RBCC Red Blood Cell Collection

MT-CO2 (COII, COXII, MTCO2) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Cytochrome c oxidase subunit 2 (Cytochrome c oxidase polypeptide II)

UniProt P00403
ID COX2_HUMAN Reviewed; 227 AA.
AC P00403; Q37526;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 21-JUL-1986, sequence version 1.
DT 22-JAN-2014, entry version 150.
DE RecName: Full=Cytochrome c oxidase subunit 2;
DE AltName: Full=Cytochrome c oxidase polypeptide II;
GN Name=MT-CO2; Synonyms=COII, COXII, MTCO2;
OS Homo sapiens (Human).
OG Mitochondrion.
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 [LARGE SCALE GENOMIC DNA].
RX PubMed=7219534; DOI=10.1038/290457a0;
RA Anderson S., Bankier A.T., Barrell B.G., de Bruijn M.H.L.,
RA Coulson A.R., Drouin J., Eperon I.C., Nierlich D.P., Roe B.A.,
RA Sanger F., Schreier P.H., Smith A.J.H., Staden R., Young I.G.;
RT "Sequence and organization of the human mitochondrial genome.";
RL Nature 290:457-465(1981).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2550900; DOI=10.1093/nar/17.16.6734;
RA Power M.D., Kiefer M.C., Barr P.J., Reeves R.;
RT "Nucleotide sequence of human mitochondrial cytochrome c oxidase II
RT cDNA.";
RL Nucleic Acids Res. 17:6734-6734(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=226894; DOI=10.1038/282189a0;
RA Barrell B.G., Bankier A.T., Drouin J.;
RT "A different genetic code in human mitochondria.";
RL Nature 282:189-194(1979).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Placenta;
RX PubMed=7530363; DOI=10.1073/pnas.92.2.532;
RA Horai S., Hayasaka K., Kondo R., Tsugane K., Takahata N.;
RT "Recent African origin of modern humans revealed by complete sequences
RT of hominoid mitochondrial DNAs.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:532-536(1995).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS VAL-30 AND THR-148.
RX PubMed=8277847;
RA Ruvolo M., Zehr S., von Dornum M., Pan D., Chang B., Lin J.;
RT "Mitochondrial COII sequences and modern human origins.";
RL Mol. Biol. Evol. 10:1115-1135(1993).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=12949126; DOI=10.1093/molbev/msg230;
RA Moilanen J.S., Finnila S., Majamaa K.;
RT "Lineage-specific selection in human mtDNA: lack of polymorphisms in a
RT segment of MTND5 gene in haplogroup J.";
RL Mol. Biol. Evol. 20:2132-2142(2003).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=11130070; DOI=10.1038/35047064;
RA Ingman M., Kaessmann H., Paeaebo S., Gyllensten U.;
RT "Mitochondrial genome variation and the origin of modern humans.";
RL Nature 408:708-713(2000).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=12840039; DOI=10.1101/gr.686603;
RA Ingman M., Gyllensten U.;
RT "Mitochondrial genome variation and evolutionary history of Australian
RT and New Guinean aborigines.";
RL Genome Res. 13:1600-1606(2003).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=14760490; DOI=10.1007/s00414-004-0427-6;
RA Coble M.D., Just R.S., O'Callaghan J.E., Letmanyi I.H., Peterson C.T.,
RA Irwin J.A., Parsons T.J.;
RT "Single nucleotide polymorphisms over the entire mtDNA genome that
RT increase the power of forensic testing in Caucasians.";
RL Int. J. Legal Med. 118:137-146(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 39-227.
RC TISSUE=Endometrial adenocarcinoma;
RA Swanson K.V., Griffiss J.;
RT "Gonococcal microcolony formation on HEC-1-B cells alters selective
RT mitochondrial transcripts.";
RL Submitted (MAY-1997) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 42-227.
RC TISSUE=Fetal liver;
RA Dmitrenko V.V., Kavsan V.M.;
RT "Nucleotide sequence of mitochondrial cytochrome C oxidase II from
RT human fetal liver.";
RL Submitted (SEP-1990) to the EMBL/GenBank/DDBJ databases.
RN [12]
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 [13]
RP VARIANTS ALA-11; PRO-123 AND MET-187.
RX PubMed=1757091; DOI=10.1007/BF00206061;
RA Marzuki S., Noer A.S., Lertrit P., Thyagarajan D., Kapsa R.,
RA Utthanaphol P., Byrne E.;
RT "Normal variants of human mitochondrial DNA and translation products:
RT the building of a reference data base.";
RL Hum. Genet. 88:139-145(1991).
RN [14]
RP VARIANT COLORECTAL CANCER MET-142.
RX PubMed=9806551; DOI=10.1038/3108;
RA Polyak K., Li Y., Zhu H., Lengauer C., Willson J.K.V., Markowitz S.D.,
RA Trush M.A., Kinzler K.W., Vogelstein B.;
RT "Somatic mutations of the mitochondrial genome in human colorectal
RT tumours.";
RL Nat. Genet. 20:291-293(1998).
RN [15]
RP VARIANT MT-C4D LYS-29, AND CHARACTERIZATION OF VARIANT MT-C4D LYS-29.
RX PubMed=10486321; DOI=10.1086/302590;
RA Rahman S., Taanman J.-W., Cooper J.M., Nelson I., Hargreaves I.,
RA Meunier B., Hanna M.G., Garcia J.J., Capaldi R.A., Lake B.D.,
RA Leonard J.V., Schapira A.H.V.;
RT "A missense mutation of cytochrome oxidase subunit II causes defective
RT assembly and myopathy.";
RL Am. J. Hum. Genet. 65:1030-1039(1999).
CC -!- FUNCTION: Cytochrome c oxidase is the component of the respiratory
CC chain that catalyzes the reduction of oxygen to water. Subunits 1-
CC 3 form the functional core of the enzyme complex. Subunit 2
CC transfers the electrons from cytochrome c via its binuclear copper
CC A center to the bimetallic center of the catalytic subunit 1.
CC -!- COFACTOR: Copper A.
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane; Multi-pass
CC membrane protein.
CC -!- DISEASE: Mitochondrial complex IV deficiency (MT-C4D)
CC [MIM:220110]: A disorder of the mitochondrial respiratory chain
CC with heterogeneous clinical manifestations, ranging from isolated
CC myopathy to severe multisystem disease affecting several tissues
CC and organs. Features include hypertrophic cardiomyopathy,
CC hepatomegaly and liver dysfunction, hypotonia, muscle weakness,
CC exercise intolerance, developmental delay, delayed motor
CC development and mental retardation. Some affected individuals
CC manifest a fatal hypertrophic cardiomyopathy resulting in neonatal
CC death. A subset of patients manifest Leigh syndrome. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the cytochrome c oxidase subunit 2 family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MT-CO2";
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DR EMBL; V00662; CAA24029.1; -; Genomic_DNA.
DR EMBL; J01415; AAB58946.1; -; Genomic_DNA.
DR EMBL; X15759; CAA33766.1; -; mRNA.
DR EMBL; M25171; AAA31850.1; -; Genomic_DNA.
DR EMBL; D38112; BAA07293.1; -; Genomic_DNA.
DR EMBL; U12690; AAA20843.1; -; Genomic_DNA.
DR EMBL; U12691; AAA20844.1; -; Genomic_DNA.
DR EMBL; U12692; AAA20845.1; -; Genomic_DNA.
DR EMBL; U12693; AAA20846.1; -; Genomic_DNA.
DR EMBL; U12694; AAA20847.1; -; Genomic_DNA.
DR EMBL; AF004339; AAB63450.1; -; Genomic_DNA.
DR EMBL; AY339402; AAP89039.1; -; Genomic_DNA.
DR EMBL; AY339403; AAP89052.1; -; Genomic_DNA.
DR EMBL; AY339404; AAP89065.1; -; Genomic_DNA.
DR EMBL; AY339405; AAP89078.1; -; Genomic_DNA.
DR EMBL; AY339406; AAP89091.1; -; Genomic_DNA.
DR EMBL; AY339407; AAP89104.1; -; Genomic_DNA.
DR EMBL; AY339408; AAP89117.1; -; Genomic_DNA.
DR EMBL; AY339409; AAP89130.1; -; Genomic_DNA.
DR EMBL; AY339410; AAP89143.1; -; Genomic_DNA.
DR EMBL; AY339411; AAP89156.1; -; Genomic_DNA.
DR EMBL; AY339412; AAP89169.1; -; Genomic_DNA.
DR EMBL; AY339413; AAP89182.1; -; Genomic_DNA.
DR EMBL; AY339414; AAP89195.1; -; Genomic_DNA.
DR EMBL; AY339415; AAP89208.1; -; Genomic_DNA.
DR EMBL; AY339416; AAP89221.1; -; Genomic_DNA.
DR EMBL; AY339417; AAP89234.1; -; Genomic_DNA.
DR EMBL; AY339418; AAP89247.1; -; Genomic_DNA.
DR EMBL; AY339419; AAP89260.1; -; Genomic_DNA.
DR EMBL; AY339420; AAP89273.1; -; Genomic_DNA.
DR EMBL; AY339421; AAP89286.1; -; Genomic_DNA.
DR EMBL; AY339422; AAP89299.1; -; Genomic_DNA.
DR EMBL; AY339423; AAP89312.1; -; Genomic_DNA.
DR EMBL; AY339424; AAP89325.1; -; Genomic_DNA.
DR EMBL; AY339425; AAP89338.1; -; Genomic_DNA.
DR EMBL; AY339426; AAP89351.1; -; Genomic_DNA.
DR EMBL; AY339427; AAP89364.1; -; Genomic_DNA.
DR EMBL; AY339428; AAP89377.1; -; Genomic_DNA.
DR EMBL; AY339429; AAP89390.1; -; Genomic_DNA.
DR EMBL; AY339430; AAP89403.1; -; Genomic_DNA.
DR EMBL; AY339431; AAP89416.1; -; Genomic_DNA.
DR EMBL; AY339432; AAP89429.1; -; Genomic_DNA.
DR EMBL; AY339433; AAP89442.1; -; Genomic_DNA.
DR EMBL; AY339434; AAP89455.1; -; Genomic_DNA.
DR EMBL; AY339435; AAP89468.1; -; Genomic_DNA.
DR EMBL; AY339436; AAP89481.1; -; Genomic_DNA.
DR EMBL; AY339437; AAP89494.1; -; Genomic_DNA.
DR EMBL; AY339438; AAP89507.1; -; Genomic_DNA.
DR EMBL; AY339439; AAP89520.1; -; Genomic_DNA.
DR EMBL; AY339440; AAP89533.1; -; Genomic_DNA.
DR EMBL; AY339441; AAP89546.1; -; Genomic_DNA.
DR EMBL; AY339442; AAP89559.1; -; Genomic_DNA.
DR EMBL; AY339443; AAP89572.1; -; Genomic_DNA.
DR EMBL; AY339444; AAP89585.1; -; Genomic_DNA.
DR EMBL; AY339445; AAP89598.1; -; Genomic_DNA.
DR EMBL; AY339446; AAP89611.1; -; Genomic_DNA.
DR EMBL; AY339447; AAP89624.1; -; Genomic_DNA.
DR EMBL; AY339448; AAP89637.1; -; Genomic_DNA.
DR EMBL; AY339449; AAP89650.1; -; Genomic_DNA.
DR EMBL; AY339450; AAP89663.1; -; Genomic_DNA.
DR EMBL; AY339451; AAP89676.1; -; Genomic_DNA.
DR EMBL; AY339452; AAP89689.1; -; Genomic_DNA.
DR EMBL; AY339453; AAP89702.1; -; Genomic_DNA.
DR EMBL; AY339454; AAP89715.1; -; Genomic_DNA.
DR EMBL; AY339455; AAP89728.1; -; Genomic_DNA.
DR EMBL; AY339456; AAP89741.1; -; Genomic_DNA.
DR EMBL; AY339457; AAP89754.1; -; Genomic_DNA.
DR EMBL; AY339458; AAP89767.1; -; Genomic_DNA.
DR EMBL; AY339459; AAP89780.1; -; Genomic_DNA.
DR EMBL; AY339460; AAP89793.1; -; Genomic_DNA.
DR EMBL; AY339461; AAP89806.1; -; Genomic_DNA.
DR EMBL; AY339462; AAP89819.1; -; Genomic_DNA.
DR EMBL; AY339463; AAP89832.1; -; Genomic_DNA.
DR EMBL; AY339464; AAP89845.1; -; Genomic_DNA.
DR EMBL; AY339465; AAP89858.1; -; Genomic_DNA.
DR EMBL; AY339466; AAP89871.1; -; Genomic_DNA.
DR EMBL; AY339467; AAP89884.1; -; Genomic_DNA.
DR EMBL; AY339468; AAP89897.1; -; Genomic_DNA.
DR EMBL; AY339469; AAP89910.1; -; Genomic_DNA.
DR EMBL; AY339470; AAP89923.1; -; Genomic_DNA.
DR EMBL; AY339471; AAP89936.1; -; Genomic_DNA.
DR EMBL; AY339472; AAP89949.1; -; Genomic_DNA.
DR EMBL; AY339473; AAP89962.1; -; Genomic_DNA.
DR EMBL; AY339474; AAP89975.1; -; Genomic_DNA.
DR EMBL; AY339475; AAP89988.1; -; Genomic_DNA.
DR EMBL; AY339476; AAP90001.1; -; Genomic_DNA.
DR EMBL; AY339477; AAP90014.1; -; Genomic_DNA.
DR EMBL; AY339478; AAP90027.1; -; Genomic_DNA.
DR EMBL; AY339479; AAP90040.1; -; Genomic_DNA.
DR EMBL; AY339480; AAP90053.1; -; Genomic_DNA.
DR EMBL; AY339481; AAP90066.1; -; Genomic_DNA.
DR EMBL; AY339482; AAP90079.1; -; Genomic_DNA.
DR EMBL; AY339483; AAP90092.1; -; Genomic_DNA.
DR EMBL; AY339484; AAP90105.1; -; Genomic_DNA.
DR EMBL; AY339485; AAP90118.1; -; Genomic_DNA.
DR EMBL; AY339486; AAP90131.1; -; Genomic_DNA.
DR EMBL; AY339487; AAP90144.1; -; Genomic_DNA.
DR EMBL; AY339488; AAP90157.1; -; Genomic_DNA.
DR EMBL; AY339489; AAP90170.1; -; Genomic_DNA.
DR EMBL; AY339490; AAP90183.1; -; Genomic_DNA.
DR EMBL; AY339492; AAP90209.1; -; Genomic_DNA.
DR EMBL; AY339493; AAP90222.1; -; Genomic_DNA.
DR EMBL; AY339494; AAP90235.1; -; Genomic_DNA.
DR EMBL; AY339495; AAP90248.1; -; Genomic_DNA.
DR EMBL; AY339496; AAP90261.1; -; Genomic_DNA.
DR EMBL; AY339498; AAP90287.1; -; Genomic_DNA.
DR EMBL; AY339499; AAP90300.1; -; Genomic_DNA.
DR EMBL; AY339500; AAP90313.1; -; Genomic_DNA.
DR EMBL; AY339501; AAP90326.1; -; Genomic_DNA.
DR EMBL; AY339502; AAP90339.1; -; Genomic_DNA.
DR EMBL; AY339503; AAP90352.1; -; Genomic_DNA.
DR EMBL; AY339504; AAP90365.1; -; Genomic_DNA.
DR EMBL; AY339505; AAP90378.1; -; Genomic_DNA.
DR EMBL; AY339506; AAP90391.1; -; Genomic_DNA.
DR EMBL; AY339507; AAP90404.1; -; Genomic_DNA.
