUFA1 gene
(300078).

Complex I deficiency with mitochondrial inheritance has been associated
with mutation in 6 mitochondrial-encoded components of complex I: MTND1
(516000), MTND2 (516001), MTND3 (516002), MTND4 (516003), MTND5
(516005), MTND6 (516006). Most of these patients have a phenotype of
Leber hereditary optic neuropathy (LHON; 535000) or Leigh syndrome
(256000). Features of complex I deficiency may also be caused by
mutation in other mitochondrial genes, including MTTS2 (590085).

CLINICAL FEATURES

- Patients with Unknown Mutations

Morgan-Hughes et al. (1979) presented the first report of isolated
complex I deficiency. Two sisters had a mitochondrial myopathy
characterized by weakness, marked exercise intolerance, and fluctuating
lactic acidemia. Increased weakness was precipitated by unaccustomed
exertion, fasting, or alcohol. During exercise, blood lactate and
pyruvate levels rose abruptly and markedly. Mitochondrial respiratory
rates were greatly decreased with all NAD-linked substrates, but normal
with succinate and with TMPD plus ascorbate. Mitochondrial cytochrome
components were normal. Morgan-Hughes et al. (1979) concluded that the
defect was at the level of the NADH-CoQ reductase complex.

Land et al. (1981) reported a young man with weakness, exercise
intolerance, muscle wasting, and exercise-induced lactic acidosis.
Biochemical studies showed deficiency of NADH-cytochrome b reductase.
The defect appeared to be situated between NADH dehydrogenase and the
CoQ-cytochrome b complex. Land et al. (1981) postulated a derangement of
a nonheme iron-sulfur center.

Moreadith et al. (1984) reported a male infant with complex I deficiency
who developed respiratory distress and hypoglycemia on the first day of
life. At 6 weeks, he showed generalized hypotonia and concentric
biventricular cardiac hypertrophy on echocardiography. Lactic acidemia
was progressive, and the child died at 16 weeks of age. Skeletal muscle
biopsy showed giant mitochondria in which both inner and outer membranes
were arranged in whorls. Biochemical studies of mitochondria from 4
organs showed a moderate to profound decrease in the ability to oxidize
pyruvate, malate plus glutamate, citrate and other NAD-linked
respiratory substrates. Oxidation of succinate was normal. Further
studies localized the defect to the inner membrane mitochondrial
NADH-ubiquinone oxidoreductase. Electron paramagnetic resonance
spectroscopy showed almost total loss of the iron-sulfur clusters of
complex I. The most pronounced deficiency was in skeletal muscle, the
least in kidney mitochondria. There was no record of a similar problem
in the family and the parents were not related. Since the parents
subsequently had a normal male child, Moreadith et al. (1984) excluded
mitochondrial inheritance and suggested either autosomal recessive
inheritance or a de novo dominant mutation.

In a later study on tissue from the same patient, Moreadith et al.
(1987) found that antisera against complex I immunoprecipitated
NADH-ferricyanide reductase from the control but not the patient's
mitochondria. Immunoprecipitation and SDS-PAGE of complex I polypeptides
demonstrated that most of the 25 polypeptides comprising complex I were
present in the affected mitochondria. A more detailed analysis using
subunit selective antisera against the main polypeptides of the
iron-protein fragments of complex I showed a selective absence of the
75- and 13-kD polypeptides, suggesting a deficiency of at least 2
polypeptides comprising the iron-protein fragment of complex I.
Moreadith et al. (1987) hypothesized that the genetic defect involved
transcription or translation of the polypeptides, the transport of these
polypeptides into the mitochondria, or the site of assembly of complex
I.

Hoppel et al. (1987) investigated a mitochondrial defect in a male
infant with fatal congenital lactic acidosis, high lactate-to-pyruvate
ratio, hypotonia, and cardiomyopathy. His sister had died with a similar
disorder. Resting oxygen consumption was 150% of controls. Pathologic
findings included increased numbers of skeletal muscle mitochondria
(many with proliferated, concentric cristae), cardiomegaly, fatty
infiltration of the viscera, and spongy encephalopathy. Mitochondria
from liver and muscle biopsies oxidized NADH-linked substrates at rates
20 to 50% of controls, whereas succinate oxidation by muscle
mitochondria was increased. Mitochondrial NADH dehydrogenase activity
(complex I) was 0 to 10% of controls, whereas activity of other electron
transport complexes in related enzymes was normal. Hoppel et al. (1987)
suggested a familial deficiency of a component of mitochondrial NADH
dehydrogenase proximal to the rotenone-sensitive site.

Wijburg et al. (1989) reported a sibship born to healthy first-cousin
Moroccan parents with 2 well-studied children with severe congenital
lactic acidosis as well as 4 others with a clinical history compatible
with the same defect. Treatment initially by artificial respiration and
peritoneal dialysis followed later by high doses of menadione effected a
remarkable recovery. Despite the parental consanguinity, Barth et al.
(1989) suggested that the defect in this family involved the
mitochondrial genome: they detected a possible deletion in the
mitochondrial-encoded MTND3 protein in skeletal muscle.

Slipetz et al. (1991) studied 2 unrelated patients with complex I
deficiency with different phenotypes. One patient had hypotonia,
seizures, and hepatomegaly, and died of lactic acidosis on day 13 of
life. Biochemical analysis of complex I subunits showed absence of a
20-kD protein predicted to be encoded by the nuclear genome. Complex I
activity was 6% of control values. The other child had marked growth and
developmental delay, and showed altered neurologic function and seizures
beginning at age 8 years. Other features included ptosis, sensorineural
hearing loss, hypotonia, incoordination, and hyporeflexia. Mild facial
coarseness was also observed. No complex I subunit abnormalities were
detected by immunoprecipitation or Western blot analysis, but complex I
activity was 15% of control values.

Bentlage et al. (1995) showed deficits of specific complex I protein
subunits in patients with complex I deficiency.

Dionisi-Vici et al. (1997) reported 2 infant sibs with fatal progressive
macrocephaly and hypertrophic cardiomyopathy. Onset of symptoms was at
the end of the first month of life with massive brain swelling. Light
microscopy showed extensive small-vessel proliferation and gliosis.
Complex I deficiency was detected in cultured fibroblasts, skeletal
muscle, and heart muscle.