DR EMBL; AY339508; AAP90417.1; -; Genomic_DNA.
DR EMBL; AY339509; AAP90430.1; -; Genomic_DNA.
DR EMBL; AY339510; AAP90443.1; -; Genomic_DNA.
DR EMBL; AY339511; AAP90456.1; -; Genomic_DNA.
DR EMBL; AY339512; AAP90469.1; -; Genomic_DNA.
DR EMBL; AY339513; AAP90482.1; -; Genomic_DNA.
DR EMBL; AY339514; AAP90495.1; -; Genomic_DNA.
DR EMBL; AY339515; AAP90508.1; -; Genomic_DNA.
DR EMBL; AY339516; AAP90521.1; -; Genomic_DNA.
DR EMBL; AY339517; AAP90534.1; -; Genomic_DNA.
DR EMBL; AY339518; AAP90547.1; -; Genomic_DNA.
DR EMBL; AY339519; AAP90560.1; -; Genomic_DNA.
DR EMBL; AY339520; AAP90573.1; -; Genomic_DNA.
DR EMBL; AY339521; AAP90586.1; -; Genomic_DNA.
DR EMBL; AY339522; AAP90599.1; -; Genomic_DNA.
DR EMBL; AY339523; AAP90612.1; -; Genomic_DNA.
DR EMBL; AY339524; AAP90625.1; -; Genomic_DNA.
DR EMBL; AY339525; AAP90638.1; -; Genomic_DNA.
DR EMBL; AY339526; AAP90651.1; -; Genomic_DNA.
DR EMBL; AY339527; AAP90664.1; -; Genomic_DNA.
DR EMBL; AY339528; AAP90677.1; -; Genomic_DNA.
DR EMBL; AY339529; AAP90690.1; -; Genomic_DNA.
DR EMBL; AY339530; AAP90703.1; -; Genomic_DNA.
DR EMBL; AY339531; AAP90716.1; -; Genomic_DNA.
DR EMBL; AY339532; AAP90729.1; -; Genomic_DNA.
DR EMBL; AY339533; AAP90742.1; -; Genomic_DNA.
DR EMBL; AY339534; AAP90755.1; -; Genomic_DNA.
DR EMBL; AY339535; AAP90768.1; -; Genomic_DNA.
DR EMBL; AY339536; AAP90781.1; -; Genomic_DNA.
DR EMBL; AY339537; AAP90794.1; -; Genomic_DNA.
DR EMBL; AY339538; AAP90807.1; -; Genomic_DNA.
DR EMBL; AY339539; AAP90820.1; -; Genomic_DNA.
DR EMBL; AY339540; AAP90833.1; -; Genomic_DNA.
DR EMBL; AY339541; AAP90846.1; -; Genomic_DNA.
DR EMBL; AY339543; AAP90872.1; -; Genomic_DNA.
DR EMBL; AY339544; AAP90885.1; -; Genomic_DNA.
DR EMBL; AY339545; AAP90898.1; -; Genomic_DNA.
DR EMBL; AY339546; AAP90911.1; -; Genomic_DNA.
DR EMBL; AY339547; AAP90924.1; -; Genomic_DNA.
DR EMBL; AY339548; AAP90937.1; -; Genomic_DNA.
DR EMBL; AY339549; AAP90950.1; -; Genomic_DNA.
DR EMBL; AY339550; AAP90963.1; -; Genomic_DNA.
DR EMBL; AY339551; AAP90976.1; -; Genomic_DNA.
DR EMBL; AY339552; AAP90989.1; -; Genomic_DNA.
DR EMBL; AY339553; AAP91002.1; -; Genomic_DNA.
DR EMBL; AY339555; AAP91028.1; -; Genomic_DNA.
DR EMBL; AY339556; AAP91041.1; -; Genomic_DNA.
DR EMBL; AY339557; AAP91054.1; -; Genomic_DNA.
DR EMBL; AY339558; AAP91067.1; -; Genomic_DNA.
DR EMBL; AY339559; AAP91080.1; -; Genomic_DNA.
DR EMBL; AY339560; AAP91093.1; -; Genomic_DNA.
DR EMBL; AY339561; AAP91106.1; -; Genomic_DNA.
DR EMBL; AY339562; AAP91119.1; -; Genomic_DNA.
DR EMBL; AY339563; AAP91132.1; -; Genomic_DNA.
DR EMBL; AY339564; AAP91145.1; -; Genomic_DNA.
DR EMBL; AY339565; AAP91158.1; -; Genomic_DNA.
DR EMBL; AY339566; AAP91171.1; -; Genomic_DNA.
DR EMBL; AY339567; AAP91184.1; -; Genomic_DNA.
DR EMBL; AY339568; AAP91197.1; -; Genomic_DNA.
DR EMBL; AY339569; AAP91210.1; -; Genomic_DNA.
DR EMBL; AY339570; AAP91223.1; -; Genomic_DNA.
DR EMBL; AY339571; AAP91236.1; -; Genomic_DNA.
DR EMBL; AY339572; AAP91249.1; -; Genomic_DNA.
DR EMBL; AY339573; AAP91262.1; -; Genomic_DNA.
DR EMBL; AY339574; AAP91275.1; -; Genomic_DNA.
DR EMBL; AY339575; AAP91288.1; -; Genomic_DNA.
DR EMBL; AY339576; AAP91301.1; -; Genomic_DNA.
DR EMBL; AY339577; AAP91314.1; -; Genomic_DNA.
DR EMBL; AY339578; AAP91327.1; -; Genomic_DNA.
DR EMBL; AY339579; AAP91340.1; -; Genomic_DNA.
DR EMBL; AY339580; AAP91353.1; -; Genomic_DNA.
DR EMBL; AY339581; AAP91366.1; -; Genomic_DNA.
DR EMBL; AY339582; AAP91379.1; -; Genomic_DNA.
DR EMBL; AY339583; AAP91392.1; -; Genomic_DNA.
DR EMBL; AY339584; AAP91405.1; -; Genomic_DNA.
DR EMBL; AY339585; AAP91418.1; -; Genomic_DNA.
DR EMBL; AY339586; AAP91431.1; -; Genomic_DNA.
DR EMBL; AY339587; AAP91444.1; -; Genomic_DNA.
DR EMBL; AY339588; AAP91457.1; -; Genomic_DNA.
DR EMBL; AY339589; AAP91470.1; -; Genomic_DNA.
DR EMBL; AY339590; AAP91483.1; -; Genomic_DNA.
DR EMBL; AY339591; AAP91496.1; -; Genomic_DNA.
DR EMBL; AY339592; AAP91509.1; -; Genomic_DNA.
DR EMBL; AY339593; AAP91522.1; -; Genomic_DNA.
DR EMBL; AF346963; AAK17210.1; -; Genomic_DNA.
DR EMBL; AF346964; AAK17223.1; -; Genomic_DNA.
DR EMBL; AF346965; AAK17236.1; -; Genomic_DNA.
DR EMBL; AF346966; AAK17249.1; -; Genomic_DNA.
DR EMBL; AF346967; AAK17262.1; -; Genomic_DNA.
DR EMBL; AF346970; AAK17301.1; -; Genomic_DNA.
DR EMBL; AF346972; AAK17327.1; -; Genomic_DNA.
DR EMBL; AF346973; AAK17340.1; -; Genomic_DNA.
DR EMBL; AF346974; AAK17353.1; -; Genomic_DNA.
DR EMBL; AF346975; AAK17366.1; -; Genomic_DNA.
DR EMBL; AF346976; AAK17379.1; -; Genomic_DNA.
DR EMBL; AF346977; AAK17392.1; -; Genomic_DNA.
DR EMBL; AF346978; AAK17405.1; -; Genomic_DNA.
DR EMBL; AF346979; AAK17418.1; -; Genomic_DNA.
DR EMBL; AF346980; AAK17431.1; -; Genomic_DNA.
DR EMBL; AF346981; AAK17444.1; -; Genomic_DNA.
DR EMBL; AF346982; AAK17457.1; -; Genomic_DNA.
DR EMBL; AF346983; AAK17470.1; -; Genomic_DNA.
DR EMBL; AF346984; AAK17483.1; -; Genomic_DNA.
DR EMBL; AF346985; AAK17496.1; -; Genomic_DNA.
DR EMBL; AF346986; AAK17509.1; -; Genomic_DNA.
DR EMBL; AF346988; AAK17535.1; -; Genomic_DNA.
DR EMBL; AF346989; AAK17548.1; -; Genomic_DNA.
DR EMBL; AF346990; AAK17561.1; -; Genomic_DNA.
DR EMBL; AF346991; AAK17574.1; -; Genomic_DNA.
DR EMBL; AF346993; AAK17600.1; -; Genomic_DNA.
DR EMBL; AF346994; AAK17613.1; -; Genomic_DNA.
DR EMBL; AF346995; AAK17626.1; -; Genomic_DNA.
DR EMBL; AF346998; AAK17665.1; -; Genomic_DNA.
DR EMBL; AF346999; AAK17678.1; -; Genomic_DNA.
DR EMBL; AF347000; AAK17691.1; -; Genomic_DNA.
DR EMBL; AF347001; AAK17704.1; -; Genomic_DNA.
DR EMBL; AF347002; AAK17717.1; -; Genomic_DNA.
DR EMBL; AF347003; AAK17730.1; -; Genomic_DNA.
DR EMBL; AF347004; AAK17743.1; -; Genomic_DNA.
DR EMBL; AF347005; AAK17756.1; -; Genomic_DNA.
DR EMBL; AF347006; AAK17769.1; -; Genomic_DNA.
DR EMBL; AF347007; AAK17782.1; -; Genomic_DNA.
DR EMBL; AF347009; AAK17808.1; -; Genomic_DNA.
DR EMBL; AF347010; AAK17821.1; -; Genomic_DNA.
DR EMBL; AF347011; AAK17834.1; -; Genomic_DNA.
DR EMBL; AF347014; AAK17873.1; -; Genomic_DNA.
DR EMBL; AF347015; AAK17886.1; -; Genomic_DNA.
DR EMBL; AY289051; AAP47883.1; -; Genomic_DNA.
DR EMBL; AY289053; AAP47909.1; -; Genomic_DNA.
DR EMBL; AY289054; AAP47922.1; -; Genomic_DNA.
DR EMBL; AY289056; AAP47948.1; -; Genomic_DNA.
DR EMBL; AY289057; AAP47961.1; -; Genomic_DNA.
DR EMBL; AY289058; AAP47974.1; -; Genomic_DNA.
DR EMBL; AY289059; AAP47987.1; -; Genomic_DNA.
DR EMBL; AY289060; AAP48000.1; -; Genomic_DNA.
DR EMBL; AY289061; AAP48013.1; -; Genomic_DNA.
DR EMBL; AY289062; AAP48026.1; -; Genomic_DNA.
DR EMBL; AY289063; AAP48039.1; -; Genomic_DNA.
DR EMBL; AY289064; AAP48052.1; -; Genomic_DNA.
DR EMBL; AY289065; AAP48065.1; -; Genomic_DNA.
DR EMBL; AY289066; AAP48078.1; -; Genomic_DNA.
DR EMBL; AY289067; AAP48091.1; -; Genomic_DNA.
DR EMBL; AY289068; AAP48104.1; -; Genomic_DNA.
DR EMBL; AY289069; AAP48117.1; -; Genomic_DNA.
DR EMBL; AY289071; AAP48143.1; -; Genomic_DNA.
DR EMBL; AY289072; AAP48156.1; -; Genomic_DNA.
DR EMBL; AY289073; AAP48169.1; -; Genomic_DNA.
DR EMBL; AY289074; AAP48182.1; -; Genomic_DNA.
DR EMBL; AY289075; AAP48195.1; -; Genomic_DNA.
DR EMBL; AY289076; AAP48208.1; -; Genomic_DNA.
DR EMBL; AY289077; AAP48221.1; -; Genomic_DNA.
DR EMBL; AY289078; AAP48234.1; -; Genomic_DNA.
DR EMBL; AY289079; AAP48247.1; -; Genomic_DNA.
DR EMBL; AY289080; AAP48260.1; -; Genomic_DNA.
DR EMBL; AY289081; AAP48273.1; -; Genomic_DNA.
DR EMBL; AY289082; AAP48286.1; -; Genomic_DNA.
DR EMBL; AY289083; AAP48299.1; -; Genomic_DNA.
DR EMBL; AY289084; AAP48312.1; -; Genomic_DNA.
DR EMBL; AY289085; AAP48325.1; -; Genomic_DNA.
DR EMBL; AY289086; AAP48338.1; -; Genomic_DNA.
DR EMBL; AY289087; AAP48351.1; -; Genomic_DNA.
DR EMBL; AY289088; AAP48364.1; -; Genomic_DNA.
DR EMBL; AY289089; AAP48377.1; -; Genomic_DNA.
DR EMBL; AY289090; AAP48390.1; -; Genomic_DNA.
DR EMBL; AY289091; AAP48403.1; -; Genomic_DNA.
DR EMBL; AY289092; AAP48416.1; -; Genomic_DNA.
DR EMBL; AY289093; AAP48428.1; -; Genomic_DNA.
DR EMBL; AY289094; AAP48441.1; -; Genomic_DNA.
DR EMBL; AY289095; AAP48454.1; -; Genomic_DNA.
DR EMBL; AY289096; AAP48467.1; -; Genomic_DNA.
DR EMBL; AY289099; AAP48506.1; -; Genomic_DNA.
DR EMBL; AY289100; AAP48519.1; -; Genomic_DNA.
DR EMBL; AY289102; AAP48545.1; -; Genomic_DNA.
DR EMBL; AY495090; AAR92499.1; -; Genomic_DNA.
DR EMBL; AY495091; AAR92512.1; -; Genomic_DNA.
DR EMBL; AY495092; AAR92525.1; -; Genomic_DNA.
DR EMBL; AY495093; AAR92538.1; -; Genomic_DNA.
DR EMBL; AY495094; AAR92551.1; -; Genomic_DNA.
DR EMBL; AY495095; AAR92564.1; -; Genomic_DNA.
DR EMBL; AY495096; AAR92577.1; -; Genomic_DNA.
DR EMBL; AY495097; AAR92590.1; -; Genomic_DNA.
DR EMBL; AY495098; AAR92603.1; -; Genomic_DNA.
DR EMBL; AY495099; AAR92616.1; -; Genomic_DNA.
DR EMBL; AY495100; AAR92629.1; -; Genomic_DNA.
DR EMBL; AY495101; AAR92642.1; -; Genomic_DNA.
DR EMBL; AY495102; AAR92655.1; -; Genomic_DNA.
DR EMBL; AY495103; AAR92668.1; -; Genomic_DNA.
DR EMBL; AY495104; AAR92681.1; -; Genomic_DNA.
DR EMBL; AY495105; AAR92694.1; -; Genomic_DNA.
DR EMBL; AY495106; AAR92707.1; -; Genomic_DNA.
DR EMBL; AY495107; AAR92720.1; -; Genomic_DNA.
DR EMBL; AY495108; AAR92733.1; -; Genomic_DNA.
DR EMBL; AY495109; AAR92746.1; -; Genomic_DNA.
DR EMBL; AY495110; AAR92759.1; -; Genomic_DNA.
DR EMBL; AY495111; AAR92772.1; -; Genomic_DNA.
DR EMBL; AY495112; AAR92785.1; -; Genomic_DNA.
DR EMBL; AY495113; AAR92798.1; -; Genomic_DNA.
DR EMBL; AY495114; AAR92811.1; -; Genomic_DNA.
DR EMBL; AY495115; AAR92824.1; -; Genomic_DNA.
DR EMBL; AY495116; AAR92837.1; -; Genomic_DNA.
DR EMBL; AY495117; AAR92850.1; -; Genomic_DNA.
DR EMBL; AY495118; AAR92863.1; -; Genomic_DNA.
DR EMBL; AY495119; AAR92876.1; -; Genomic_DNA.
DR EMBL; AY495120; AAR92889.1; -; Genomic_DNA.
DR EMBL; AY495121; AAR92902.1; -; Genomic_DNA.
DR EMBL; AY495122; AAR92915.1; -; Genomic_DNA.
DR EMBL; AY495123; AAR92928.1; -; Genomic_DNA.
DR EMBL; AY495124; AAR92941.1; -; Genomic_DNA.
DR EMBL; AY495125; AAR92954.1; -; Genomic_DNA.
DR EMBL; AY495126; AAR92967.1; -; Genomic_DNA.
DR EMBL; AY495127; AAR92980.1; -; Genomic_DNA.
DR EMBL; AY495128; AAR92993.1; -; Genomic_DNA.
DR EMBL; AY495129; AAR93006.1; -; Genomic_DNA.
DR EMBL; AY495130; AAR93019.1; -; Genomic_DNA.
DR EMBL; AY495131; AAR93032.1; -; Genomic_DNA.
DR EMBL; AY495132; AAR93045.1; -; Genomic_DNA.
DR EMBL; AY495133; AAR93058.1; -; Genomic_DNA.
DR EMBL; AY495134; AAR93071.1; -; Genomic_DNA.
DR EMBL; AY495135; AAR93084.1; -; Genomic_DNA.
DR EMBL; AY495136; AAR93097.1; -; Genomic_DNA.
DR EMBL; AY495137; AAR93110.1; -; Genomic_DNA.
DR EMBL; AY495138; AAR93123.1; -; Genomic_DNA.
DR EMBL; AY495139; AAR93136.1; -; Genomic_DNA.
DR EMBL; AY495140; AAR93149.1; -; Genomic_DNA.
DR EMBL; AY495141; AAR93162.1; -; Genomic_DNA.
DR EMBL; AY495142; AAR93175.1; -; Genomic_DNA.
DR EMBL; AY495143; AAR93188.1; -; Genomic_DNA.
DR EMBL; AY495144; AAR93201.1; -; Genomic_DNA.
DR EMBL; AY495145; AAR93214.1; -; Genomic_DNA.
DR EMBL; AY495146; AAR93227.1; -; Genomic_DNA.
DR EMBL; AY495147; AAR93240.1; -; Genomic_DNA.
DR EMBL; AY495148; AAR93253.1; -; Genomic_DNA.
DR EMBL; AY495149; AAR93266.1; -; Genomic_DNA.
DR EMBL; AY495150; AAR93279.1; -; Genomic_DNA.
DR EMBL; AY495151; AAR93292.1; -; Genomic_DNA.
DR EMBL; AY495152; AAR93305.1; -; Genomic_DNA.
DR EMBL; AY495153; AAR93318.1; -; Genomic_DNA.
DR EMBL; AY495154; AAR93331.1; -; Genomic_DNA.
DR EMBL; AY495155; AAR93344.1; -; Genomic_DNA.
DR EMBL; AY495156; AAR93357.1; -; Genomic_DNA.
DR EMBL; AY495157; AAR93370.1; -; Genomic_DNA.
DR EMBL; AY495158; AAR93383.1; -; Genomic_DNA.
DR EMBL; AY495159; AAR93396.1; -; Genomic_DNA.
DR EMBL; AY495160; AAR93409.1; -; Genomic_DNA.
DR EMBL; AY495161; AAR93422.1; -; Genomic_DNA.
DR EMBL; AY495162; AAR93435.1; -; Genomic_DNA.
DR EMBL; AY495163; AAR93448.1; -; Genomic_DNA.
DR EMBL; AY495164; AAR93461.1; -; Genomic_DNA.
DR EMBL; AY495166; AAR93487.1; -; Genomic_DNA.
DR EMBL; AY495167; AAR93500.1; -; Genomic_DNA.
DR EMBL; AY495168; AAR93513.1; -; Genomic_DNA.
DR EMBL; AY495169; AAR93526.1; -; Genomic_DNA.
DR EMBL; AY495170; AAR93539.1; -; Genomic_DNA.
DR EMBL; AY495172; AAR93565.1; -; Genomic_DNA.
DR EMBL; AY495173; AAR93578.1; -; Genomic_DNA.
DR EMBL; AY495174; AAR93591.1; -; Genomic_DNA.
DR EMBL; AY495175; AAR93604.1; -; Genomic_DNA.
DR EMBL; AY495176; AAR93617.1; -; Genomic_DNA.
DR EMBL; AY495177; AAR93630.1; -; Genomic_DNA.
DR EMBL; AY495178; AAR93643.1; -; Genomic_DNA.
DR EMBL; AY495179; AAR93656.1; -; Genomic_DNA.
DR EMBL; AY495180; AAR93669.1; -; Genomic_DNA.
DR EMBL; AY495181; AAR93682.1; -; Genomic_DNA.
DR EMBL; AY495182; AAR93695.1; -; Genomic_DNA.
DR EMBL; AY495183; AAR93708.1; -; Genomic_DNA.
DR EMBL; AY495184; AAR93721.1; -; Genomic_DNA.
DR EMBL; AY495185; AAR93734.1; -; Genomic_DNA.
DR EMBL; AY495186; AAR93747.1; -; Genomic_DNA.
DR EMBL; AY495187; AAR93760.1; -; Genomic_DNA.
DR EMBL; AY495188; AAR93773.1; -; Genomic_DNA.
DR EMBL; AY495189; AAR93786.1; -; Genomic_DNA.
DR EMBL; AY495190; AAR93799.1; -; Genomic_DNA.
DR EMBL; AY495191; AAR93812.1; -; Genomic_DNA.
DR EMBL; AY495192; AAR93825.1; -; Genomic_DNA.
DR EMBL; AY495193; AAR93838.1; -; Genomic_DNA.
DR EMBL; AY495194; AAR93851.1; -; Genomic_DNA.
DR EMBL; AY495195; AAR93864.1; -; Genomic_DNA.
DR EMBL; AY495196; AAR93877.1; -; Genomic_DNA.
DR EMBL; AY495197; AAR93890.1; -; Genomic_DNA.
DR EMBL; AY495198; AAR93903.1; -; Genomic_DNA.
DR EMBL; AY495199; AAR93916.1; -; Genomic_DNA.
DR EMBL; AY495200; AAR93929.1; -; Genomic_DNA.
DR EMBL; AY495201; AAR93942.1; -; Genomic_DNA.
DR EMBL; AY495202; AAR93955.1; -; Genomic_DNA.
DR EMBL; AY495203; AAR93968.1; -; Genomic_DNA.
DR EMBL; AY495204; AAR93981.1; -; Genomic_DNA.
DR EMBL; AY495205; AAR93994.1; -; Genomic_DNA.
DR EMBL; AY495206; AAR94007.1; -; Genomic_DNA.
DR EMBL; AY495207; AAR94020.1; -; Genomic_DNA.
DR EMBL; AY495208; AAR94033.1; -; Genomic_DNA.
DR EMBL; AY495209; AAR94046.1; -; Genomic_DNA.
DR EMBL; AY495210; AAR94059.1; -; Genomic_DNA.
DR EMBL; AY495211; AAR94072.1; -; Genomic_DNA.
DR EMBL; AY495212; AAR94085.1; -; Genomic_DNA.
DR EMBL; AY495213; AAR94098.1; -; Genomic_DNA.
DR EMBL; AY495214; AAR94111.1; -; Genomic_DNA.
DR EMBL; AY495215; AAR94124.1; -; Genomic_DNA.
DR EMBL; AY495216; AAR94137.1; -; Genomic_DNA.
DR EMBL; AY495217; AAR94150.1; -; Genomic_DNA.
DR EMBL; AY495218; AAR94163.1; -; Genomic_DNA.
DR EMBL; AY495219; AAR94176.1; -; Genomic_DNA.
DR EMBL; AY495220; AAR94189.1; -; Genomic_DNA.
DR EMBL; AY495221; AAR94202.1; -; Genomic_DNA.
DR EMBL; AY495223; AAR94228.1; -; Genomic_DNA.
DR EMBL; AY495224; AAR94241.1; -; Genomic_DNA.
DR EMBL; AY495225; AAR94254.1; -; Genomic_DNA.
DR EMBL; AY495226; AAR94267.1; -; Genomic_DNA.
DR EMBL; AY495227; AAR94280.1; -; Genomic_DNA.
DR EMBL; AY495228; AAR94293.1; -; Genomic_DNA.
DR EMBL; AY495229; AAR94306.1; -; Genomic_DNA.
DR EMBL; AY495230; AAR94319.1; -; Genomic_DNA.
DR EMBL; AY495231; AAR94332.1; -; Genomic_DNA.
DR EMBL; AY495232; AAR94345.1; -; Genomic_DNA.
DR EMBL; AY495233; AAR94358.1; -; Genomic_DNA.
DR EMBL; AY495234; AAR94371.1; -; Genomic_DNA.
DR EMBL; AY495235; AAR94384.1; -; Genomic_DNA.
DR EMBL; AY495236; AAR94397.1; -; Genomic_DNA.
DR EMBL; AY495237; AAR94410.1; -; Genomic_DNA.
DR EMBL; AY495238; AAR94423.1; -; Genomic_DNA.
DR EMBL; AY495239; AAR94436.1; -; Genomic_DNA.
DR EMBL; AY495240; AAR94449.1; -; Genomic_DNA.
DR EMBL; AY495241; AAR94462.1; -; Genomic_DNA.
DR EMBL; AY495242; AAR94475.1; -; Genomic_DNA.
DR EMBL; AY495243; AAR94488.1; -; Genomic_DNA.
DR EMBL; AY495244; AAR94501.1; -; Genomic_DNA.
DR EMBL; AY495245; AAR94514.1; -; Genomic_DNA.
DR EMBL; AY495246; AAR94527.1; -; Genomic_DNA.
DR EMBL; AY495247; AAR94540.1; -; Genomic_DNA.
DR EMBL; AY495248; AAR94553.1; -; Genomic_DNA.
DR EMBL; AY495249; AAR94566.1; -; Genomic_DNA.
DR EMBL; AY495250; AAR94579.1; -; Genomic_DNA.
DR EMBL; AY495251; AAR94592.1; -; Genomic_DNA.
DR EMBL; AY495252; AAR94605.1; -; Genomic_DNA.
DR EMBL; AY495253; AAR94618.1; -; Genomic_DNA.
DR EMBL; AY495254; AAR94631.1; -; Genomic_DNA.
DR EMBL; AY495255; AAR94644.1; -; Genomic_DNA.
DR EMBL; AY495256; AAR94657.1; -; Genomic_DNA.
DR EMBL; AY495257; AAR94670.1; -; Genomic_DNA.
DR EMBL; AY495258; AAR94683.1; -; Genomic_DNA.
DR EMBL; AY495259; AAR94696.1; -; Genomic_DNA.
DR EMBL; AY495260; AAR94709.1; -; Genomic_DNA.
DR EMBL; AY495261; AAR94722.1; -; Genomic_DNA.
DR EMBL; AY495262; AAR94735.1; -; Genomic_DNA.
DR EMBL; AY495263; AAR94748.1; -; Genomic_DNA.
DR EMBL; AY495264; AAR94761.1; -; Genomic_DNA.
DR EMBL; AY495265; AAR94774.1; -; Genomic_DNA.
DR EMBL; AY495266; AAR94787.1; -; Genomic_DNA.
DR EMBL; AY495267; AAR94800.1; -; Genomic_DNA.
DR EMBL; AY495268; AAR94813.1; -; Genomic_DNA.
DR EMBL; AY495269; AAR94826.1; -; Genomic_DNA.
DR EMBL; AY495270; AAR94839.1; -; Genomic_DNA.
DR EMBL; AY495271; AAR94852.1; -; Genomic_DNA.
DR EMBL; AY495272; AAR94865.1; -; Genomic_DNA.
DR EMBL; AY495273; AAR94878.1; -; Genomic_DNA.
DR EMBL; AY495274; AAR94891.1; -; Genomic_DNA.
DR EMBL; AY495275; AAR94904.1; -; Genomic_DNA.
DR EMBL; AY495276; AAR94917.1; -; Genomic_DNA.
DR EMBL; AY495277; AAR94930.1; -; Genomic_DNA.
DR EMBL; AY495278; AAR94943.1; -; Genomic_DNA.
DR EMBL; AY495279; AAR94956.1; -; Genomic_DNA.
DR EMBL; AY495280; AAR94969.1; -; Genomic_DNA.
DR EMBL; AY495281; AAR94982.1; -; Genomic_DNA.
DR EMBL; AY495282; AAR94995.1; -; Genomic_DNA.
DR EMBL; AY495283; AAR95008.1; -; Genomic_DNA.
DR EMBL; AY495284; AAR95021.1; -; Genomic_DNA.
DR EMBL; AY495285; AAR95034.1; -; Genomic_DNA.
DR EMBL; AY495286; AAR95047.1; -; Genomic_DNA.
DR EMBL; AY495287; AAR95060.1; -; Genomic_DNA.
DR EMBL; AY495288; AAR95073.1; -; Genomic_DNA.
DR EMBL; AY495289; AAR95086.1; -; Genomic_DNA.
DR EMBL; AY495290; AAR95099.1; -; Genomic_DNA.
DR EMBL; AY495291; AAR95112.1; -; Genomic_DNA.
DR EMBL; AY495292; AAR95125.1; -; Genomic_DNA.
DR EMBL; AY495293; AAR95138.1; -; Genomic_DNA.
DR EMBL; AY495294; AAR95151.1; -; Genomic_DNA.
DR EMBL; AY495295; AAR95164.1; -; Genomic_DNA.
DR EMBL; AY495296; AAR95177.1; -; Genomic_DNA.
DR EMBL; AY495297; AAR95190.1; -; Genomic_DNA.
DR EMBL; AY495298; AAR95203.1; -; Genomic_DNA.
DR EMBL; AY495299; AAR95216.1; -; Genomic_DNA.
DR EMBL; AY495300; AAR95229.1; -; Genomic_DNA.
DR EMBL; AY495301; AAR95242.1; -; Genomic_DNA.
DR EMBL; AY495302; AAR95255.1; -; Genomic_DNA.
DR EMBL; AY495303; AAR95268.1; -; Genomic_DNA.
DR EMBL; AY495304; AAR95281.1; -; Genomic_DNA.
DR EMBL; AY495305; AAR95294.1; -; Genomic_DNA.
DR EMBL; AY495306; AAR95307.1; -; Genomic_DNA.
DR EMBL; AY495307; AAR95320.1; -; Genomic_DNA.
DR EMBL; AY495308; AAR95333.1; -; Genomic_DNA.
DR EMBL; AY495309; AAR95346.1; -; Genomic_DNA.
DR EMBL; AY495310; AAR95359.1; -; Genomic_DNA.
DR EMBL; AY495311; AAR95372.1; -; Genomic_DNA.
DR EMBL; AY495312; AAR95385.1; -; Genomic_DNA.
DR EMBL; AY495313; AAR95398.1; -; Genomic_DNA.
DR EMBL; AY495314; AAR95411.1; -; Genomic_DNA.
DR EMBL; AY495315; AAR95424.1; -; Genomic_DNA.
DR EMBL; AY495316; AAR95437.1; -; Genomic_DNA.
DR EMBL; AY495317; AAR95450.1; -; Genomic_DNA.
DR EMBL; AY495318; AAR95463.1; -; Genomic_DNA.
DR EMBL; AY495319; AAR95476.1; -; Genomic_DNA.
DR EMBL; AY495320; AAR95489.1; -; Genomic_DNA.
DR EMBL; AY495321; AAR95502.1; -; Genomic_DNA.
DR EMBL; AY495322; AAR95515.1; -; Genomic_DNA.
DR EMBL; AY495323; AAR95528.1; -; Genomic_DNA.
DR EMBL; AY495325; AAR95554.1; -; Genomic_DNA.
DR EMBL; AY495326; AAR95567.1; -; Genomic_DNA.
DR EMBL; AY495327; AAR95580.1; -; Genomic_DNA.
DR EMBL; AY495328; AAR95593.1; -; Genomic_DNA.
DR EMBL; AY495329; AAR95606.1; -; Genomic_DNA.
DR EMBL; AY495330; AAR95619.1; -; Genomic_DNA.
DR EMBL; X55654; CAA39187.1; -; mRNA.
DR PIR; A00472; OBHU2.
DR RefSeq; YP_003024029.1; NC_012920.1.
DR PDB; 3VRJ; X-ray; 1.90 A; C=46-55.
DR PDBsum; 3VRJ; -.
DR ProteinModelPortal; P00403; -.
DR SMR; P00403; 2-220.
DR IntAct; P00403; 15.
DR MINT; MINT-2799304; -.
DR STRING; 9606.ENSP00000354876; -.
DR BindingDB; P00403; -.
DR ChEMBL; CHEMBL6174; -.
DR TCDB; 3.D.4.11.1; the proton-translocating cytochrome oxidase (cox) superfamily.
DR PhosphoSite; P00403; -.
DR DMDM; 117020; -.
DR PaxDb; P00403; -.
DR PeptideAtlas; P00403; -.
DR PRIDE; P00403; -.
DR Ensembl; ENST00000361739; ENSP00000354876; ENSG00000198712.
DR GeneID; 4513; -.
DR KEGG; hsa:4513; -.
DR CTD; 4513; -.
DR GeneCards; GCMTP007587; -.
DR H-InvDB; HIX0080298; -.
DR HGNC; HGNC:7421; MT-CO2.
DR HPA; CAB016243; -.
DR MIM; 220110; phenotype.
DR MIM; 516040; gene.
DR neXtProt; NX_P00403; -.
DR Orphanet; 254905; Isolated cytochrome C oxidase deficiency.
DR Orphanet; 255210; Maternally-inherited Leigh syndrome.
DR Orphanet; 550; MELAS syndrome.
DR PharmGKB; PA31227; -.
DR eggNOG; COG1622; -.
DR HOGENOM; HOG000264988; -.
DR HOVERGEN; HBG012727; -.
DR InParanoid; P00403; -.
DR KO; K02261; -.
DR OMA; EDVLHSW; -.
DR OrthoDB; EOG7TJ3JX; -.
DR PhylomeDB; P00403; -.
DR ProtClustDB; MTH00098; -.
DR Reactome; REACT_111217; Metabolism.
DR GeneWiki; MT-CO2; -.
DR GenomeRNAi; 4513; -.
DR NextBio; 17431; -.
DR PRO; PR:P00403; -.
DR ArrayExpress; P00403; -.
DR Bgee; P00403; -.
DR Genevestigator; P00403; -.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005743; C:mitochondrial inner membrane; TAS:Reactome.
DR GO; GO:0045277; C:respiratory chain complex IV; IDA:UniProtKB.
DR GO; GO:0005507; F:copper ion binding; IEA:InterPro.
DR GO; GO:0004129; F:cytochrome-c oxidase activity; NAS:UniProtKB.
DR GO; GO:0006123; P:mitochondrial electron transport, cytochrome c to oxygen; NAS:UniProtKB.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 1.10.287.90; -; 1.
DR Gene3D; 2.60.40.420; -; 1.
DR InterPro; IPR001505; Copper_CuA.
DR InterPro; IPR008972; Cupredoxin.
DR InterPro; IPR014222; Cyt_c_oxidase_su2.
DR InterPro; IPR002429; Cyt_c_oxidase_su2_C.
DR InterPro; IPR011759; Cyt_c_oxidase_su2_TM_dom.
DR Pfam; PF00116; COX2; 1.
DR Pfam; PF02790; COX2_TM; 1.
DR SUPFAM; SSF49503; SSF49503; 1.
DR SUPFAM; SSF81464; SSF81464; 1.
DR TIGRFAMs; TIGR02866; CoxB; 1.
DR PROSITE; PS00078; COX2; 1.
DR PROSITE; PS50857; COX2_CUA; 1.
DR PROSITE; PS50999; COX2_TM; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Copper; Disease mutation;
KW Electron transport; Membrane; Metal-binding; Mitochondrion;
KW Mitochondrion inner membrane; Polymorphism; Reference proteome;
KW Respiratory chain; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1 227 Cytochrome c oxidase subunit 2.
FT /FTId=PRO_0000183610.
FT TOPO_DOM 1 26 Mitochondrial intermembrane (Potential).
FT TRANSMEM 27 48 Helical; (Potential).
FT TOPO_DOM 49 62 Mitochondrial matrix (Potential).
FT TRANSMEM 63 82 Helical; (Potential).
FT TOPO_DOM 83 227 Mitochondrial intermembrane (Potential).
FT METAL 161 161 Copper A (Probable).
FT METAL 196 196 Copper A (Probable).
FT METAL 200 200 Copper A (Probable).
FT METAL 204 204 Copper A (Probable).
FT VARIANT 11 11 D -> A.
FT /FTId=VAR_008863.
FT VARIANT 29 29 M -> K (in MT-C4D; affect the stability
FT of the COX complex).
FT /FTId=VAR_035085.
FT VARIANT 30 30 I -> V.
FT /FTId=VAR_011344.
FT VARIANT 123 123 L -> P.
FT /FTId=VAR_008571.
FT VARIANT 142 142 V -> M (in colorectal cancer).
FT /FTId=VAR_008390.
FT VARIANT 148 148 A -> T.
FT /FTId=VAR_011345.
FT VARIANT 187 187 T -> M.
FT /FTId=VAR_008572.
SQ SEQUENCE 227 AA; 25565 MW; 402A3145241DDEE6 CRC64;
MAHAAQVGLQ DATSPIMEEL ITFHDHALMI IFLICFLVLY ALFLTLTTKL TNTNISDAQE
METVWTILPA IILVLIALPS LRILYMTDEV NDPSLTIKSI GHQWYWTYEY TDYGGLIFNS
YMLPPLFLEP GDLRLLDVDN RVVLPIEAPI RMMITSQDVL HSWAVPTLGL KTDAIPGRLN
QTTFTATRPG VYYGQCSEIC GANHSFMPIV LELIPLKIFE MGPVFTL
//