Procaccio et al. (1999) reported 2 unrelated patients with fatal
infantile lactic acidosis associated with isolated complex I deficiency.
Reexpression of complex I subunits and recovery of complex I activity in
patients' mitochondria after transnuclear complementation by nuclei from
cells without mitochondria enabled the authors to infer the nuclear DNA
origin of the defects in both patients. Patient 1 showed reduced amounts
of the 24- and 51-kD subunits and normal amounts of all the other
investigated subunits. Patient 2 showed severely decreased amounts of
all the investigated subunits. Patient 1 developed generalized hypotonia
with poor gesticulation in the first 24 hours of life. By day 2, he was
very floppy with poor response to painful stimuli and required
ventilatory assistance. Hepatic enlargement was noticed, and chest
x-rays showed slight cardiomegaly. Cranial ultrasonography showed brain
edema, and severe lactic acidosis was detected. The patient went into a
deep coma and died at 11 days. Patient 2 vomited frequently in the first
2 weeks of life and at 5 weeks showed deterioration of neurologic status
with hypotonia, weakness, and lethargy. In the first month, the head
circumference was noted to be rapidly increasing from 33 to 40 cm.
Computed tomographic scan showed a very hypodense brain with increased
brain volume and extensive cerebral edema. Marked metabolic acidosis
with hyperlactic acidemia was demonstrated. Despite intensive care, the
neurologic state worsened rapidly and brain death occurred at 6 weeks of
age. Autopsy showed acute necrotizing encephalopathy, but no
hypertrophic cardiomyopathy.

In a study of 157 patients with respiratory chain defects, von
Kleist-Retzow et al. (1998) found complex I deficiency in 33% and
combined complex I and IV deficiency in another 28%. The main clinical
features in this series were truncal hypotonia (36%), antenatal (20%)
and postnatal (31%) growth retardation, cardiomyopathy (24%),
encephalopathy (20%), and liver failure (20%). No correlation was found
between the type of respiratory chain defect and the clinical
presentation, but complex I and complex I+IV deficiencies were
significantly more frequent in cases of cardiomyopathy (p less than
0.01) and hepatic failure (p less than 0.05), respectively. The sex
ratio was skewed toward males being affected with complex I deficiency.
A high rate of parental consanguinity was observed in complex IV (20%)
and complex I+IV (28%) deficiencies.

Loeffen et al. (2000) retrospectively examined clinical and biochemical
characteristics of 27 patients, all of whom presented in infancy and
young childhood with isolated enzymatic complex I deficiency established
in cultured skin fibroblasts; common pathogenic mtDNA point mutations
and major rearrangements were absent. Clinical phenotypes included Leigh
syndrome in 7 patients, Leigh-like syndrome in 6, fatal infantile lactic
acidosis in 3, neonatal cardiomyopathy with lactic acidosis in 3,
macrocephaly with progressive leukodystrophy in 2, and a residual group
of unspecified encephalomyopathy in 6, subdivided into progressive (in
4) and stable (in 2) variants.

- Patients with Identified Mutations in Nuclear-Encoded Genes

Schuelke et al. (1999) reported 2 brothers with complex I deficiency
caused by mutations in the NDUFV1 gene (161015.0001; 161015.0002).
Pregnancy, delivery, and early infancy were normal in both children. At
the age of 5 months, they presented with repeated vomiting and developed
strabismus, progressive muscular hypotonia, myoclonic epilepsy, and
psychomotor regression. Cranial CT scans showed brain atrophy, but
cranial MRIs were not available to confirm Leigh syndrome. Lactate and
pyruvate concentrations in blood and cerebrospinal fluid were elevated.
Isolated complex I deficiency was demonstrated in muscle and cultured
fibroblasts. The boys died at 14 and 17 months from aspiration
pneumonia. Schuelke et al. (1999) reported another child with complex I
deficiency and mutation in the NDUFV1 gene (161015.0003). Features
included infantile myoclonic epilepsy, spasticity, psychomotor
regression, and macrocephaly. Serial cranial MRI scans showed brain
atrophy and a progressive macrocytic leukodystrophy. At age 10 years,
she had severe spasticity and blindness.

Benit et al. (2001) reported an infant with complex I deficiency caused
by mutations in the NDUFV1 gene (161015.0004; 161015.0005). He was first
hospitalized at age 1 year for seizures and moderately elevated levels
of plasma lactate. Other features included cerebellar ataxia,
psychomotor regression, strabismus, and ptosis. Magnetic resonance
imaging showed brain atrophy in multiple symmetric areas of
hyperintensity in the brainstem. He died at age 3 years of an acute
episode of metabolic acidosis.

Van den Heuvel et al. (1998) reported a patient with fatal multisystemic
complex I deficiency and homozygous mutation in the NDUFS4 gene
(602694.0001). He had normal muscle morphology and a remarkably
nonspecific fatally progressive course without increased lactate
concentrations in body fluids. He presented at 8 months of age with
severe vomiting, failure to thrive, and hypotonia. At the age of 13
months, he showed severe psychomotor retardation, convulsions,
bradypnea, cyanosis, hypotonia, and depressed tendon reflexes. Cerebral
MRI showed generalized brain atrophy and symmetric basal ganglia
abnormalities. He died of cardiorespiratory failure at the age of 16
months.

Loeffen et al. (2001) reported 3 unrelated families with isolated
complex I deficiency caused by mutations in the nuclear-encoded NDUFS2
gene (602985.0001-602985.0003). The first family, which was
consanguineous, had 2 affected children. The first affected child, a
male, was normal until 6 months of age when he manifested neurologic
regression, with horizontal nystagmus and bilateral muscle atrophy with
decreased axial muscle tone. Brain CT showed bilateral hypodensities of
the basal ganglia, and echocardiogram showed left ventricular
hypertrophy. He died of apnea at 24 months of age. The third-born child,
a female, had similar symptoms except that they presented earlier and
her deterioration was faster. In the second family, the affected child
had neonatal onset of severe lactic acidosis and hypertrophic
cardiomyopathy. She died at 4 days of age. The third family, which was
consanguineous, had 4 children, 3 of whom died with a clinical phenotype
including failure to thrive, horizontal nystagmus, ataxia, hypotonia,
and pallor of the optic discs. CT and MRI findings revealed hypodensity
of the basal ganglia and midbrain.

Benit et al. (2003) reported a male infant, born of consanguineous
parents of African ancestry, who had complex I deficiency caused by
mutation in the NDUFV2 gene (600532.0002). He presented at 5 days of
life with hypertrophic cardiomyopathy, truncal hypotonia, and
encephalopathy. Persistent hyperlactatemia was observed and he died at 3
months of age. Two younger brothers subsequently died of hypertrophic
cardiomyopathy in their first year of life. Benit et al. (2003) noted
that the phenotype was similar to that described by Loeffen et al.
(2001) in patients with mutations in the NDUFS2 gene.