MIM 220110
*RECORD*
*FIELD* NO
220110
*FIELD* TI
#220110 MITOCHONDRIAL COMPLEX IV DEFICIENCY
;;CYTOCHROME c OXIDASE DEFICIENCY;;
COX DEFICIENCY
read more*FIELD* TX
A number sign (#) is used with this entry because cytochrome c oxidase
deficiency can be caused by mutation in several nuclear-encoded and
mitochondrial-encoded genes. Mutations associated with the disorder have
been identified in several mitochondrial COX genes, MTCO1 (516030),
MTCO2 (516040), MTCO3 (516050), as well as in mitochondrial tRNA(ser)
(MTTS1; 590080) and tRNA(leu) (MTTL1; 590050).

Mutations in nuclear genes include those in COX10 (602125), COX6B1
(124089), SCO1 (603644), FASTKD2 (612322), C2ORF64 (613920), C12ORF62
(614478), and COX20 (614698). COX deficiency caused by mutation in SCO2
(604272) and COX15 (603646) have been found to be associated with fatal
infantile cardioencephalomyopathy (604377).

Cytochrome c oxidase deficiency associated with Leigh syndrome (see
256000) may be caused by mutation in the SURF1 gene (185620), COX15 gene
(603646), or TACO1 gene (612958). Cytochrome c oxidase deficiency
associated with the French-Canadian type of Leigh syndrome (LSFC;
220111) is caused by mutation in the LRPPRC gene (607544).

DESCRIPTION

Complex IV (cytochrome c oxidase; EC 1.9.3.1) is the terminal enzyme of
the respiratory chain and consists of 13 polypeptide subunits, 3 of
which are encoded by mitochondrial DNA. The 3 mitochondrially encoded
proteins in the cytochrome oxidase complex are the actual catalytic
subunits that carry out the electron transport function (Saraste, 1983).
See 123995 for discussion of some of the nuclear-encoded subunits.

Shoubridge (2001) provided a comprehensive review of cytochrome c
oxidase deficiency and noted that most isolated COX deficiencies are
inherited as autosomal recessive disorders caused by mutations in
nuclear-encoded genes; mutations in the mtDNA-encoded COX subunit genes
are relatively rare.

CLINICAL FEATURES

Cytochrome c oxidase deficiency is clinically heterogeneous, ranging
from isolated myopathy to severe multisystem disease, with onset from
infancy to adulthood (Shoubridge, 2001).

Van Biervliet et al. (1977) described a Dutch family in which 3 sibs,
including twin sisters, died of infantile mitochondrial myopathy, lactic
acidosis, and de Toni-Fanconi-Debre renal syndrome due to cytochrome c
oxidase deficiency. Lipid droplets and focal glycogen accumulation could
be attributed to blockage of terminal oxidative metabolism. A similar
defect in the renal tubule was presumably responsible for proteinuria,
glycosuria, hyperphosphaturia, hypercalciuria, and generalized amino
aciduria. Heart, liver, and brain were spared.

Willems et al. (1977) reported an association between cytochrome c
oxidase deficiency and Leigh encephalomyelopathy in a child who died at
age 6 years. See 256000 for a full discussion of COX deficiency
associated with Leigh syndrome.

DiMauro et al. (1980) reported an infant with hypotonia, ptosis,
diminished reflexes, poor suck, lactic acidosis, proteinuria,
glucosuria, and amino aciduria who died at age 3.5 months. Muscle biopsy
showed increased lipid droplets and abnormal mitochondria. Cytochrome c
oxidase was decreased in skeletal muscle and kidney. Muller-Hocker et
al. (1983) studied 2 Turkish sisters who developed apathy, failure of
suckling, and generalized progressive muscular hypotonia in the newborn
period and died at age 7 weeks. Both children had generalized
hyperaminoaciduria. Hepatic encephalopathy was absent. Autopsy showed
fatty metamorphosis of the liver, bilateral hydroureters, renotubular
calcifications, and generalized lipid storage myopathy, mainly in type I
fibers. Cytochrome c oxidase activity was absent not only in the
myopathic fibers but also in 'most of the morphologically unchanged
muscle fibers.'

Eshel et al. (1991) described an inbred Bedouin kindred with 6 affected
children in 3 sibships related as double first cousins. They had a
mitochondrial myopathy presenting with progressive muscular weakness,
failure to thrive, proximal renal tubular acidosis, and lactic acidemia
leading to death. The affected children were 3 females and 3 males. Of
the children studied most extensively, 2 died at age 5 months and 1 at
age 16 months. Cytochrome c oxidase was markedly reduced in skeletal
muscle extracts of all 3. The findings were those described originally
by Van Biervliet et al. (1977).

Chabrol et al. (1994) described a 3-year-old girl who, after 3 months of
treatment with valproate for myoclonic epilepsy, developed fatal hepatic
failure. Deficiency of cytochrome c oxidase found in circulating
lymphocytes and in postmortem liver and cultured skin fibroblasts was
thought to have rendered the patient susceptible to hepatic failure. A
fully functional respiratory chain was found in muscle. Valproate
sensitivity has been described in association with ornithine
transcarbamylase deficiency (311250), argininemia (207800), and
citrullinemia (215700), all causes of hyperammonemia.

Bakker et al. (1996) reported the case of a boy, a second child of
nonconsanguineous parents, who was born after a term pregnancy and
normal delivery. It was the third pregnancy of the mother: the first
ended at 19 weeks with death in utero of twins; the second ended at term
with the birth of a healthy boy. The patient was admitted to hospital at
the age of 1 day for evaluation of feeding difficulties and tachypnea.
Laboratory investigations revealed severe metabolic acidosis with
elevated lactate and pyruvate levels. In fibroblasts, lymphoblasts, and
liver, complex IV showed about a 2-fold reduction in enzymatic activity;
in muscle the reduction was more severe. Structural and functional
abnormalities of the brain became evident after the initial lactic
acidosis had been corrected by treatment. Periventricular leukomalacia
was absent, whereas myelination had progressed around the lateral
ventricles, the anterior and posterior capsular limbs, and the thalamus.
A remarkable subcortical atrophy of the cerebellar hemispheres was
present, and the cerebellum was affected by severe atrophy of both the
vermis and the cerebellar hemispheres. Bakker et al. (1996) reported
that the abnormalities found on neuroimaging reflected a progressive
brain disorder rather than sequelae of perinatal injury, but noted that
MRI findings typical of Leigh syndrome, another presentation of COX
deficiency (DiMauro et al., 1994), were not found in this patient. The
authors suggested that this case was a rare type of early-onset
progressive encephalopathy associated with COX deficiency.

In a study of 157 patients with respiratory chain defects, von
Kleist-Retzow et al. (1998) found that the deficiency resided in complex
I in 33%, in complex IV in 28%, and in complex I and IV in 28%.
Deficiency of complex II and complex III accounted for 4% and 7% of
cases, respectively. 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. For the entire series the sex ratio was mostly
balanced but 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, and in North
African families (76%), suggesting autosomal recessive inheritance.

Rubio-Gozalbo et al. (1999) reported a boy with features of spinal
muscular atrophy who presented with hypotonia, severe axial and limb
weakness with frog posture, but normal bulbar musculature. The boy died
at the age of 5 months from progressive respiratory failure. EMG showed
a patchy distribution of positive sharp waves and fibrillation
potentials, but normal motor nerve conduction velocities. Muscle biopsy
showed a preponderance of type I fibers, with atrophy of both fiber
types. An asymptomatic hypertrophic cardiomyopathy was present.
Cytochrome c oxidase activity was absent from all but intrafusal muscle
fibers and the activity was reduced in cultured skin fibroblasts.
Western blot analysis demonstrated decreased levels of all COX subunits.
Analysis of mitochondrial DNA and the SMN gene were unrevealing.

Haller et al. (1989) found COX deficiency in a 27-year-old nurse with
lifelong exercise intolerance marked by exertional dyspnea and
tachycardia in association with premature fatigue of active muscles with
lactic acidosis on exertion.

Ghezzi et al. (2008) reported 2 children of a consanguineous Bedouin
couple who had a total of 7 children. The first child was a female born
at term after an uneventful pregnancy by cesarean section due to
nonprogression of labor. She had bilateral congenital hip dislocation
present at birth. Social and motor development were reported as normal
until 7 months of age. At that time she suffered from febrile illness
and developed refractory generalized tonic-clonic convulsions. Brain MRI
showed generalized symmetric atrophy, and she subsequently developed
psychomotor delay and left-sided hemiplegia with facial nerve
involvement. CT scan at 5 years of age showed severe atrophic changes on
the right hemisphere. Plasma lactate was mildly increased (2.4-3.2 mM in
different samples). At 14 years of age, she was able to obey simple
commands in 2 languages, could recognize colors, and had a 20-word
vocabulary. She could sit herself up and move herself relatively
smoothly along the floor while sitting, but was never able to stand or
walk. Her hearing was intact but eyesight was impaired because of
bilateral optic atrophy. She had left spastic hemiparesis; on the right
side muscle tone was decreased with reduced strength. The EEG revealed
bilateral epileptic activity. Biochemical assays on isolated
mitochondria showed reduced activity of cytochrome C oxidase, to 21% of
the control mean. All other mitochondrial respiratory chain complexes of
the pyruvate dehydrogenase complex were within normal limits. The second
child, male, was the sixth child of the couple, born at term with
uneventful early development. After a febrile gastroenteritis at 1 year
of age, the patient experienced subacute neurologic deterioration with
muscle hypotonia and extrapyramidal movements, mainly in the left limbs.
Brain MRI disclosed increased signal intensities on the left caudate
nucleus, globus pallidus, and crus cerebri. Epilepsy, first noted at
around 1 year, became refractory to treatment in the third year of life.
The patient experienced prolonged episodes of status epilepticus. A
brain CT scan at 30 months revealed generalized and white matter
atrophy, more pronounced on the left basal ganglia, with bilateral
dilatation of the ventricles and basal cysternae. At 4 years he was
bedridden with neither communication nor any voluntary activity. He had
bilateral optic atrophy and strabismus. Muscle tone was decreased with
hyperreflexia and dystonic posturing. Cerebrospinal fluid (CSF) lactate
was increased to 3.8 mM (normal less than 1.8 mM), and the activity of
COX in his lymphocytes was reported as markedly decreased. Plasma
lactate was normal. In both sibs echocardiography, abdominal ultrasound,
blood count, and liver and renal function tests were normal.

MOLECULAR GENETICS

- Mutations in Mitochondrial-encoded Genes

In a 15-year-old girl with COX deficiency manifesting as
exercise-induced muscle cramps and myoglobinuria, Keightley et al.
(1996) identified a 15-bp deletion in the MTCO3 gene (516050.0003). In a
36-year-old woman with COX deficiency, exercise intolerance, proximal
myopathy, and episodes of encephalopathy accompanied by lactic acidemia,
Hanna et al. (1998) identified a nonsense mutation in the MTCO3 gene
(516050.0004). Tiranti et al. (2000) identified a frameshift mutation in
the MTCO3 gene (516050.0005) in a COX-deficient girl with spastic
paraparesis, ophthalmoplegia, moderate mental retardation, lactic
acidosis, and 'Leigh-like lesions' in the basal ganglia.

Jaksch et al. (1998) studied 21 unrelated individuals with mitochondrial
disorders and predominant (7 individuals) or isolated (14 individuals)
COX deficiency. Twenty-five mitochondrial genes (3 COX subunit genes and
22 tRNA genes) and 10 nuclear COX subunit genes were examined for
disease-associated mutations. Two distinct tRNA mutations (590080.0001
and 590080.0003) were found in each of 4 patients in a subgroup with
sensorineural hearing loss, ataxia, myoclonic epilepsy, and mental
retardation. One of these patients, as well as her mother and sister,
also had a mutation (516030.0004) in the mitochondrial encoded COX
subunit I gene (MTCO1).

Bruno et al. (1999) reported a 21-year-old Italian woman who at the age
of 3 years had been found to have bilateral cataracts, which required
surgical treatment. At age 7 years, she developed progressive
sensorineural hearing loss. During the following years, she developed
myoclonic epilepsy with electroencephalographic (EEG) evidence of slow
waves and isolated spikes, cerebellar ataxia, mild muscle weakness, and
progressive visual loss. At 12 years, she showed hyperlactic acidemia
and elevated serum creatine kinase. Clinical examination at age 21 years
showed diffuse muscle atrophy, severe generalized muscle weakness, limb
ataxia, severe visual defect with optic atrophy, and complete deafness.
Brain MRI showed diffuse cerebellar atrophy and bilateral symmetric
hyperintensities in the basal ganglia. Mitochondrial DNA analysis
revealed a mutation in the COX subunit I gene (516030.0006).

In a family with COX deficiency, Clark et al. (1999) identified a
mutation in the initiation codon of the MTCO2 gene (516040.0001). The
index case was the mother, a 57-year-old woman of normal intellect with
a 5- to-10-year history of fatigue and unsteadiness of gait. There was
no clinical evidence of retinal disease, deafness, muscle weakness, or
cardiac disease. Her 34-year-old son was severely affected. Although
normal at birth and in early childhood, at age 5 years he developed
progressive gait ataxia, becoming wheelchair-bound by age 25 years. He
was severely cognitively impaired. Clinical examination demonstrated
bilateral optic atrophy, pigmentary retinopathy, a marked decrease in
color vision, and mild distal muscle wasting. The mutation load was
present at 67% in muscle from the index case and at 91% in muscle from
the clinically affected son. Muscle biopsy samples revealed isolated COX
deficiency and mitochondrial proliferation.

Sacconi et al. (2003) performed a broad search for mutations using 25
mitochondrial genes (3 COX subunit genes and 22 tRNA genes) and 7
nuclear COX subunit genes in 30 patients with known cytochrome C
deficiency and varying clinical phenotypes. Only 3 mutations were found,
all in nuclear genes. The authors suggested that mtDNA COX mutations are
rare.

Meulemans et al. (2006) reported a 13-year-old boy with combined
deficiency of mitochondrial complex I (252010) and IV 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.

- Mutations in Nuclear-encoded Genes

In a series of 18 patients with isolated COX deficiency, Parfait et al.
(1997) failed to detect mutations in the 3 mitochondrially encoded COX
subunits of complex IV (MTCO1, MTCO2, and MTCO3). The authors concluded
that disease-causing mutations may lie in nuclear genes encoding COX
subunits or proteins involved in assembly of the complex.

Zhu et al. (1998) and Tiranti et al. (1998) identified mutations in the
SURF1 gene (see, e.g., 185620.0001) in patients with Leigh syndrome due
to cytochrome c oxidase deficiency.

Papadopoulou et al. (1999) identified mutations in the SCO2 gene (see,
e.g., 604272.0001) in 3 unrelated infants COX deficiency associated with
fatal infantile cardioencephalomyopathy (604377). Immunohistochemical
studies implied that the enzymatic deficiency, which was most severe in
cardiac and skeletal muscle, was due to the loss of mitochondrial
DNA-encoded COX subunits.

Valnot et al. (2000) performed a genetic linkage study of a
consanguineous family with an isolated cytochrome c oxidase defect and
mapped the disease gene to chromosome 17p13.1-q11.1, near COX10, a gene
that encodes a complex IV assembly protein. A homozygous missense
mutation in the COX10 gene (602125.0001) was identified. Western blot
analysis of patient fibroblasts revealed almost undetectable levels of
COX subunit II. Furthermore, the mutant allele failed to correct a yeast
cox10 mutant strain, thus confirming the biochemical effects of the
mutation.

Valnot et al. (2000) described COX deficiency caused by mutation in the
SCO1 gene (603644.0001-603644.0002). Patients presented with hepatic
failure and neurologic disturbance.

In 21 of 22 patients with the French-Canadian type of Leigh syndrome
associated with COX deficiency, Mootha et al. (2003) identified a
homozygous mutation in the LRPPRC gene (607544.0001). The remaining
patient was a compound heterozygote for 607544.0001 and 607544.0002.

Sacconi et al. (2003) performed a broad search for mutations using 25
mitochondrial genes and 7 nuclear COX subunit genes in 30 patients with
known cytochrome C deficiency and varying clinical phenotypes. Only 3
mutations were found; a novel SURF1 mutation in a Leigh syndrome patient
and 1 novel and 1 known SCO2 mutation in a patient with hypertrophic
cardiomyopathy.

In a patient with Leigh syndrome due cytochrome c oxidase deficiency,
Oquendo et al. (2004) identified homozygosity for a mutation in the
COX15 gene (603646.0001).

Antonicka et al. (2003) reported 2 unrelated patients with COX
deficiency caused by mutations in the COX10 gene
(602125.0002-602125.0005). One of the patients had sensorineural hearing
loss, anemia, and hypertrophic cardiomyopathy, whereas the other patient
had features consistent with Leigh syndrome. The authors emphasized the
different phenotypic characteristics.

Massa et al. (2008) identified a homozygous mutation in the COX6B1 gene
(124089.0001) in 2 sibs with COX deficiency. After a normal development,
the boys had onset of muscle weakness and pain or unsteady gait and
visual disturbances at ages 8 and 6, respectively. The older boy had
rapidly progressive neurologic deterioration with leukodystrophic brain
changes and seizures and died at age 10 years. The younger boy had
ataxia, muscle weakness, cognitive decline, decreased visual acuity, and
leukodystrophic changes in the brain. Both had increased serum and CSF
lactate and decreased COX activity (20% of normal) in muscle biopsy.

In 2 children with COX deficiency born of first-cousin Bedouin parents,
Ghezzi et al. (2008) identified homozygosity for a nonsense mutation in
the FASTKD2 gene (612322.0001). Both patients had normal early
development, with development of neurologic deterioration, including
hemiplegia and epilepsy, after a febrile illness.

In affected members of a family with childhood-onset and slowly
progressive Leigh syndrome due to mitochondrial complex IV deficiency,
Weraarpachai et al. (2009) identified a homozygous 1-bp insertion
(472insC; 612958.0001) in the TACO1 gene. Synthesis of the MTCO1 subunit
was decreased by approximately 65%, and there was a greatly reduced
steady-state level of fully assembled complex IV. Expression of wildtype
TACO1 rescued the MTCO1 assembly defect and complex IV activity.

In 2 Turkish sibs, born of consanguineous Turkish parents, with
cytochrome c oxidase deficiency manifest as lethal neonatal hypertrophic
cardiomyopathy, Huigsloot et al. (2011) identified a homozygous mutation
in the C2ORF64 gene (A53P; 613920.0001). The patients died at ages 8 and
10 days of life, respectively. Postmortem examination showed
accumulation of lipid droplets in cardiomyocytes and mitochondrial
proliferation; however, neither patient had documented functional
impairment of brain or skeletal muscle. The activity and amount of
complex IV was severely reduced in patient fibroblasts and heart muscle,

In 3 sibs, born of consanguineous Portuguese parents, with COX
deficiency, Weraarpachai et al. (2012) identified a homozygous mutation
in the C12ORF62 gene (M19I; 614478.0001). The proband presented with
neurologic and respiratory distress immediately after birth. She was
dysmorphic with hypotelorism, microphthalmia, an ogival palate, and a
single unilateral palmar crease. She developed severe metabolic lactic
acidosis and ketonuria, and died 24 hours after birth. Postmortem
examination showed brain hypertrophy, altered myelination, numerous
cavities throughout the brain, hepatomegaly, hypertrophic
cardiomyopathy, renal hypoplasia, and adrenal hyperplasia. Her sibs had
a similar disease course. Biochemical analysis of patient fibroblasts
showed reduced COX activity at 30 to 40% of controls, which was
associated with a specific reduction in the amount of fully assembled
COX. The mutation was found using a combination of microcell-mediated
chromosome transfer, homozygosity mapping, and transcript profiling.

In a boy, born of consanguineous Turkish parents, with complex IV
deficiency, Szklarczyk et al. (2013) identified a homozygous mutation in
the COX20 gene (T52P; 614698.0001). The boy was born at term with low
birth weight and length and decreased head circumference. He showed
muscular hypotonia and delayed walking with unsteady gait that developed
into cerebellar ataxia with intention tremor and pyramidal signs. Speech
was delayed. Laboratory studies showed increased serum and CSF lactate
suggestive of a mitochondrial disorder. Respiratory chain complex
studies showed reduced activity of mitochondrial complex IV. Brain MRI,
echocardiography, and hearing and vision tests were all normal. At age
10 years, he had short stature and low weight with a normal head
circumference. The mutation was found by analyzing candidate genes. No
mutation in the COX20 gene was found in 39 additional patients with COX
deficiency.

CYTOGENETICS

Van Bon et al. (2013) reported a 12-year-old girl, born of
consanguineous Turkish parents, with severe intellectual disability,
lack of speech development, facial dysmorphism, increased serum lactate,
and isolated mitochondrial complex IV deficiency associated with a
homozygous 78-kb deletion on chromosome 19q13.11 including exons 15-19
of the CEP89 gene (615470) as well as the SLC7A9 gene (604144). The
unaffected parents were heterozygous for the deletion. The patient also
had cystinuria (220100), which is known to be caused by biallelic loss
of SLC7A9. However, the additional features had never been reported in
cystinuria, implicating loss of CEP89 in complex IV deficiency. In
infancy, the patient showed delayed development, cataracts, severe
deafness, and poor feeding. Brain MRI was normal, but electromyography
revealed signs of myopathy and auditory evoked potentials showed signs
of peripheral conduction dysfunction. Dysmorphic features included
hypotelorism, small low-set ears, columella below the alae nasi,
micrognathia, short broad neck, camptodactyly of fifth fingers, and
calcinosis cutis. She had difficulty walking, a broad-based gait, and
ataxic arm movements. Based on knockdown studies in Drosophila, van Bon
et al. (2013) concluded that CEP89 plays an important role in
mitochondrial complex IV activity and is required for proper cognitive
and neuronal function. Mutations in the CEP89 gene were not found in 29
additional patients with complex IV deficiency.

GENOTYPE/PHENOTYPE CORRELATIONS

The nuclear genes COX10, SURF1, and SCO2, all linked to isolated COX
deficiency, are involved in the maturation and assembly of COX,
emphasizing the major role of such genes in COX pathology. Valnot et al.
(2000) noted the difference in clinical phenotype caused by mutations in
these 3 genes. SURF1 mutations are associated with subacute necrotizing
encephalomyopathy, known as Leigh syndrome. Patients with SCO2 mutations
present with encephalocardiomyopathy. Patients with the COX10 mutation
present with tubulopathy and leukodystrophy.

Bohm et al. (2006) published a retrospective, multicenter study of 180
children with COX deficiency in the Slavonic population, including 101
patients with isolated complex IV deficiency and 79 with combined
respiratory chain complex deficiency. Pathogenic mutations were
identified in 75 patients. Mutations in the SURF1 gene were found in 47
children from 35 families, with a specific 2-bp deletion (845delCT;
185620.0014) present in 89% of independent alleles. All children with
SURF1 mutations had Leigh syndrome. Nine children with encephalomyopathy
and/or cardiomyopathy had mutations in the SCO2 gene, all of whom
carried the 1541G-A allele (604272.0002). Nine children with combined
deficiency had different mitochondrial DNA deletions or depletions,
including 6 with a common MTTL1 mutation (3243A-G; 590050.0001).
Clinically, patients presented in infancy or early childhood with
encephalopathy and nervous system impairment combined with failure to
thrive. Blood and CSF lactate were increased in 85% and 81% of examined
cases, respectively. Children with earlier disease onset, especially
those with mutations in the SURF1 and SCO2 genes, had more severe
disease. Sixty-six percent of the patients died in childhood, nearly
half of them within the first 18 months of life.

POPULATION GENETICS

In the French Canadian population of the Saguenay-Lac-Saint-Jean region
of Quebec Province, De Braekeleer (1991) estimated the prevalence at
birth of cytochrome c oxidase deficiency to be 1 in 2,473, giving a
carrier frequency of 1 in 28.

ANIMAL MODEL

Agostino et al. (2003) created a constitutive knockout mouse for SURF1
(185620). Postimplantation embryonic lethality affected 90% of Surf1 -/-
homozygotes; approximately 30% of liveborn animals died within the first
postnatal month, and an additional 15% died within the first 6 months of
life. Significant deficit in muscle strength and motor performance was
observed, without obvious abnormalities in brain morphology or overt
neurologic symptoms. A profound and isolated defect of COX activity in
skeletal muscle and liver was detected, and reduced histochemical
reaction to COX and mitochondrial proliferation in skeletal muscle was
present.

Mutations in SCO2 (604272) cause a fatal infantile
cardioencephalomyopathy with cytochrome c oxidase (COX) deficiency. Yang
et al. (2010) generated mice harboring a Sco2 knockout allele and a Sco2
knockin allele expressing a E129K mutation, corresponding to the E140K
(604272.0002) mutation found in almost all human SCO2-mutated patients.
Whereas homozygous knockout mice were embryonic lethals, homozygous
knockin and compound heterozygous knockin/knockout mice were viable, but
had muscle weakness. Biochemical assay of viable mice showed respiratory
chain deficiencies as well as complex IV assembly defects in multiple
tissues. There was a concomitant reduction in mitochondrial copper
content, but the total amount of copper in examined tissues was not
reduced.

*FIELD* SA
Arts et al. (1987); Glerum et al. (1987); Minchom et al. (1983); Monnens
et al. (1975); Ogier et al. (1988); Robinson et al. (1986)
*FIELD* RF
1. Agostino, A.; Invernizzi, F.; Tiveron, C.; Fagiolari, G.; Prelle,
A.; Lamantea, E.; Giavazzi, A.; Battaglia, G.; Tatangelo, L.; Tiranti,
V.; Zeviani, M.: Constitutive knockout of Surf1 is associated with
high embryonic lethality, mitochondrial disease and cytochrome c oxidase
deficiency in mice. Hum. Molec. Genet. 12: 399-413, 2003.

2. Antonicka, H.; Leary, S. C.; Guercin, G.-H.; Agar, J. N.; Horvath,
R.; Kennaway, N. G.; Harding, C. O.; Jaksch, M.; Shoubridge, E. A.
: Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis
and account for multiple, early-onset clinical phenotypes associated
with isolated COX deficiency. Hum. Molec. Genet. 12: 2693-2702,
2003.

3. Arts, W. F. M.; Scholte, H. R.; Loonen, M. C. B.; Przyrembel, H.;
Fernandes, J.; Trijbels, J. M. F.; Luyt-Houwen, I. E. M.: Cytochrome
c oxidase deficiency in subacute necrotizing encephalomyelopathy. J.
Neurol. Sci. 77: 103-115, 1987.

4. Bakker, H. D.; Van Den Bogert, C.; Drewes, J. G.; Barth, P. G.;
Scholte, H. R.; Wanders, R. J. A.; Ruitenbeek, W.: Progressive generalized
brain atrophy and infantile spasms associated with cytochrome c oxidase
deficiency. J. Inherit. Metab. Dis. 19: 153-156, 1996.

5. Bohm, M.; Pronicka, E.; Karczmarewicz, E.; Pronicki, M.; Piekutowska-Abramczuk,
D.; Sykut-Cegielska, J.; Mierzewska, H.; Hansikova, H.; Vesela, K.;
Tesarova, M.; Houstkova, H.; Houstek, J.; Zeman, J.: Retrospective,
multicentric study of 180 children with cytochrome c oxidase deficiency. Pediat.
Res. 59: 21-26, 2006.

6. Bruno, C.; Martinuzzi, A.; Tang, Y.; Andreu, A. L.; Pallotti, F.;
Bonilla, E.; Shanske, S.; Fu, J.; Sue, C. M.; Angelini, C.; DiMauro,
S.; Manfredi, G.: A stop-codon mutation in the human mtDNA cytochrome
c oxidase I gene disrupts the functional structure of complex IV. Am.
J. Hum. Genet. 65: 611-620, 1999.

7. Chabrol, B.; Mancini, J.; Chretien, D.; Rustin, P.; Munnich, A.;
Pinsard, N.: Valproate-induced hepatic failure in a case of cytochrome
c oxidase deficiency. Europ. J. Pediat. 153: 133-135, 1994.

8. Clark, K. M.; Taylor, R. W.; Johnson, M. A.; Chinnery, P. F.; Chrzanowska-Lightowlers,
Z. M. A.; Andrews, R. M.; Nelson, I. P.; Wood, N. W.; Lamont, P. J.;
Hanna, M. G.; Lightowlers, R. N.; Turnbull, D. M.: An mtDNA mutation
in the initiation codon of the cytochrome c oxidase subunit II gene
results in lower levels of the protein and a mitochondrial encephalomyopathy. Am.
J. Hum. Genet. 64: 1330-1339, 1999.

9. De Braekeleer, M.: Hereditary disorders in Saguenay-Lac-St-Jean
(Quebec, Canada). Hum. Hered. 41: 141-146, 1991.

10. DiMauro, S.; Hirano, M.; Bonilla, E.; Moraes, C. T.; Schon, E.
A.: Cytochrome oxidase deficiency: progress and problems.In: Shapira,
A. H. V.; DiMauro, S. (eds.): Mitochondrial Disorders in Neurology.
Oxford: Butterworth-Heinemann 1994. Pp. 91-115.