Benit et al. (2004) reported a boy from Reunion Island with complex I
deficiency and features of Leigh syndrome caused by mutations in the
NDUFS3 gene (603846.0001-603846.0002). The boy's psychomotor development
was normal until 9 years of age, although a single episode of febrile
convulsions occurred at 9 months of age and kyphoscoliosis had been
noted. Persistent stiff neck had developed at the age of 9 years. He
gradually developed severe axial dystonia with oral and pharyngeal motor
dysfunction, dysphagia, and a tetraparetic syndrome. At 10 years of age,
mild elevation of CFS lactate was found. Complex I deficiency was
identified by skeletal muscle biopsy. Two years later, he developed
acute pancreatitis and severe respiratory insufficiency. He died 1.5
years later after rapid multisystem deterioration.

In 2 unrelated patients with mitochondrial complex I deficiency, Kirby
et al. (2004) reported 2 unrelated patients with complex I deficiency
caused by different homozygous mutations in the NDUFS6 gene
(603848.0001; 603848.0002). Both patients had lethal infantile
mitochondrial disease with death within the first 2 weeks of life.
Spiegel et al. (2009) reported 2 unrelated infants, both of Jewish
Caucasus descent, with fatal infantile lactic acidosis resulting from
severe complex I deficiency due to a homozygous mutation in the NDUFS6
gene (C115Y; 603848.0003). Complex I activity was about 50% or less in
muscle biopsies. The Jewish population of the Caucasus region of central
Asia is believed to have originated from southern Iran and is a
genetically isolated community.

Martin et al. (2005) reported a Spanish child with complex I deficiency
and features of Leigh syndrome caused by a homozygous mutation in the
nuclear-encoded NDUFS1 gene (157655.0004). At 8.5 months of age, she was
hospitalized for recurrent vomiting, hypotonia, and growth retardation.
Other findings included irritability, horizontal nystagmus,
hyperreflexia, and bilateral lesions in the substantia nigra and
midbrain. There was increased lactic acid in serum and CSF. Her status
worsened and she died at age 14 months. A younger brother with a similar
clinical picture died at age 8 months. Biochemical studies showed that
skeletal muscle complex I activity was reduced to 25% normal values.

Ogilvie et al. (2005) reported a patient with a severe childhood-onset
progressive encephalopathy caused by mutation in the gene encoding
mimitin (609653.0001). The authors noted that the clinical presentation
of the patient did not resemble that seen in Leigh syndrome, nor did it
resemble that of most other patients with mitochondrial disease. The
patient shared most of the characteristic diagnostic criteria for
leukoencephalopathy with vanishing white matter (603896), which is
caused by mutations in various genes encoding cytosolic translation
factors. Ogilvie et al. (2005) remarked that the fact that no other
patients with mutations in the mimitin gene have been found may reflect
the lack of association of this clinical phenotype with mitochondrial
disease.

In 2 unrelated Spanish male patients with complex I deficiency,
Fernandez-Moreira et al. (2007) identified hemizygous mutations in the
NDUFA1 gene (300078.0001 and 300078.0002, respectively). One of the
patients had a severe presentation consistent with Leigh syndrome and
early death, and the other had developmental delay and myoclonic
epilepsy.

Berger et al. (2008) reported 3 consanguineous families of Israeli
Bedouin origin in which 6 offspring had severe mitochondrial complex I
deficiency associated with a homozygous mutation in the NDUFA11 gene
(612638.0001). Three of the affected children presented with a fatal
infantile metabolic acidosis with death between ages 6 and 40 days.
Affected children in 1 family survived beyond infancy but developed
severe encephalocardiomyopathy with brain atrophy, no motor development,
and hypertrophic cardiomyopathy. The parents of each family did not
recall any relationship between the families, but haplotype analysis
indicated a founder effect. RT-PCR analysis indicated that the mutation
was a leaky mutation, with a 2:1 ratio of wildtype to normal transcript
in patient fibroblasts. Berger et al. (2008) hypothesized a modifier
gene effect or differential transcript expression in various tissues to
explain the different clinical presentations observed in these families.

Sugiana et al. (2008) reported a male infant, born of consanguineous
Egyptian parents, with lethal neonatal complex I deficiency due to
homozygous mutation in the C20ORF7 gene (612360.0001). He had
intrauterine growth retardation, minor facial dysmorphism, unusual hair
patterning, abnormal toes, and a small sacral pit. Cerebral ultrasound
showed agenesis of the corpus callosum and ventricular septation. He
also had a congenital left diaphragmatic hernia, adrenal insufficiency,
and increased lactate in the blood and CSF. He died of cardiorespiratory
arrest due to progressive lactic acidosis on day 7. Prenatal diagnosis
identified 2 additional affected fetuses in subsequent pregnancies.

Gerards et al. (2010) reported 2 adult sibs, born of consanguineous
Moroccan parents, who developed symptoms of complex I deficiency with
Leigh syndrome in early childhood associated with a homozygous mutation
in the C20ORF7 gene (L159F; 612360.0002). The phenotype was less severe
than that described by Sugiana et al. (2008). The sibs reported by
Gerards et al. (2010) were aged 29 and 33 years at the time of the
study, but presented with progressive spasticity at age 3, which
subsequently developed into an extrapyramidal choreodystonic movement
disorder. Delayed mental development also occurred, and both were
moderately mentally retarded in their teens. Brain imaging of 1 patient
at age 23 showed a small caudate and hyperintense lesions in the basal
ganglia. Laboratory studies of 1 sib showed increased lactate in the
cerebrospinal fluid, and both sibs had decreased complex I activity in
skeletal muscle (36% and 48% of controls, respectively). A third
affected sib died at age 36 years. Electrophoresis studies of patient
leukocytes showed a decrease of mature complex I levels to 30 to 40% of
normal controls. The clinically unaffected family members who were
heterozygous for the mutation had mature complex I levels of 70 to 90%
of normal controls. The patients studied were also homozygous for a
common hypomorphic P193L variant in the CRLS1 gene (608188), which may
have contributed to the phenotype. Gerards et al. (2010) noted the
phenotypic overlap with infantile bilateral striatal necrosis (IBSN;
271930).