11. DiMauro, S.; Mendell, J. R.; Sahenk, Z.; Bachman, D.; Scarpa,
A.; Scofield, R. M.; Reiner, C.: Fatal infantile mitochondrial myopathy
and renal dysfunction due to cytochrome-c-oxidase deficiency. Neurology 30:
795-804, 1980.

12. Eshel, G.; Lahat, E.; Fried, K.; Barr, J.; Barash, V.; Gutman,
A.; DiMauro, S.; Aladjem, M.: Autosomal recessive lethal infantile
cytochrome c oxidase deficiency. Am. J. Dis. Child. 145: 661-664,
1991.

13. Ghezzi, D.; Saada, A.; D'Adamo, P.; Fernandez-Vizarra, E.; Gasparini,
P.; Tiranti, V.; Elpeleg, O.; Zeviani, M.: FASTKD2 nonsense mutation
in an infantile mitochondrial encephalomyopathy associated with cytochrome
C oxidase deficiency. Am. J. Hum. Genet. 83: 415-423, 2008.

14. Glerum, M.; Robinson, B. H.; Spratt, C.; Wilson, J.; Patrick,
D.: Abnormal kinetic behavior of cytochrome oxidase in a case of
Leigh disease. Am. J. Hum. Genet. 41: 584-593, 1987.

15. Haller, R. G.; Lewis, S. F.; Estabrook, R. W.; DiMauro, S.; Servidei,
S.; Foster, D. W.: Exercise intolerance, lactic acidosis, and abnormal
cardiopulmonary regulation in exercise associated with adult skeletal
muscle cytochrome c oxidase deficiency. J. Clin. Invest. 84: 155-161,
1989.

16. Hanna, M. G.; Nelson, I. P.; Rahman, S.; Lane, R. J. M.; Land,
J.; Heales, S.; Cooper, M. J.; Schapira, A. H. V.; Morgan-Hughes,
J. A.; Wood, N. W.: Cytochrome c oxidase deficiency associated with
the first stop-codon point mutation in human mtDNA. Am. J. Hum. Genet. 63:
29-36, 1998.

17. Huigsloot, M.; Nijtmans, L. G.; Szklarczyk, R.; Baars, M. J. H.;
van den Brand, M. A. M.; HendriksFranssen, M. G. M.; van den Heuvel,
L. P.; Smeitink, J. A. M.; Huynen, M. A.; Rodenburg, R. J. T.: A
mutation in C2orf64 causes impaired cytochrome C oxidase assembly
and mitochondrial cardiomyopathy. Am. J. Hum. Genet. 88: 488-493,
2011.

18. Jaksch, M.; Hofmann, S.; Kleinle, S.; Liechti-Gallati, S.; Pongratz,
D. E.; Muller-Hocker, J.; Jedele, K. B.; Meitinger, T.; Gerbitz, K.-D.
: A systematic mutation screen of 10 nuclear and 25 mitochondrial
candidate genes in 21 patients with cytochrome c oxidase (COX) deficiency
shows tRNA-ser(UCN) mutations in a subgroup with syndromal encephalopathy. J.
Med. Genet. 35: 895-900, 1998.

19. Keightley, J. A.; Hoffbuhr, K. C.; Burton, M. D.; Salas, V. M.;
Johnston, W. S. W.; Penn, A. M. W.; Buist, N. R. M.; Kennaway, N.
G.: A microdeletion in cytochrome c oxidase (COX) subunit III associated
with COX deficiency and recurrent myoglobinuria. Nature Genet. 12:
410-416, 1996.

20. Massa, V.; Fernandez-Vizarra, E.; Alshahwan, S.; Bakhsh, E.; Goffrini,
P.; Ferrero, I.; Mereghetti, P.; D'Adamo, P.; Gasparini, P.; Zeviani,
M.: Severe infantile encephalomyopathy caused by a mutation in COX6B1,
a nucleus-encoded subunit of cytochrome c oxidase. Am. J. Hum. Genet. 82:
1281-1289, 2008.

21. Meulemans, A.; Seneca, S.; Lagae, L.; Lissens, W.; De Paepe, B.;
Smet, J.; Van Coster, R.; De Meirleir, L.: A novel mitochondrial
transfer RNA-Asn mutation causing multiorgan failure. Arch. Neurol. 63:
1194-1198, 2006.

22. Minchom, P. E.; Dormer, R. L.; Hughes, I. A.; Stansbie, D.; Cross,
A. R.; Hendry, G. A. F.; Jones, O. T. G.; Johnson, M. A.; Sherratt,
H. S. A.; Turnbull, D. M.: Fatal infantile mitochondrial myopathy
due to cytochrome c oxidase deficiency. J. Neurol. Sci. 60: 453-463,
1983.

23. Monnens, L.; Gabreels, F.; Willems, J.: A metabolic myopathy
associated with chronic lactic acidemia, growth failure, and nerve
deafness. (Letter) J. Pediat. 86: 983 only, 1975.

24. Mootha, V. K.; Lepage, P.; Miller, K.; Bunkenborg, J.; Reich,
M.; Hjerrild, M.; Delmonte, T.; Villeneuve, A.; Sladek, R.; Xu, F.;
Mitchell, G. A.; Morin, C.; Mann, M.; Hudson, T. J.; Robinson, B.;
Rioux, J. D.; Lander, E. S.: Identification of a gene causing human
cytochrome c oxidase deficiency by integrative genomics. Proc. Nat.
Acad. Sci. 100: 605-610, 2003.

25. Muller-Hocker, J.; Pongratz, D.; Deufel, T.; Trijbels, J. M. F.;
Endres, W.; Hubner, G.: Fatal lipid storage myopathy with deficiency
of cytochrome-c-oxidase and carnitine: a contribution to the combined
cytochemical-finestructural identification of cytochrome-c-oxidase
in longterm frozen muscle. Virchows Arch. A Path. Anat. Histopath. 399:
11-23, 1983.

26. Ogier, H.; Lombes, A.; Scholte, H. R.; Poll-The, B. T.; Fardeau,
M.; Alcardi, J.; Vignes, B.; Niaudet, P.; Saudubray, J. M.: de Toni-Fanconi-Debre
syndrome with Leigh syndrome revealing severe muscle cytochrome c
oxidase deficiency. J. Pediat. 112: 734-739, 1988.

27. Oquendo, C. E.; Antonicka, H.; Shoubridge, E. A.; Reardon, W.;
Brown, G. K.: Functional and genetic studies demonstrate that mutation
in the COX15 gene can cause Leigh syndrome. (Letter) J. Med. Genet. 41:
540-544, 2004.

28. Papadopoulou, L. C.; Sue, C. M.; Davidson, M. M.; Tanji, K.; Nishino,
I.; Sadlock, J. E.; Krishna, S.; Walker, W.; Selby, J.; Glerum, D.
M.; Van Coster, R.; Lyon, G.; and 9 others: Fatal infantile cardioencephalomyopathy
with COX deficiency and mutations in SCO2, a COX assembly gene. Nature
Genet. 23: 333-337, 1999.

29. Parfait, B.; Percheron, A.; Chretien, D.; Rustin, P.; Munnich,
A.; Rotig, A.: No mitochondrial cytochrome oxidase (COX) gene mutations
in 18 cases of COX deficiency. Hum. Genet. 101: 247-250, 1997.

30. Robinson, B. H.; Ward, J.; Goodyer, P.; Beaudet, A.: Respiratory
chain defects in the mitochondria of cultured skin fibroblasts from
three patients with lacticacidemia. J. Clin. Invest. 77: 1422-1427,
1986.

31. Rubio-Gozalbo, M. D.; Smeitink, J. A. M.; Ruitenbeek, W.; Ter
Laak, H.; Mullaart, R. A.; Schuelke, M.; Mariman, E. C. M.; Sengers,
R. C. A.; Gabreels, F. J. M.: Spinal muscular atrophy-like picture,
cardiomyopathy, and cytochrome c oxidase deficiency. Neurology 52:
383-386, 1999.

32. Sacconi, S.; Salviati, L.; Sue, C. M.; Shanske, S.; Davidson,
M. M.; Bonilla, E.; Naini, A. B.; De Vivo, D. C.; DiMauro, S.: Mutation
screening in patients with isolated cytochrome c deficiency. Pediat.
Res. 53: 224-230, 2003.

33. Saraste, M.: How complex is a respiratory complex? Trends Biochem.
Sci. 8: 139-142, 1983.

34. Shoubridge, E. A.: Cytochrome c oxidase deficiency. Am. J. Med.
Genet. 106: 46-52, 2001.

35. Szklarczyk, R.; Wanschers, B. F. J.; Nijtmans, L. G.; Rodenburg,
R. J.; Zschocke, J.; Dikow, N.; van den Brand, M. A. M.; Hendriks-Franssen,
M. G. M.; Gilissen, C.; Veltman, J. A.; Nooteboom, M.; Koopman, W.
J. H.; Willems, P. H. G. M.; Smeitink, J. A. M.; Huynen, M. A.; van
den Heuvel, L. P.: A mutation in the FAM36A gene, the human ortholog
of COX20, impairs cytochrome c oxidase assembly and is associated
with ataxia and muscle hypotonia. Hum. Molec. Genet. 22: 656-667,
2013.

36. Tiranti, V.; Corona, P.; Greco, M.; Taanman, J.-W.; Carrara, F.;
Lamantea, E.; Nijtmans, L.; Uziel, G.; Zeviani, M.: A novel frameshift
mutation of the mtDNA COIII gene leads to impaired assembly of cytochrome
c oxidase in a patient affected by Leigh-like syndrome. Hum. Molec.
Genet. 9: 2733-2742, 2000.

37. Tiranti, V.; Hoertnagel, K.; Carrozzo, R.; Galimberti, C.; Munaro,
M.; Grantiero, M.; Zelante, L.; Gasparini, P.; Marzella, R.; Rocchi,
M.; Bayona-Bafaluy, M. P.; Enriquez, J.-A.; Uziel, G.; Bertini, E.;
Dionisi-Vici, C.; Franco, B.; Meitinger, T.; Zeviani, M.: Mutations
of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency. Am.
J. Hum. Genet. 63: 1609-1621, 1998.

38. Valnot, I.; Osmond, S.; Gigarel, N.; Mehaye, B.; Amiel, J.; Cormier-Daire,
V.; Munnich, A.; Bonnefont, J.-P.; Rustin, P.; Rotig, A.: Mutations
of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency
with neonatal-onset hepatic failure and encephalopathy. Am. J. Hum.
Genet. 67: 1104-1109, 2000.

39. Valnot, I.; von Kleist-Retzow, J.-C.; Barrientos, A.; Gorbatyuk,
M.; Taanman, J.-W.; Mehaye, B.; Rustin, P.; Tzagoloff, A.; Munnich,
A.; Rotig, A.: A mutation in the human heme A:farnesyltransferase
gene (COX10) causes cytochrome c oxidase deficiency. Hum. Molec.
Genet. 9: 1245-1249, 2000.

40. Van Biervliet, J. P. G. M.; Bruinvis, L.; Ketting, D.; De Bree,
P. K.; Van Der Heiden, C.; Wadman, S. K.: Hereditary mitochondrial
myopathy with lactic acidemia, a de Toni-Fanconi-Debre syndrome, and
a defective respiratory chain in voluntary striated muscles. Pediat.
Res. 11: 1088-1093, 1977.

41. van Bon, B. W. M.; Oortveld, M. A. W.; Nijtmans, L. G.; Fenckova,
M.; Nijhof, B.; Besseling, J.; Vos, M.; Kramer, J. M.; de Leeuw, N.;
Castells-Nobau, A.; Asztalos, L.; Viragh, E.; and 11 others: CEP89
is required for mitochondrial metabolism and neuronal function in
man and fly. Hum. Molec. Genet. 22: 3138-3151, 2013.

42. von Kleist-Retzow, J.-C.; Cormier-Daire, V.; de Lonlay, P.; Parfait,
B.; Chretien, D.; Rustin, P.; Feingold, J.; Rotig, A.; Munnich, A.
: A high rate (20%-30%) of parental consanguinity in cytochrome-oxidase
deficiency. Am. J. Hum. Genet. 63: 428-435, 1998.

43. Weraarpachai, W.; Antonicka, H.; Sasarman, F.; Seeger, J.; Schrank,
B.; Kolesar, J. E.; Lochmuller, H.; Chevrette, M.; Kaufman, B. A.;
Horvath, R.; Shoubridge, E. A.: Mutation in TACO1, encoding a translational
inactivator of COX I, results in cytochrome c oxidase deficiency and
late-onset Leigh syndrome. Nature Genet. 833-837, 2009.

44. Weraarpachai, W.; Sasarman, F.; Nishimura, T.; Antonicka, H.;
Aure, K.; Rotig, A.; Lombes, A.; Shoubridge, E. A.: Mutations in
C12orf62, a factor that couples COX I synthesis with cytochrome c
oxidase assembly, cause fatal neonatal lactic acidosis. Am. J. Hum.
Genet. 90: 142-151, 2012.

45. Willems, J. L.; Monnens, L. A. H.; Trijbels, J. M. F.; Veerkamp,
J. H.; Meyer, A. E. F. H.; van Dam, K.; van Haelst, U.: Leigh's encephalomyelopathy
in a patient with cytochrome c oxidase deficiency in muscle tissue. Pediatrics 60:
850-857, 1977.

46. Yang, H.; Brosel, S.; Acin-Perez, R.; Slavkovich, V.; Nishino,
I.; Khan, R.; Goldberg, I. J.; Graziano, J.; Manfredi, G.; Schon,
E. A.: Analysis of mouse models of cytochrome c oxidase deficiency
owing to mutations in Sco2. Hum. Molec. Genet. 19: 170-180, 2010.

47. Zhu, Z.; Yao, J.; Johns, T.; Fu, K.; De Bie, I.; Macmillan, C.;
Cuthbert, A. P.; Newbold, R. F.; Wang, J.; Chevrette, M.; Brown, G.
K.; Brown, R. M.; Shoubridge, E. A.: SURF1, encoding a factor involved
in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nature
Genet. 20: 337-343, 1998.

*FIELD* CS
INHERITANCE:
Autosomal recessive;
Mitochondrial

GROWTH:
[Other];
Failure to thrive

HEAD AND NECK:
[Eyes];
Optic atrophy;
Pigmentary retinopathy;
Ptosis;
[Ears];
Hearing loss, sensorineural

CARDIOVASCULAR:
[Heart];
Hypertrophic cardiomyopathy (associated with mutation in the COX10
and C2ORF64 genes)

RESPIRATORY:
Respiratory difficulties;
Respiratory failure due to muscle weakness;
Exertional dyspnea

ABDOMEN:
[Liver];
Liver dysfunction;
Hepatomegaly;
Liver biopsy shows increased lipid droplets and abnormal mitochondria

GENITOURINARY:
[Kidneys];
'De Toni-Fanconi-Debre' syndrome;
Renal tubular dysfunction;
Biopsy shows decreased cytochrome c oxidase

MUSCLE, SOFT TISSUE:
Muscle weakness;
Hypotonia;
Exercise intolerance;
Muscle biopsy shows decrease or absence of cytochrome c oxidase;
Increased lipid droplets and abnormal mitochondria

NEUROLOGIC:
[Central nervous system];
Developmental delay;
Delayed motor development;
Hypotonia;
Ataxia;
Pyramidal syndrome;
Seizures;
Mental retardation;
Increased CSF lactate;
Symmetric lesions in the basal ganglia consistent with Leigh syndrome
(256000), in a subset of patients

METABOLIC FEATURES:
Lactic acidosis

HEMATOLOGY:
Anemia (associated with mutation in the COX10 gene)

LABORATORY ABNORMALITIES:
Increased serum lactate;
Increased CSF lactate;
Proteinuria;
Glucosuria;
Aminoaciduria;
Hyperphosphaturia;
Decreased activity of cytochrome c oxidase in muscle and fibroblasts

MISCELLANEOUS:
Marked clinical heterogeneity;
Symptom onset ranges from infancy to adulthood;
Death may occur in infancy;
Genetic heterogeneity (may be caused by mutation in nuclear-encoded
or mitochondrial-encoded genes);
Subset of patients have Leigh syndrome (256000);
Subset of patients have French-Canadian Leigh syndrome (220111);
Subset of patients with SCO2 (604272) mutations have cardioencephalomyopathy
(604377)

MOLECULAR BASIS:
Caused by mutation in the homolog of the S. cerevisiae SCO1 gene
(SCO1, 603644.0001);
Caused by mutation in the surfeit 1 gene (SURF1, 185620.0001);
Caused by mutation in the leucine-rich PPR motif-containing protein
gene (LRPPRC, 607544.0001);
Caused by mutation in the cytochrome c oxidase subunit VIb, polypeptide
1 gene (COX6B1, 124089.0001);
Caused by mutation in the cytochrome c oxidase subunit X gene (COX10,
602125.0001);
Caused by mutation in the cytochrome c oxidase subunit I gene (MTCO1,
516030.0004);
Caused by mutation in the cytochrome c oxidase subunit II gene (MTCO2,
516040.0001);
Caused by mutation in the cytochrome c oxidase subunit III gene (MTCO3,
516050.0004);
Caused by mutation in the mitochondrial tRNA serine 1 gene (MTTS1,
590080.0003);
Caused by mutation in the mitochondrial tRNA lysine 1 gene (MTTL1,
590050.0001);
Caused by mutation in the cytochrome c oxidase subunit 15 gene (COX15,
603646);
Caused by mutation in the translational activator of mitochondrially
encoded cytochrome c oxidase subunit 1 gene (TACO1, 612958.0001);
Caused by mutation in the chromosome 2 open reading frame 64 gene
(C2ORF64, 613920.0001);
Caused by mutation in the chromosome 12 open reading frame 62 gene
(C12ORF62, 614478.0001);
Caused by mutation in the homolog of the S. cerevisiae, cytochrome
c oxidase 20 gene (COX20, 614698.0001).

*FIELD* CN
Cassandra L. Kniffin - updated: 4/10/2012
Cassandra L. Kniffin - updated: 5/5/2011
Cassandra L. Kniffin - updated: 9/10/2008
Cassandra L. Kniffin - updated: 5/30/2007
Cassandra L. Kniffin - updated: 1/5/2005
Cassandra L. Kniffin - revised: 7/10/2003

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

*FIELD* ED
ckniffin: 09/23/2013
ckniffin: 4/10/2012
ckniffin: 5/5/2011
ckniffin: 9/8/2009
joanna: 10/10/2008
ckniffin: 9/10/2008
ckniffin: 5/30/2007
joanna: 4/20/2005
ckniffin: 1/5/2005
ckniffin: 9/2/2004
joanna: 8/19/2003
ckniffin: 7/10/2003

*FIELD* CN
Cassandra L. Kniffin - updated: 10/23/2013
Cassandra L. Kniffin - updated: 7/9/2013
Cassandra L. Kniffin - updated: 2/16/2012
Cassandra L. Kniffin - updated: 5/2/2011
George E. Tiller - updated: 11/12/2010
Cassandra L. Kniffin - updated: 8/21/2009
Ada Hamosh - updated: 12/3/2008
Cassandra L. Kniffin - updated: 9/10/2008
Cassandra L. Kniffin - updated: 5/30/2007
Cassandra L. Kniffin - updated: 11/7/2006
Cassandra L. Kniffin - updated: 1/5/2005
George E. Tiller - updated: 1/4/2005
Natalie E. Krasikov - updated: 3/26/2004
Cassandra L. Kniffin - updated: 7/10/2003
Cassandra L. Kniffin - updated: 7/9/2003
Deborah L. Stone - updated: 11/24/2001
Victor A. McKusick - updated: 7/24/2001
Victor A. McKusick - updated: 3/1/2001
George E. Tiller - updated: 7/10/2000
Victor A. McKusick - updated: 6/11/1999
Orest Hurko - updated: 3/23/1999
Michael J. Wright - updated: 3/3/1999
Victor A. McKusick - updated: 11/24/1998
Victor A. McKusick - updated: 9/11/1998
Victor A. McKusick - updated: 12/2/1997
Victor A. McKusick - updated: 4/15/1997
Jon B. Obray - updated: 7/13/1996

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
carol: 10/25/2013
ckniffin: 10/23/2013
tpirozzi: 7/11/2013
tpirozzi: 7/10/2013
ckniffin: 7/9/2013
carol: 3/13/2013
carol: 2/21/2012
ckniffin: 2/16/2012
terry: 10/26/2011
wwang: 5/2/2011
ckniffin: 5/2/2011
wwang: 11/22/2010
terry: 11/12/2010
terry: 10/14/2010
carol: 9/17/2010
alopez: 8/21/2009
ckniffin: 8/21/2009
alopez: 12/3/2008
wwang: 9/15/2008
ckniffin: 9/10/2008
wwang: 6/6/2007
ckniffin: 5/30/2007
wwang: 11/10/2006
ckniffin: 11/7/2006
carol: 9/20/2005
ckniffin: 8/31/2005
terry: 4/19/2005
terry: 4/6/2005
ckniffin: 1/5/2005
alopez: 1/4/2005
carol: 9/2/2004
ckniffin: 9/2/2004
carol: 3/26/2004
carol: 7/10/2003
ckniffin: 7/10/2003
ckniffin: 7/9/2003
carol: 11/24/2001
mcapotos: 8/8/2001
terry: 7/24/2001
mcapotos: 3/12/2001
mcapotos: 3/9/2001
mcapotos: 3/7/2001
terry: 3/1/2001
carol: 12/12/2000
alopez: 7/10/2000
alopez: 12/28/1999
alopez: 11/1/1999
carol: 6/11/1999
terry: 6/11/1999
carol: 3/23/1999
carol: 3/22/1999
mgross: 3/3/1999
carol: 1/19/1999
dkim: 12/14/1998
alopez: 11/30/1998
terry: 11/24/1998
carol: 9/16/1998
terry: 9/11/1998
carol: 8/19/1998
terry: 6/3/1998
mark: 12/9/1997
terry: 12/2/1997
terry: 7/9/1997
jenny: 4/15/1997
terry: 4/7/1997
randy: 9/7/1996
carol: 7/15/1996
carol: 7/13/1996
mark: 3/15/1996
terry: 3/5/1996
terry: 5/7/1994
carol: 4/8/1994
warfield: 3/21/1994
mimadm: 2/19/1994
carol: 8/27/1993
supermim: 3/16/1992

MIM 516040
*RECORD*
*FIELD* NO
516040
*FIELD* TI
*516040 COMPLEX IV, CYTOCHROME c OXIDASE SUBUNIT II; MTCO2
;;CYTOCHROME c OXIDASE II; COII
read more*FIELD* TX

DESCRIPTION

Cytochrome c oxidase subunit II (COII or MTCO2) is 1 of 3 mitochondrial
DNA (mtDNA) encoded subunits (MTCO1, MTCO2, MTCO3) of respiratory
Complex IV. Complex IV is located within the mitochondrial inner
membrane and is the third and final enzyme of the electron transport
chain of mitochondrial oxidative phosphorylation. It collects electrons
from ferrocytochrome c (reduced cytochrome c) and transfers them to
oxygen to give water. The energy released is used to transport protons
across the mitochondrial inner membrane. Complex IV is composed of 13
polypeptides. Subunits I, II and III (MTCO1, MTCO2, MTCO3) are encoded
by the mtDNA while subunits IV, Va, Vb, VIa, VIb, VIc, VIIa, VIIb, VIIc,
and VIII are nuclear encoded (Kadenbach et al., 1983; Capaldi, 1990;
Shoffner and Wallace, 1995). Subunits VIa, VIIa, and VIII have systemic
as well as heart-muscle isoforms (Capaldi, 1990; Lomax and Grossman,
1989).

Subunit II contains one redox center, CuA, and collects electrons from
ferrocytochrome b. The electrons are then transferred to cytochrome a of
subunit I and on to the cytochrome a3-CuB binuclear reaction center. CuA
most likely resides in a loop containing conserved cysteines at amino
acids 196 and 200 and a conserved histidine at 204, with the fourth
ligand being histidine 161. Cytochrome c interacts with subunit II
through the association of a ring of lysines around the heme edge of
cytochrome c with carboxyls in subunit II, specifically glutamate 129,
aspartate 132, and glutamate 198 (Hill, 1993; Capaldi, 1990).

The predicted molecular weight (MW) of MTCO2 is 25.5 kD (Anderson et
al., 1981; Wallace et al., 1994). However, its apparent MW on
SDS-polyacrylamide gels (PAGE) is 23.6 kD using Tris-glycine buffer
(Oliver et al., 1984; Oliver and Wallace, 1982; Wallace et al., 1986),
whereas it is 20 kD when using urea-phosphate buffer (Ching and Attardi,
1982; Hare et al., 1980).

MAPPING

MTCO2 is encoded by the guanine-rich heavy (H) strand of the mtDNA
located between nucleotide pairs (nps) 7586 and 8294 (Anderson et al.,
1981; Wallace et al., 1994). It is maternally inherited along with the
mtDNA (Giles et al., 1980; Case and Wallace, 1981).

GENE STRUCTURE

The MTCO2 gene encompasses 708 nucleotide pairs (nps) of continuous
mtDNA sequence, lacking introns, and encoding a single polypeptide. The
mRNA begins with the AUG start codon, proceeds through the polypeptide
sequence to a UAG stop codon, and continues on through a 25-np 3-prime
nontranslated region. This transcript is transcribed as a part of the
H-strand polycistronic transcript, flanked by tRNAAsp on the 5-prime end
and tRNALys on the 3-prime end. Cleavage at the tRNAs releases
transcript 16, the MTCO2 mRNA. The transcript is then polyadenylated
(Ojala et al., 1981; Attardi et al., 1982; Wallace et al., 1994).

The 25-np 3-prime-nontranslated sequence
(5-prime-CACCCCCTCTACCCCCTCTAGAGGG) contains 2 9-np repeats which are
polymorphic in the world populations. One polymorphism involves the
deletion of 1 repeat and is common in Asian, Polynesian and Native
American mtDNAs. A second polymorphism involves additional Cs' inserted
within the runs of Cs (Cann and Wilson, 1983; Wrischnik et al., 1987;
Hertzberg et al., 1989; Ballinger et al., 1992; Schurr et al., 1990;
Torroni et al., 1992; Torroni et al., 1993).

MOLECULAR GENETICS

Both small insertions and deletions have been identified in the 25 nps
that encode the 3-prime nontranslated region of the MTCO2 mRNA. A 9-np
deletion of 1 repeat between nps 8271 and 8281 or 8280 and 8290 is
common in Asians, Polynesians, and Native Americans (Ballinger et al.,
1992; Cann and Wilson, 1983; Harihara et al., 1992; Hertzberg et al.,
1989; Horai and Matsunaga, 1986; Passarino et al., 1993; Schurr et al.,
1990; Shields et al., 1992; Torroni et al., 1992, 1993, 1994; Wallace
and Torroni, 1992; Wrischnik et al., 1987) and 3 copies of the repeat
has been described in a few Asians (Shields et al., 1992; Passarino et
al., 1993). A duplication of 4 Cs at np 8277 is also found in certain
Asian populations (Ballinger et al., 1992; Cann and Wilson, 1983;
Wrischnik et al., 1987).

Restriction site polymorphisms have also been identified at the
following nucleotide positions for the indicated enzymes (where '+' =
site gain, '-' = site loss relative to the reference sequence, Anderson
et al., 1981): Alu I: -7641, -8074, +8198; Ava II: +8249; Dde I: -7750;
Hae III: +7607, +7792, -7853, +7979, +8148, +8165, -8250; Hha I: -7598,
+7617, +7828; HincII: -7853, +7937; HinfI: +7672, +7970; Mbo I: +7570,
-7658, -7859, +7933; Msp I: -8112, -8150; Rsa I: +7697, +7702, -7897,
-7912, -8012, +8078, +8156; Taq I: -8005 (Wallace et al., 1994).

Mounting evidence suggests that defects in energy metabolism contribute
to the pathogenesis of Alzheimer disease (AD; see 502500). Cytochrome c
oxidase (CO) is kinetically abnormal, and its activity is decreased, in
brain and peripheral tissue in late-onset AD. CO is encoded by both the
mitochondrial and the nuclear genomes. Its catalytic centers, however,
are encoded exclusively by 2 mitochondrial genes, the MTCO1 gene and the
MTCO2 gene (516040), encoding CO subunits I and II, respectively. Davis
et al. (1997) searched these genes, as well as other mitochondrial
genes, for mutations that might alter CO activity and cosegregate with
AD. Specific missense mutations in MTCO1 and MTCO2 but not MTCO3 were
found to segregate at a higher frequency with AD compared with other
neurodegenerative or metabolic diseases. These mutations appeared
together in the same mitochondrial DNA molecule and defined a unique
mutant mitochondrial genome. Asymptomatic offspring of AD mothers had
higher levels of these mutations than offspring of AD fathers,
suggesting that these mutations can be maternally inherited. Cell lines
expressing these mutant mitochondrial DNA molecules exhibited a specific
decrease in CO activity and increased production of reactive oxygen
species. Davis et al. (1997) suggested that a CO defect may represent a
primary etiologic event, directly participating in the cascade of events
that results in AD. Hirano et al. (1997) and Wallace et al. (1997)
presented evidence that the missense mutations that Davis et al. (1997)
thought were related to Alzheimer disease were in fact located in mtDNA
pseudogenes that are embedded in the nuclear genome where they have been
transferred as part of the extensive transfer of genetic material from
the primitive bacterial form, that was the progenitor of the
mitochondrion, to the nucleus.

Deficiency of cytochrome c oxidase (COX) causes a clinically
heterogeneous variety of neuromuscular and non-neuromuscular disorders
in childhood and adulthood and theoretically can result from either
nuclear or mitochondrial mutations with obvious differences in mode of
inheritance (see 220110). In an attempt to determine the respective
roles of mtDNA and nuclear DNA mutations in COX deficiency, Parfait et
al. (1997) sequenced the 3 mitochondrially encoded COX subunits of
complex IV. The study was performed in a series of 18 patients with
isolated COX deficiency. They failed to detect any deleterious mutations
in this series. Moreover, no mtDNA deletion was observed and sequencing
of the flanking tRNA gene involved in the maturation of the COX
transcripts failed to detect deleterious mutations as well. This study
supported the view that the disease-causing mutations do not lie in the
mitochondrial genome but rather in the nuclear genes encoding either the
COX subunits or the proteins involved in assembly of the complex. The
results suggested further that a recurrence risk of 25% (as for an
autosomal recessive rather than other modes of inheritance) can be used
in genetic counseling of COX deficiencies. On the other hand, Clark et
al. (1999) identified a mutation in the MTCO2 gene in a family with COX
II deficiency; see 516040.0001.

*FIELD* AV
.0001
CYTOCHROME c OXIDASE DEFICIENCY
MTCO2, 7587T-C

In a family with cytochrome c oxidase (COX) deficiency (220110), Clark
et al. (1999) identified a 7587T-C transition in the initiation codon of
the MTCO2 gene, predicting a change from methionine to threonine. The
index case was the mother, a 57-year-old woman of normal intellect with
a 5-to-10-year history of fatigue and unsteadiness of gait. There was no
clinical evidence of retinal disease, deafness, muscle weakness, or
cardiac disease. Her 34-year-old son was severely affected. Although
normal at birth and in early childhood, at age 5 years he developed
progressive gait ataxia. This progressed so that he became
wheelchair-bound by age 25 years. He was severely cognitively impaired.
Clinical examination demonstrated bilateral optic atrophy, pigmentary
retinopathy, a marked decrease in color vision, and mild distal muscle
wasting. The mutation load was present at 67% in muscle from the index
case and at 91% in muscle from the clinically affected son. Muscle
biopsy samples revealed isolated COX deficiency and mitochondrial
proliferation. Single-muscle-fiber analysis demonstrated that the 7587C
copy was at much higher load in COX-negative fibers than in COX-positive
fibers. After microphotometric enzyme analysis, the mutation was shown
to cause a decrease in COX activity when the mutant load was greater
than 55 to 65%. In fibroblasts from the affected son, which contained
more than 95% mutant mtDNA, there was no detectable synthesis or any
steady-state level of COX II.

.0002
COLORECTAL CANCER
MTCO2, 8009G-A, VAL142MET

Early on, Warburg (1956) suggested that alterations of oxidative
phosphorylation in tumor cells play a causative role in cancerous
growth. Interest in mitochondria with regard to neoplasia has revived,
largely because of their role in apoptosis and other aspects of tumor
biology. The mitochondrial genome is particularly susceptible to
mutations because of the high level of reactive oxygen species (ROS)
generated in this organelle, coupled with a low level of DNA repair. In
a colorectal cancer, Polyak et al. (1998) found 3 somatic mutations in
the mitochondrial genome. One was an 8009G-A transition in the MTCO2
gene, causing a val142-to-met missense substitution. The other 2
occurred in the MTCYB gene; see 516020.0003 and 516020.0004.