Saada et al. (2009) identified mutations in the NDUFAF3 gene
(612911.0001-612911.0003) in 5 patients with severe complex I
deficiency. All patients died by age 6 months. Three sibs in the first
family presented similarly with severe lactic acidosis. In a second
family, the infant was hypoactive, sucked poorly, had macrocephaly, a
weak cry, wide anterior fontanel, and axial hypotonia. He also had
intermittent tonic movements and pallor of the optic discs. At 3 months
of age, there was no eye contact and marked axial hypotonia with brisk
tendon reflexes. In the third family, a daughter of unrelated parents of
Jewish origin was affected. She developed myoclonic seizures at age 3
months, and brain MRI revealed diffuse brain leukomalacia. She died at
age 6 months of respiratory failure. Complex I activity was decreased in
cells derived from all patients.

Dunning et al. (2007) reported a patient with mitochondrial complex I
deficiency manifest as cardioencephalomyopathy who was compound
heterozygous for 2 mutations in the NDUFAF1 (606934.0001 and
606934.0002). He presented at age 11 months with failure to thrive and
developed severe cardiac failure due to hypertrophic cardiomyopathy in
association with a viral illness at age 15 months. He had developmental
delay, lactic acidosis, and hypotonia. He was diagnosed with
Wolff-Parkinson-White syndrome (194200) at age 3, cortical visual
dysfunction at age 7, and pigmentary retinopathy at age 11. At age 20,
he had mild to moderate intellectual disability and myopathy. Fassone et
al. (2011) identified compound heterozygosity for 2 mutations in the
NDUFAF1 gene (606934.0003 and 606934.0004) in a French infant with fatal
infantile hypertrophic cardiomyopathy and isolated complex I deficiency.
The patient presented at age 6.5 months in cardiogenic shock with
metabolic acidosis after a respiratory viral infection. Echocardiogram
showed pericardial effusion, biventricular hypertrophy, and left
ventricular dysfunction. Skeletal muscle biopsy showed increased lipid
deposition and accumulation of enlarged and abnormal mitochondria and an
isolated severe deficiency of complex I activity (25% of controls). She
died soon after, despite aggressive treatment. Postmortem examination
showed an enlarged globular heart and myocardial hypertrophy with foci
of myofiber loss and replacement fibrosis. Liver histology showed
macrovesicular steatosis, but respiratory chain enzymes in the liver
were normal. NDUFAF1 protein levels were severely reduced in patient
mitoplasts, and there was a severe reduction in the complex I holoenzyme
compared to controls. In addition, patient fibroblasts showed an
accumulation of abnormal complex I assembly intermediates, suggesting a
defect in the assembly process.

Ferreira et al. (2011) reported 2 sibs, born of consanguineous parents,
with complex I deficiency due to a homozygous mutation in the NDUFS1
gene (T595A; 157655.0005). The patients had a neurodegenerative disorder
of the white matter beginning around the first year of life. One showed
loss of early developmental milestones and the other showed early
delayed psychomotor development and irritability. Both had dystonic
posturing, difficulty swallowing, and increased lactate in bodily
fluids. Although there were episodes of deterioration, there was also
some improvement in symptoms with age. Brain MRI showed progressive
cavitating leukoencephalopathy with multiple cystic lesions in the white
matter. Muscle biopsy of 1 sib showed significantly decreased complex I
activity (45% of controls) and a decreased amount of complex I subunits.
Reduced fully assembled complex I was seen in mitochondria isolated from
fibroblasts from the other sib, but only under stress conditions.
Modeling of the mutation in yeast showed that reduced complex I activity
was due mainly to decreased accumulation of fully assembled active
complex I in the membrane and not to diminished activity of the mutant
enzyme.

In a patient with severe complex I deficiency resulting in early death
at age 4 months (patient 2 in Lamont et al., 2004), Calvo et al. (2012)
identified a homozygous mutation in the NDUFB3 gene (W22R; 603839.0001).
The pregnancy was complicated by intrauterine growth retardation and
premature birth at 31 weeks' gestation; respiratory insufficiency
required extensive artificial ventilation in the neonatal period. After
discharge home, she showed hypotonia with poor feeding and significant
lactic acidosis and died unexpectedly at age 4 months. Skeletal muscle
biopsy showed variation in the shape and size of muscle fibers, and
atrophic fibers containing nemaline rods. Biochemical analysis showed
complex I deficiency with borderline low complex III deficiency, the
latter of which may have been an artifact. Fibroblasts from the patient
showed 2 to 15% residual complex I protein levels and activity,
depending on the method used, and expression of wildtype NDUFB3 rescued
the defect.

In 2 brothers with mitochondrial complex I deficiency, Haack et al.
(2012) identified a homozygous mutation in the NDUFB9 gene, (L64P;
601445.0001). The mutation, which was found by sequencing of 75
candidate genes in 152 patients with complex I deficiency, segregated
with the disorder in the family and was not found in the dbSNP or 1000
Genomes databases or in 200 control chromosomes. Patient fibroblasts
showed 39% residual complex I activity, which was restored upon
transfection with wildtype NDUFB9. Western blot analysis showed
decreased levels of NDUFB9 and complex I subunits, consistent with
reduced assembly of the overall complex. The proband had onset in
infancy of progressive hypotonia associated with increased serum
lactate.

Kevelam et al. (2013) reported 6 patients, including 2 sibs, with
complex I deficiency due to biallelic mutations in the NUBPL gene
(613621.0001; 613621.0003-613621.0006). The first mutations were
identified by whole-exome sequencing and confirmed by Sanger sequencing.
All patients had a characteristic leukoencephalopathic pattern on brain
MRI. Initial studies showed confluent or multifocal cerebral white
matter lesions, predominantly affecting the deep white matter while
sparing the U-fibers and internal and external capsules. There were also
signal abnormalities and swelling of the corpus callosum. Signal
abnormalities were present in the cerebellar cortex, but not in the deep
white matter. Later imaging of most patients showed improvement of the
cerebral white matter and corpus callosum abnormalities, but worsening
of the cerebellar abnormalities and additional brainstem abnormalities.
One patient had severe atrophy of the corpus callosum. All patients
developed motor problems due to ataxia in the first years of life, but
other features were somewhat variable: some patients showed continuous
regression and others showed episodic regression. Five patients had
spasticity and only 2 achieved unsupported walking. Cognitive
capabilities varied between normal and significantly deficient. Complex
I deficiency ranged between 27% and 83% of normal, and there was no
correlation between residual complex I activity and clinical severity.

- Patients with Identified Mutations in Mitochondrial-Encoded
Genes

Taylor et al. (2001) reported a 42-year-old man who had onset of
migraine symptoms associated with flashing lights in his vision and
right arm weakness at age 24 years. He subsequently developed myoclonus,
seizures, cognitive decline, ataxia, peripheral neuropathy, eye movement
abnormalities, and optic atrophy. Muscle biopsy showed a deficit (40% of
controls) in complex I activity, but no ragged-red fibers. A
heteroplasmic 10191T-C transition in the mitochondrial-encoded MTND3
gene (516002.0001) was identified in his skeletal muscle (77%) and blood
(14%), as well as in his mother (3% in blood) and 2 unaffected sibs
(barely detectable in blood).

McFarland et al. (2004) identified a mutation in the MTND3 gene
(516002.0001) in a patient with infantile encephalopathy and complex I
deficiency. From birth, he was lethargic with hypotonia, areflexia, and
muscle atrophy. Micrognathia and talipes equinovarus were noted.

Meulemans et al. (2006) reported a 13-year-old boy with combined
deficiency of mitochondrial complex I and IV (220110) associated with a
mutation in the MTTN gene (590010.0003). He had a complex phenotype
involving multiple organ systems. As a young child, he had failure to
thrive, renal failure, and mental retardation. He later developed
progressive ataxia, muscle weakness, seizures, and increased serum and
CSF lactate. Brain CT scan showed basal ganglia calcifications.
Mitochondrial mutation load in the patient's skeletal muscle and
fibroblasts was 97% and 50%, respectively.

Musumeci et al. (2000) studied a 43-year-old man, originally reported by
Bet et al. (1990), who had complained of severe exercise intolerance and
myalgia since childhood. A heteroplasmic 7-bp inversion was found in the
MTND1 gene (516000.0009) Morphologic and biochemical studies of muscles
showed 40% ragged-red fibers and an approximately 40% reduction of
complex I activity consistent with complex I deficiency. At age 43
years, he still complained of exercise intolerance; neurologic
examination showed mild proximal limb weakness but was otherwise normal.
His family history was noncontributory. The mother was alive and had
always been a very active person. Blakely et al. (2006) reported a
female infant with the same 7-bp inversion in the MTND1 gene described
by Musumeci et al. (2000). However, the infant had a much more severe
phenotype and died at age 1 month with marked biventricular hypertrophy,
aortic coarctation, and severe lactic acidosis. The mutation was present
at high levels in several tissues including the heart (85%), muscle
(84%), liver (87%), and cultured skin fibroblasts (70%). Complex I
activity was estimated to be 24% of control values. There was no
evidence of the mutation or respiratory complex I defect in a muscle
biopsy from the patient's mother. Blakely et al. (2006) noted that their
findings illustrated the enormous phenotypic diversity that exists among
pathogenic mtDNA mutations and reemphasized the need for appropriate
genetic counseling for families affected by mtDNA disease.

- Neuroradiologic Features

Lebre et al. (2011) performed a retrospective review of the
neuroradiologic features of 30 patients with complex I deficiency due to
either nuclear (10 patients) or mitochondrial (20 patients) mutations.
All patients had MRI abnormalities in the brainstem that were
hyperintense on T2-weighted images and hypointense on T1-weighted
images. Brainstem lesions were associated with at least 1 striatal
anomaly (putamen or caudate) in 27 of 30 patients. Ten patients had
thalamic anomalies, all of whom also had striatal lesions. Caudate
lesions were more common in patients with mtDNA (50%) compared to those
with nuclear (10%) mutations. Stroke-like lesions predominantly
affecting the gray matter were observed in 40% of patients with mtDNA
mutations, but in none of patients with nuclear mutations. A diffuse
supratentorial leukoencephalopathy involving the deep lobar white matter
was observed in over 50% of patients with nuclear mutations, but in none
of patients with mtDNA mutations. Cerebellar hyperintensities were found
in 45% of patients, regardless of the mutated genome, but cerebellar
atrophy was found only in those with mtDNA mutations. All 10 patients
studied had increased lactate on magnetic resonance spectroscopy.

CLINICAL MANAGEMENT

Bar-Meir et al. (2001) studied the effects of agents commonly used in
the treatment of mitochondrial complex I deficiency in fibroblasts from
a patient with a homozygous mutation in the NDUFS2 gene (602985.0001).
They observed marked improvement with riboflavin, which nearly
normalized the ATP production.

MOLECULAR GENETICS

Smeitink and van den Heuvel (1999) reviewed the nuclear gene mutations
that had been identified in patients with isolated complex I deficiency.
These included a 5-bp duplication in the NDUFS4 gene (602694.0001), a
double mutation in the NDUFS8 gene (P79L, R102H; see 602141.0001), a
mutation in the NDUFS7 gene (V122M; 601825.0001), and 2 mutations in the
NDUFV1 gene: a double mutation (R59X, T423M; see 161015.0001) and a
single-amino acid substitution (A341V; 161015.0003).

In a patient with a severe progressive form of encephalopathy, Ogilvie
et al. (2005) identified a homozygous mutation in the B17.2L gene
(609653.0001).

Calvo et al. (2010) used high-throughput, pooled sequencing of candidate
genes to analyze 60 patients with complex I deficiency. Using this
method, a molecular basis for the disorder was found in 13 of 60
previously unsolved cases. Mutations in known disease-associated genes
were found in 11 patients, and 2 unrelated patients had mutations in 2
novel disease-associated genes: NUBPL (613621) and FOXRED1 (613622).

Fassone et al. (2010) described an Iranian-Jewish child with complex I
deficiency caused by homozygosity for an arg354-to-trp mutation in
FOXRED1 (613622.0003). Silencing of FOXRED1 in human fibroblasts
resulted in reduced complex I steady-state levels and activity, while
lentiviral-mediated FOXRED1 transgene expression rescued complex I
deficiency in the patient fibroblasts. The authors concluded that this
FAD-dependent oxidoreductase is a complex I-specific molecular
chaperone.

In 4 patients from 3 families with severe mitochondrial complex I
deficiency and very low complex I activity (less than 30% of normal),
Hoefs et al. (2010) identified 5 different biallelic mutations in the
NDUFS1 gene (see, e.g., 157655.0006-157655.0008). Patient cells also
showed decreased amounts of fully assembled complex I and accumulation
of subcomplexes, indicating disturbance in the assembly or stability of
complex I. All patients had a severe, progressive disease course
resulting in death in childhood due to neurologic disability. Brain MRI
performed in 2 patients showed severe and progressive white matter
abnormalities. Hoefs et al. (2010) suggested that patients with very low
complex I deficiency should be specifically screened for NDUFS1
mutations.