.0003
CYTOCHROME c OXIDASE DEFICIENCY
MTCO2, 7671T-A

In a 14-year-old boy with proximal myopathy and lactic acidosis, Rahman
et al. (1999) found, on muscle histochemistry and mitochondrial
respiratory-chain enzymology, a marked reduction in COX activity
(220110). Immunohistochemistry and immunoblot analyses with COX
subunit-specific monoclonal antibodies showed a pattern suggestive of a
primary mtDNA defect, most likely involving subunit II of cytochrome c
oxidase. Sequence analysis of mitochondrial DNA demonstrated a novel
heteroplasmic T-to-A transversion at nucleotide 7671 in the MTCO2 gene.
The mutation changed a methionine to a lysine residue in the middle of
the first N-terminal membrane-spanning region of COX II. Based on these
and other observations, the authors suggested that in the COX protein, a
structural association of COX II with COX I is necessary to stabilize
the binding of heme a3 to COX I.

.0004
CYTOCHROME c OXIDASE DEFICIENCY
MTCO2, 2-BP DEL, 8042AT

In twin brothers, Wong et al. (2001) described severe lactic acidosis
caused by cytochrome c oxidase deficiency (220110). The one in whom
molecular studies were performed died at 12 days of age, following a
course of apnea, bradycardia, and severe lactic acidosis. The twin
brother died at 2 days of age, after a similar course. The mutation
found in the MTCO2 gene, 8042delAT, produced a truncated protein that
was 72 amino acids, shorter than the wildtype protein. The mutant
protein, missing one third of the amino acid residues at the C terminal
essential for hydrophilic interaction with cytochrome c, ligand binding
to copper and magnesium ions, and the formation of proton water
channels, apparently could not perform essential mitochondrial
respiratory functions.

.0005
CYTOCHROME c OXIDASE DEFICIENCY
MTCO2, 7896G-A

Campos et al. (2001) reported what they judged to be the first nonsense
mutation in the MTCO2 gene. The 3-year-old proposita was normal at birth
but had psychomotor delay and failure to thrive after age 3 months. In
addition to early-onset hypotonia, there was mild hypertrophic
cardiomyopathy and pigmentary retinopathy, and COX deficiency in muscle
(220110). A 7896G-A nonsense mutation was found, predicted to cause
premature termination of the translation, with loss of 123 amino acids
at the C terminus of COX II. The mutation was heteroplasmic in muscle,
blood, and fibroblasts of the patient.

*FIELD* SA
Torroni et al. (1994); Torroni et al. (1993)
*FIELD* RF
1. Anderson, S.; Bankier, A. T.; Barrell, B. G.; de Bruijn, M. H.
L.; Coulson, A. R.; Drouin, J.; Eperon, I. C.; Nierlich, D. P.; Roe,
B. A.; Sanger, F.; Schreier, P. H.; Smith, A. J. H.; Staden, R.; Young,
I. G.: Sequence and organization of the human mitochondrial genome. Nature 290:
457-465, 1981.

2. Attardi, G.; Chomyn, A.; Montoya, J.; Ojala, D.: Identification
and mapping of human mitochondrial genes. Cytogenet. Cell Genet. 32:
85-98, 1982.

3. Ballinger, S. W.; Schurr, T. G.; Torroni, A.; Gan, Y. Y.; Hodge,
J. A.; Hassan, K.; Chen, K. H.; Wallace, D. C.: Southeast Asian mitochondrial
DNA analysis reveals genetic continuity of ancient mongoloid migrations. Genetics 130:
139-152, 1992. Note: Erratum: Genetics 130: 957 only, 1992.

4. Campos, Y.; Garcia-Redondo, A.; Fernandez-Moreno, M. A.; Martinez-Pardo,
M.; Goda, G.; Rubio, J. C.; Martin, M. A.; del Hoyo, P.; Cabello,
A.; Bornstein, B.; Garesse, R.; Arenas, J.: Early-onset multisystem
mitochondrial disorder caused by a nonsense mutation in the mitochondrial
DNA cytochrome c oxidase II gene. Ann. Neurol. 50: 409-413, 2001.

5. Cann, R. L.; Wilson, A. C.: Length mutations in human mitochondrial
DNA. Genetics 104: 699-711, 1983.

6. Capaldi, R. A.: Structure and function of cytochrome c oxidase. Annu.
Rev. Biochem. 59: 569-596, 1990.

7. Case, J. T.; Wallace, D. C.: Maternal inheritance of mitochondrial
DNA polymorphisms in cultured human fibroblasts. Somat. Cell Genet. 7:
103-108, 1981.

8. Ching, E.; Attardi, G.: High-resolution electrophoretic fractionation
and partial characterization of the mitochondrial translation products
from HeLa cells. Biochemistry 21: 3188-3195, 1982.

9. Clark, K. M.; Taylor, R. W.; Johnson, M. A.; Chinnery, P. F.; Chrzanowska-Lightowlers,
Z. M. A.; Andrews, R. M.; Nelson, I. P.; Wood, N. W.; Lamont, P. J.;
Hanna, M. G.; Lightowlers, R. N.; Turnbull, D. M.: An mtDNA mutation
in the initiation codon of the cytochrome c oxidase subunit II gene
results in lower levels of the protein and a mitochondrial encephalomyopathy. Am.
J. Hum. Genet. 64: 1330-1339, 1999.

10. Davis, R. E.; Miller, S.; Herrnstadt, C.; Ghosh, S. S.; Fahy,
E.; Shinobu, L. A.; Galasko, D.; Thal, L. J.; Beal, M. F.; Howell,
N.; Parker, W. D., Jr.: Mutations in mitochondrial cytosome c oxidase
genes segregate with late-onset Alzheimer disease. Proc. Nat. Acad.
Sci. 94: 4526-4531, 1997.

11. Giles, R. E.; Blanc, H.; Cann, H. M.; Wallace, D. C.: Maternal
inheritance of human mitochondrial DNA. Proc. Nat. Acad. Sci. 77:
6715-6719, 1980.

12. Hare, J. F.; Ching, E.; Attardi, G.: Isolation, subunit composition
and site of synthesis of human cytochrome c oxidase. Biochemistry 19:
2023-2030, 1980.

13. Harihara, S.; Hirai, M.; Suutou, Y.; Shimizu, K.; Omoto, K.:
Frequency of a 9-bp deletion in the mitochondrial DNA among Asian
populations. Hum. Biol. 64: 161-166, 1992.

14. Hertzberg, M.; Mickleson, K. N. P.; Serjeantson, S. W.; Prior,
J. F.; Trent, R. J.: An Asian specific 9-bp deletion of mitochondrial
DNA is frequently found in Polynesians. Am. J. Hum. Genet. 44: 504-510,
1989.

15. Hill, B. C.: The sequence of electron carriers in the reaction
of cytochrome c oxidase with oxygen. J. Bioenerg. Biomembr. 25:
115-120, 1993.

16. Hirano, M.; Shtilbans, A.; Mayeux, R.; Davidson, M. M.; DiMauro,
S.; Knowles, J. A.; Schon, E. A.: Apparent mtDNA heteroplasmy in
Alzheimer's disease patients and in normals due to PCR amplification
of nucleus-embedded mtDNA pseudogenes. Proc. Nat. Acad. Sci. 94:
14894-14899, 1997.

17. Horai, S.; Matsunaga, E.: Mitochondrial DNA polymorphism in Japanese.
II. analysis with restriction enzymes of four or five base pair recognition. Hum.
Genet. 72: 105-117, 1986.

18. Kadenbach, B.; Jarausch, J.; Hartmann, R.; Merle, P.: Separation
of mammalian cytochrome c oxidase into 13 polypeptides by a sodium
dodecyl sulfate-gel electrophoretic procedure. Anal. Biochem. 129:
517-521, 1983.

19. Lomax, M. I.; Grossman, L. I.: Tissue-specific genes for respiratory
proteins. Trends Biochem. Sci. 14: 501-503, 1989. Note: Erratum:
Trends Biochem. Sci. 15: 217 only, 1990.

20. Ojala, D.; Montoya, J.; Attardi, G.: tRNA punctuation model of
RNA processing in human mitochondria. Nature 290: 470-474, 1981.

21. Oliver, N. A.; McCarthy, J.; Wallace, D. C.: Comparison of mitochondrially
synthesized polypeptides of human, mouse, and monkey cell lines by
a two-dimensional protease gel system. Somat. Cell Molec. Genet. 10:
639-643, 1984.

22. Oliver, N. A.; Wallace, D. C.: Assignment of two mitochondrially
synthesized polypeptides to human mitochondrial DNA and their use
in the study of intracellular mitochondrial interaction. Molec. Cell.
Biol. 2: 30-41, 1982.

23. Parfait, B.; Percheron, A.; Chretien, D.; Rustin, P.; Munnich,
A.; Rotig, A.: No mitochondrial cytochrome oxidase (COX) gene mutations
in 18 cases of COX deficiency. Hum. Genet. 101: 247-250, 1997.

24. Passarino, G.; Semino, O.; Modiano, G.; Santachiara-Benerecetti,
A. S.: COII/tRNA(Lys) intergenic 9-bp deletion and other mtDNA markers
clearly reveal that the Tharus (Southern Nepal) have oriental affinities. Am.
J. Hum. Genet. 53: 609-618, 1993.

25. Polyak, K.; Li, Y.; Zhu, H.; Lengauer, C.; Willson, J. K. V.;
Markowitz, S. D.; Trush, M. A.; Kinzler, K. W.; Vogelstein, B.: Somatic
mutations of the mitochondrial genome in human colorectal tumours. Nature
Genet. 20: 291-293, 1998.

26. Rahman, S.; Taanman, J.-W.; Cooper, J. M.; Nelson, I.; Hargreaves,
I.; Meunier, B.; Hanna, M. G.; Garcia, J. J.; Capaldi, R. A.; Lake,
B. D.; Leonard, J. V.; Schapira, A. H. V.: A missense mutation of
cytochrome oxidase subunit II causes defective assembly and myopathy. Am.
J. Hum. Genet. 65: 1030-1039, 1999.

27. Schurr, T. G.; Ballinger, S. W.; Gan, Y. Y.; Hodge, J. A.; Merriwether,
D. A.; Lawrence, D. N.; Knowler, W. C.; Weiss, K. M.; Wallace, D.
C.: Amerindian mitochondrial DNAs have rare Asian mutations at high
frequencies, suggesting they derived from four primary maternal lineages. Am.
J. Hum. Genet. 46: 613-623, 1990.

28. Shields, G. F.; Hecker, K.; Voevoda, M. I.; Reed, J. K.: Absence
of the Asian-specific region V mitochondrial marker in native Beringians. Am.
J. Hum. Genet. 50: 758-765, 1992.

29. Shoffner, J. M.; Wallace, D. C.: Oxidative phosphorylation diseases.In:
Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The
Metabolic and Molecular Bases of Inherited Disease. Vol. 1. New
York: McGraw-Hill (7th ed.): 1995. Pp. 1535-1609.

30. Torroni, A.; Chen, Y.; Semino, O.; Santachiara-Beneceretti, A.
S.; Scott, C. R.; Lott, M. T.; Winter, M.; Wallace, D. C.: Mitochondrial
DNA and Y-chromosome polymorphisms in four native American populations
from southern Mexico. Am. J. Hum. Genet. 54: 303-318, 1994.

31. Torroni, A.; Miller, J. A.; Moore, L. G.; Zamudio, S.; Zhuang,
J.; Droma, R.; Wallace, D. C.: Mitochondrial DNA analysis in Tibet.
Implications for the origin of the Tibetan population and its adaptation
to high altitude. Am. J. Phys. Anthrop. 93: 189-199, 1994.

32. Torroni, A.; Schurr, T. G.; Cabell, M. F.; Brown, M. D.; Neel,
J. V.; Larsen, M.; Smith, D. G.; Vullo, C. M.; Wallace, D. C.: Asian
affinities and continental radiation of the four founding Native American
mtDNAs. Am. J. Hum. Genet. 53: 563-590, 1993.

33. Torroni, A.; Schurr, T. G.; Yang, C.-C.; Szathmary, E. J.; Williams,
R. C.; Schanfield, M. S.; Troup, G. A.; Knowler, W. C.; Lawrence,
D. N.; Weiss, K. M.: Native American mitochondrial DNA analysis indicates
that the Amerind and the Nadene populations were founded by two independent
migrations. Genetics 130: 153-162, 1992.

34. Torroni, A.; Sukernik, R. I.; Schurr, T. G.; Starikovskaya, Y.
B.; Cabell, M. F.; Crawford, M. H.; Comuzzie, A. G.; Wallace, D. C.
: MtDNA variation of aboriginal Siberians reveals distinct genetic
affinities with Native Americans. Am. J. Hum. Genet. 53: 591-608,
1993.

35. Wallace, D. C.; Lott, M. T.; Torroni, A.; Brown, M. D.; Shoffner,
J. M.: Report of the committee on human mitochondrial DNA.In: Cuticchia,
A. J.; Pearson, P. L. (eds.): Human Gene Mapping, 1993: A Compendium.
Baltimore: Johns Hopkins Univ. Press (pub.) 1994. Pp. 813-845.

36. Wallace, D. C.; Stugard, C.; Murdock, D.; Schurr, T.; Brown, M.
D.: Ancient mtDNA sequences in the human nuclear genome: a potential
source of errors in identifying pathogenic mutations. Proc. Nat.
Acad. Sci. 94: 14900-14905, 1997.

37. Wallace, D. C.; Torroni, A.: American Indian prehistory as written
in the mitochondrial DNA: a review. Hum. Biol. 64: 403-416, 1992.

38. Wallace, D. C.; Yang, J.; Ye, J.; Lott, M. T.; Oliver, N. A.;
McCarthy, J.: Computer prediction of peptide maps: assignment of
polypeptides to human and mouse mitochondrial DNA genes by analysis
of two dimensional-proteolytic digest gels. Am. J. Hum. Genet. 38:
461-481, 1986.

39. Warburg, O.: On the origin of cancer cells. Science 123: 309-314,
1956.

40. Wong, L.-J. C.; Dai, P.; Tan, D.; Lipson, M.; Grix, A.; Sifry-Platt,
M.; Gropman, A.; Chen, T.-J.: Severe lactic acidosis caused by a
novel frame-shift mutation in mitochondrial-encoded cytochrome c oxidase
subunit II. Am. J. Med. Genet. 102: 95-99, 2001.

41. Wrischnik, L. A.; Higuchi, R. G.; Stoneking, M.; Erlich, H. A.;
Arnheim, N.; Wilson, A. C.: Length mutations in human mitochondrial
DNA: direct sequencing of enzymatically amplified DNA. Nucleic Acids
Res. 15: 529-542, 1987.

*FIELD* CN
Victor A. McKusick - updated: 11/7/2001
Victor A. McKusick - updated: 8/31/2001
Victor A. McKusick - updated: 10/8/1999
Victor A. McKusick - updated: 6/15/1999
Victor A. McKusick - updated: 4/23/1999
Victor A. McKusick - updated: 2/6/1998
Victor A. McKusick - updated: 12/2/1997
Victor A. McKusick - updated: 6/23/1997
Douglas C. Wallace - updated: 4/6/1994

*FIELD* CD
Victor A. McKusick: 3/2/1993

*FIELD* ED
terry: 08/08/2012
wwang: 3/15/2010
terry: 3/3/2010
carol: 1/19/2010
ckniffin: 7/8/2003
carol: 11/12/2001
terry: 11/7/2001
alopez: 10/17/2001
cwells: 9/17/2001
cwells: 9/6/2001
terry: 8/31/2001
terry: 3/2/2000
alopez: 10/19/1999
terry: 10/8/1999
carol: 8/11/1999
carol: 6/23/1999
jlewis: 6/23/1999
jlewis: 6/22/1999
terry: 6/15/1999
mgross: 5/3/1999
mgross: 4/26/1999
terry: 4/23/1999
carol: 8/19/1998
dholmes: 5/11/1998
terry: 2/6/1998
mark: 12/9/1997
terry: 12/2/1997
mark: 6/23/1997
carol: 6/20/1997
terry: 1/21/1997
mark: 4/9/1996
mark: 6/19/1995
pfoster: 8/16/1994
mimadm: 4/19/1994
carol: 5/26/1993
carol: 5/17/1993