Using exome sequencing, Haack et al. (2012) identified biallelic
mutations in nuclear-encoded genes in 7 (70%) of 10 unrelated index
patients with isolated complex I deficiency. The genes mutated included
NDUFB3 (603839.0001 and 603839.0002), NDUFS3 (603846.0002), NDUFS8
(602141.0005-602141.0007), ACAD9 (611103.0006; see 611126), and MTFMT
(611766.0001 and 611766.0004; see 256000).

Swalwell et al. (2011) reviewed the clinical and genetic findings in a
large cohort of 109 pediatric patients with isolated complex I
deficiency from 101 families. Pathogenic mtDNA mutations were found in
29% of probands: 21 in MTND subunit genes and 8 in mtDNA tRNA genes.
Nuclear gene defects were inferred in 38% of probands based on cell
hybrid studies, mtDNA sequencing, or mutation analysis. The most common
clinical presentation was Leigh or Leigh-like disease in patients with
either mtDNA or nuclear genetic defects. The median age at onset was
later in mtDNA patients (12 months) compared to patients with a nuclear
gene defect (3 months), although there was considerable overlap. The
report confirmed that pathogenic mtDNA mutations are a significant cause
of complex I deficiency in children.

GENOTYPE/PHENOTYPE CORRELATIONS

Mutations in the nuclear-encoded genes NDUFS1, NDUFS4, NDUFS7, NDUFS8,
and NDUFV1 result in neurologic diseases, mostly Leigh syndrome or
Leigh-like syndrome. Mutations in NDUFS2 and NDUFV2 have been associated
with hypertrophic cardiomyopathy and encephalomyopathy. Mutations in the
mitochondrial-encoded genes are associated with a wide variety of
clinical symptoms, ranging from organ-specific to multisystem diseases
(Benit et al., 2004).

Swalwell et al. (2011) reviewed the clinical and genetic findings in a
large cohort of 109 pediatric patients with isolated complex I
deficiency from 101 families. Pathogenic mtDNA mutations were found in
29% of probands: 21 in MTND subunit genes and 8 in mtDNA tRNA genes.
Nuclear gene defects were inferred in 38% of probands based on cell
hybrid studies, mtDNA sequencing, or mutation analysis. The most common
clinical presentation was Leigh or Leigh-like disease in patients with
either mtDNA or nuclear genetic defects. The median age at onset was
later in mtDNA patients (12 months) compared to patients with a nuclear
gene defect (3 months), although there was considerable overlap. The
report confirmed that pathogenic mtDNA mutations are a significant cause
of complex I deficiency in children.

ANIMAL MODEL

The laboratory of Scheffler (DeFrancesco et al., 1976; Ditta et al.,
1976; Breen and Scheffler, 1979; Soderberg et al., 1979) described
several respiration-deficient mutants of Chinese hamster cells in
culture. All depended on an ample supply of glucose in the medium to
sustain a high rate of glycolysis. When galactose was substituted for
glucose, the mutants died. This property was used to sort about 3 dozen
mutants into 7 complementation groups (Soderberg et al., 1979).
Whitfield et al. (1981) and Haiti et al. (1981) also identified
gal-minus mutants in Chinese hamster cells that had a defect in the
electron-transport chain. Specifically, several of the complementation
groups appeared to be defective in complex I of the electron transport
chain. Day and Scheffler (1982) reported that some of these
complementation groups were X-linked in the hamster and mouse. The gene
locus (-i) was symbolized 'res.' At least one complementation group was
found to be autosomal.

Qi et al. (2004) created a mouse model of severe complex I deficiency by
targeted disruption of the mRNA of a complex I subunit, Ndufa1 (300078),
using ribozymes. In vitro complex I activity was reduced by more than
80%, and reactive oxygen species were increased by 21 to 24% in cells
from affected mice. The mice showed damage to the optic nerve and
retina. Adeno-associated viral delivery of the human SOD2 gene (147460)
resulted in suppression of optic nerve degeneration and rescue of
retinal ganglion cells. The findings suggested that reactive oxygen
species contributed to retinal cell death and optic nerve damage in mice
with complex I deficiency and that expression of SOD2 attenuated the
disease process.

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24. Haack, T. B.; Madignier, F.; Herzer, M.; Lamantea, E.; Danhauser,
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25. Haiti, I. B.; Comlan de Souza, A.; Thirion, J. P.: Biochemical
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27. Hoppel, C. L.; Kerr, D. S.; Dahms, B.; Roessmann, U.: Deficiency
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29. Kirby, D. M.; Salemi, R.; Sugiana, C.; Ohtake, A.; Parry, L.;
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30. Lamont, P. J.; Thorburn, D. R.; Fabian, V.; Vajsar, J.; Hawkins,
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31. Land, J. M.; Morgan-Hughes, J. A.; Clark, J. B.: Mitochondrial
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32. Lebre, A. S.; Rio, M.; Faivre d'Arcier, L.; Vernerey, D.; Landrieu,
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33. Loeffen, J.; Elpeleg, O.; Smeitink, J.; Smeets, R.; Stockler-Ipsiroglu,
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34. Loeffen, J. L. C. M.; Smeitink, J. A. M.; Trijbels, J. M. F.;
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35. Martin, M. A.; Blazquez, A.; Gutierrez-Solana, L. G.; Fernandez-Moreira,
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36. McFarland, R.; Kirby, D. M.; Fowler, K. J.; Ohtake, A.; Ryan,
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37. Meulemans, A.; Seneca, S.; Lagae, L.; Lissens, W.; De Paepe, B.;
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38. Moreadith, R. W.; Batshaw, M. L.; Ohnishi, T.; Kerr, D.; Knox,
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685-697, 1984.

39. Moreadith, R. W.; Cleeter, M. W. J.; Ragan, C. I.; Batshaw, M.
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Invest. 79: 463-467, 1987.

40. Morgan-Hughes, J. A.; Darveniza, P.; Landon, D. N.; Land, J. M.;
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chain NADH-CoQ reductase activity. J. Neurol. Sci. 43: 27-46, 1979.

41. Musumeci, O.; Andreu, A. L.; Shanske, S.; Bresolin, N.; Comi,
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myopathy. Am. J. Hum. Genet. 66: 1900-1904, 2000.

42. Ogilvie, I.; Kennaway, N. G.; Shoubridge, E. A.: A molecular
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encephalopathy. J. Clin. Invest. 115: 2784-2792, 2005.

43. Pitkanen, S.; Feigenbaum, A.; Laframboise, R.; Robinson, B. H.
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675-686, 1996.

44. Procaccio, V.; Mousson, B.; Beugnot, R.; Duborjal, H.; Feillet,
F.; Putet, G.; Pignot-Paintrand, I.; Lombes, A.; De Coo, R.; Smeets,
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Invest. 104: 83-92, 1999.

45. Qi, X.; Lewin, A. S.; Sun, L.; Hauswirth, W. W.; Guy, J.: SOD2
gene transfer protects against optic neuropathy induced by deficiency
of complex I. Ann. Neurol. 56: 182-191, 2004.

46. Robinson, B. H.: Human complex I deficiency: clinical spectrum
and involvement of oxygen free radicals in the pathogenicity of the
defect. Biochim. Biophys. Acta 1364: 271-286, 1998.

47. Saada, A.; Vogel, R. O.; Hoefs, S. J.; van den Brand, M. A.; Wessels,
H. J.; Willems, P. H.; Venselaar, H.; Shaag, A.; Barghuti, F.; Reish,
O.; Shohat, M.; Huynen, M. A.; Smeitink, J. A. M.; van den Heuvel,
L. P.; Nijtmans, L. G.: Mutations in NDUFAF3 (C3ORF60), encoding
an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause
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2009.

48. Schuelke, M.; Smeitink, J.; Mariman, E.; Loeffen, J.; Plecko,
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49. Slipetz, D. M.; Goodyer, P. R.; Rozen, R.: Congenital deficiency
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52. Spiegel, R.; Shaag, A,; Mandel, H.; Reich, D.; Penyakov, M.; Hujeirat,
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1989.

*FIELD* CS
INHERITANCE:
Autosomal recessive;
X-linked dominant;
Mitochondrial

GROWTH:
[Other];
Failure to thrive;
Growth retardation

HEAD AND NECK:
[Head];
Macrocephaly, progressive;
[Ears];
Sensorineural deafness;
[Eyes];
Nystagmus;
Pale optic disks;
Strabismus;
Ptosis;
Blindness

CARDIOVASCULAR:
[Heart];
Hypertrophic cardiomyopathy

RESPIRATORY:
Respiratory insufficiency;
Respiratory failure

ABDOMEN:
[Liver];
Hepatic failure;
[Gastrointestinal];
Poor feeding;
Vomiting

MUSCLE, SOFT TISSUE:
Hypotonia;
Muscle weakness;
Muscle atrophy;
Exercise intolerance;
Muscle biopsy shows abnormal mitochondria

NEUROLOGIC:
[Central nervous system];
Developmental delay;
Psychomotor regression;
Hypotonia;
Lethargy;
Hyporeflexia;
Seizures;
Myoclonic epilepsy;
Ataxia;
Hyperreflexia;
Extensor plantar responses;
Spasticity;
Encephalopathy;
Brain edema;
Coma;
Acute necrotizing encephalopathy;
Leukodystrophy;
Cavitating leukoencephalopathy;
Leigh syndrome (256000);
Brainstem lesions, hyperintense on T2-weighted imaging;
Striatal lesions;
Thalamic lesions;
Cerebellar lesions;
Cerebellar atrophy

METABOLIC FEATURES:
Lactic acidosis;
Hypoglycemia

LABORATORY ABNORMALITIES:
Lactic acidemia;
Increased CSF lactate;
Decreased activity of mitochondrial respiratory chain complex I

MISCELLANEOUS:
Highly variable phenotype;
Highly variable age at onset;
Can be caused by mutations in nuclear-encoded or mitochondrial-encoded
genes

MOLECULAR BASIS:
Caused by mutation in the NADH dehydrogenase (ubiquinone) 1 alpha
subcomplex, 1 gene (NDUFA1, 300078.0001);
Caused by mutation in the NADH dehydrogenase (ubiquinone) 1 alpha
subcomplex, 2 gene (NDUFA2, 602137.0001);
Caused by mutation in the NADH dehydrogenase (ubiquinone) flavoprotein
1 gene (NDUFV1, 161015.0001);
Caused by mutation in the NADH dehydrogenase (ubiquinone) flavoprotein
2 gene (NDUFV2, 600532.0001);
Caused by mutation in the NADH dehydrogenase (ubiquinone) Fe-S protein
1 gene (NDUFS1, 157655.0001);
Caused by mutation in the NADH dehydrogenase (ubiquinone) Fe-S protein
2 gene (NDUFS2, 602985.0001);
Caused by mutation in the NADH dehydrogenase (ubiquinone) Fe-S protein
3 gene (NDUFS3, 603846.0001);
Caused by mutation in the NADH dehydrogenase (ubiquinone) Fe-S protein
4 gene (NDUFS4, 602694.0001);
Caused by mutation in the NADH dehydrogenase (ubiquinone) Fe-S protein
6 gene (NDUFS6, 603848.0001);
Caused by mutation in the NADH dehydrogenase (ubiquinone) Fe-S protein
7 gene (NDUFS7, 601825.0001);
Caused by mutation in the NADH dehydrogenase (ubiquinone) Fe-S protein
8 gene (NDUFS8, 602141.0001);
Caused by mutation in the NADH-ubiquinone oxidoreductase 1 alpha subcomplex,
2 gene (NDUFA2, 602137.0001);
Caused by mutation in the NADH-dehydrogenase 1 alpha subcomplex 10
gene (NDUFA10, 603835.0001);
Caused by mutation in the NADH-dehydrogenase 1 alpha subcomplex 11
gene (NDUFA11, 612638.0001);
Caused by mutation in the NADH-dehydrogenase 1 alpha subcomplex, assembly
factor 3 gene (NDUFAF3, 612911.0001);
Caused by mutation in the NADH-dehydrogenase 1 alpha subcomplex, assembly
factor 1 gene (NDUFAF1, 606934.0001);
Caused by mutation in the NADH-ubiquinone oxidoreductase 1 beta subcomplex
3 gene (NDUFB3, 603839.0001);
Caused by mutation in the NADH-ubiquinone oxidoreductase 1 beta subcomplex
9 gene (NDUFB9, 601445.0001);
Caused by mutation in the MYC-induced mitochondrial protein gene (MMTN,
609653.0001);
Caused by mutation in the C20ORF7 gene (612360.0001);
Caused by mutation in the complex I, subunit ND1 gene (MTND1, 516000.0001);
Caused by mutation in the complex I, subunit ND2 gene (MTND2, 516001.0001);
Caused by mutation in the complex I, subunit ND3 gene (MTND3, 516002.0001);
Caused by mutation in the complex I, subunit ND4 gene (MTND4, 516003.0001);
Caused by mutation in the complex I, subunit ND5 gene (MTND5, 516005.0001);
Caused by mutation in the complex I, subunit ND6 gene (MTND6, 516006.0001);
Caused by mutation in the mitochondrial tRNA-serine 2 gene (MTTS2,
590085.0002)

*FIELD* CN
Cassandra L. Kniffin - updated: 4/10/2012
Cassandra L. Kniffin - updated: 12/13/2011
Cassandra L. Kniffin - updated: 8/21/2009
Cassandra L. Kniffin - updated: 4/13/2009
Cassandra L. Kniffin - updated: 10/27/2008
Cassandra L. Kniffin - updated: 9/10/2008
Cassandra L. Kniffin - updated: 9/10/2007
Cassandra L. Kniffin - updated: 2/15/2007
Cassandra L. Kniffin - revised: 8/30/2005

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
ckniffin: 11/05/2013
ckniffin: 5/23/2013
ckniffin: 4/10/2012
ckniffin: 12/13/2011
ckniffin: 10/17/2011
ckniffin: 9/12/2011
ckniffin: 7/7/2011
joanna: 2/22/2011
ckniffin: 8/21/2009
joanna: 6/5/2009
ckniffin: 4/13/2009
joanna: 12/9/2008
ckniffin: 10/27/2008
joanna: 10/10/2008
ckniffin: 9/10/2008
ckniffin: 9/10/2007
ckniffin: 2/15/2007
joanna: 11/11/2005
ckniffin: 8/30/2005

*FIELD* CN
Cassandra L. Kniffin - updated: 9/17/2013
Cassandra L. Kniffin - updated: 5/23/2013
Cassandra L. Kniffin - updated: 5/1/2013
Cassandra L. Kniffin - updated: 2/13/2013
Cassandra L. Kniffin - updated: 11/29/2012
Cassandra L. Kniffin - updated: 6/12/2012
Cassandra L. Kniffin - updated: 2/1/2012
Cassandra L. Kniffin - updated: 12/13/2011
George E. Tiller - updated: 10/25/2011
Cassandra L. Kniffin - updated: 10/12/2011
Cassandra L. Kniffin - updated: 11/2/2010
Cassandra L. Kniffin - updated: 9/27/2010
Cassandra L. Kniffin - updated: 1/25/2010
Cassandra L. Kniffin - updated: 10/19/2009
Cassandra L. Kniffin - updated: 7/22/2009
Cassandra L. Kniffin - updated: 3/23/2009
Cassandra L. Kniffin - updated: 10/27/2008
Victor A. McKusick - updated: 2/19/2008
Cassandra L. Kniffin - updated: 9/10/2007
Cassandra L. Kniffin - updated: 11/7/2006
Anne M. Stumpf - updated: 11/10/2005
Cassandra L. Kniffin - updated: 10/17/2005
Cassandra L. Kniffin - reorganized: 9/21/2005
Cassandra L. Kniffin - updated: 8/30/2005
Cassandra L. Kniffin - updated: 1/5/2005
Marla J. F. O'Neill - updated: 10/14/2004
Ada Hamosh - updated: 1/29/2002
Victor A. McKusick - updated: 7/24/2001
Victor A. McKusick - updated: 2/22/2000
Victor A. McKusick - updated: 8/12/1999
Victor A. McKusick - updated: 6/18/1999
Victor A. McKusick - updated: 5/28/1999
Victor A. McKusick - updated: 9/11/1998

*FIELD* CD
Victor A. McKusick: 9/30/1987

*FIELD* ED
carol: 09/24/2013
carol: 9/24/2013
ckniffin: 9/17/2013
carol: 6/7/2013
ckniffin: 5/23/2013
ckniffin: 5/8/2013
carol: 5/2/2013
ckniffin: 5/1/2013
carol: 2/26/2013
ckniffin: 2/13/2013
carol: 12/4/2012
ckniffin: 11/29/2012
ckniffin: 8/7/2012
alopez: 6/18/2012
ckniffin: 6/12/2012
carol: 2/3/2012
terry: 2/2/2012
ckniffin: 2/1/2012
carol: 12/16/2011
ckniffin: 12/14/2011
ckniffin: 12/13/2011
alopez: 10/25/2011
carol: 10/13/2011
ckniffin: 10/12/2011
wwang: 7/20/2011
ckniffin: 7/7/2011
wwang: 5/17/2011
ckniffin: 5/16/2011
alopez: 11/2/2010
ckniffin: 11/2/2010
wwang: 9/28/2010
ckniffin: 9/27/2010
ckniffin: 9/24/2010
wwang: 1/29/2010
ckniffin: 1/25/2010
wwang: 11/12/2009
ckniffin: 10/19/2009
wwang: 8/4/2009
ckniffin: 7/22/2009
wwang: 4/9/2009
ckniffin: 3/23/2009
wwang: 11/3/2008
ckniffin: 10/27/2008
wwang: 9/16/2008
ckniffin: 9/10/2008
alopez: 2/22/2008
terry: 2/19/2008
wwang: 9/13/2007
ckniffin: 9/10/2007
wwang: 6/26/2007
terry: 6/22/2007
wwang: 2/19/2007
ckniffin: 2/15/2007
wwang: 11/10/2006
ckniffin: 11/7/2006
alopez: 11/10/2005
ckniffin: 10/17/2005
carol: 9/21/2005
ckniffin: 8/30/2005
terry: 4/6/2005
alopez: 3/9/2005
tkritzer: 1/12/2005
ckniffin: 1/5/2005
carol: 11/2/2004
terry: 10/14/2004
mgross: 8/6/2004
ckniffin: 7/7/2003
alopez: 1/31/2002
terry: 1/29/2002
mcapotos: 8/8/2001
mcapotos: 7/31/2001
terry: 7/24/2001
mgross: 6/20/2001
terry: 6/20/2001
mcapotos: 7/25/2000
mcapotos: 3/23/2000
mcapotos: 3/22/2000
mcapotos: 3/14/2000
terry: 2/22/2000
carol: 8/17/1999
jlewis: 8/12/1999
terry: 6/18/1999
mgross: 6/14/1999
mgross: 6/8/1999
terry: 5/28/1999
terry: 9/11/1998
alopez: 7/28/1997
mimadm: 2/19/1994
carol: 7/1/1993
supermim: 3/17/1992
supermim: 3/20/1990
carol: 12/20/1989
carol: 12/9/1989