RBCC Red Blood Cell Collection

SLC25A4 (ANT1) [Confidence: low (only semi-automatic identification from reviews)]
ADP/ATP translocase 1 (ADP,ATP carrier protein 1; ADP,ATP carrier protein, heart/skeletal muscle isoform T1; Adenine nucleotide translocator 1; ANT 1; Solute carrier family 25 member 4)

UniProt P12235
ID ADT1_HUMAN Reviewed; 298 AA.
AC P12235; D3DP59;
DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 4.
DT 22-JAN-2014, entry version 168.
DE RecName: Full=ADP/ATP translocase 1;
DE AltName: Full=ADP,ATP carrier protein 1;
DE AltName: Full=ADP,ATP carrier protein, heart/skeletal muscle isoform T1;
DE AltName: Full=Adenine nucleotide translocator 1;
DE Short=ANT 1;
DE AltName: Full=Solute carrier family 25 member 4;
GN Name=SLC25A4; Synonyms=ANT1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2823266; DOI=10.1073/pnas.84.21.7580;
RA Neckelmann N., Li K., Wade R.P., Shuster R., Wallace D.C.;
RT "cDNA sequence of a human skeletal muscle ADP/ATP translocator: lack
RT of a leader peptide, divergence from a fibroblast translocator cDNA,
RT and coevolution with mitochondrial DNA genes.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:7580-7584(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2541251; DOI=10.1016/0022-2836(89)90477-4;
RA Cozens A.L., Runswick M.J., Walker J.E.;
RT "DNA sequences of two expressed nuclear genes for human mitochondrial
RT ADP/ATP translocase.";
RL J. Mol. Biol. 206:261-280(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2547778;
RA Li K., Warner C.K., Hodge J.A., Minoshima S., Kudoh J., Fukuyama R.,
RA Maekawa M., Shimizu Y., Shimizu N., Wallace D.C.;
RT "A human muscle adenine nucleotide translocator gene has four exons,
RT is located on chromosome 4, and is differentially expressed.";
RL J. Biol. Chem. 264:13998-14004(1989).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=20843780; DOI=10.1093/nar/gkq750;
RA Wang W., Shen P., Thiyagarajan S., Lin S., Palm C., Horvath R.,
RA Klopstock T., Cutler D., Pique L., Schrijver I., Davis R.W.,
RA Mindrinos M., Speed T.P., Scharfe C.;
RT "Identification of rare DNA variants in mitochondrial disorders with
RT improved array-based sequencing.";
RL Nucleic Acids Res. 39:44-58(2011).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Eye, Mammary gland, and PNS;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-37.
RC TISSUE=Liver;
RX PubMed=2829183; DOI=10.1073/pnas.85.2.377;
RA Houldsworth J., Attardi G.;
RT "Two distinct genes for ADP/ATP translocase are expressed at the mRNA
RT level in adult human liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:377-381(1988).
RN [8]
RP PROTEIN SEQUENCE OF 2-31; 34-43; 64-92; 141-147; 189-199 AND 273-296,
RP CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT GLY-2, AND MASS
RP SPECTROMETRY.
RC TISSUE=B-cell lymphoma;
RA Bienvenut W.V.;
RL Submitted (OCT-2004) to UniProtKB.
RN [9]
RP INTERACTION WITH HIV-1 VPR.
RX PubMed=16120388; DOI=10.1016/j.mito.2004.06.012;
RA Deniaud A., Brenner C., Kroemer G.;
RT "Mitochondrial membrane permeabilization by HIV-1 Vpr.";
RL Mitochondrion 4:223-233(2004).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [11]
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 [12]
RP VARIANTS PEOA2 PRO-114 AND MET-289.
RX PubMed=10926541; DOI=10.1126/science.289.5480.782;
RA Kaukonen J., Juselius J.K., Tiranti V., Kyttala A., Zeviani M.,
RA Comi G.P., Keranen J., Peltonen L., Suomalainen A.;
RT "Role of adenine nucleotide translocator 1 in mtDNA maintenance.";
RL Science 289:782-785(2000).
RN [13]
RP VARIANT PEOA2 PRO-98.
RX PubMed=11756613;
RA Napoli L., Bordoni A., Zeviani M., Hadjigeorgiou G.M., Sciacco M.,
RA Tiranti V., Terentiou A., Moggio M., Papadimitriou A., Scarlato G.,
RA Comi G.P.;
RT "A novel missense adenine nucleotide translocator-1 gene mutation in a
RT Greek adPEO family.";
RL Neurology 57:2295-2298(2001).
RN [14]
RP VARIANT PEOA2 GLY-104.
RX PubMed=12112115; DOI=10.1002/ana.10172;
RA Komaki H., Fukazawa T., Houzen H., Yoshida K., Nonaka I., Goto Y.;
RT "A novel D104G mutation in the adenine nucleotide translocator 1 gene
RT in autosomal dominant progressive external ophthalmoplegia patients
RT with mitochondrial DNA with multiple deletions.";
RL Ann. Neurol. 51:645-648(2002).
RN [15]
RP VARIANT PEO MET-289.
RX PubMed=12707443;
RA Agostino A., Valletta L., Chinnery P.F., Ferrari G., Carrara F.,
RA Taylor R.W., Schaefer A.M., Turnbull D.M., Tiranti V., Zeviani M.;
RT "Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive
RT external ophthalmoplegia (PEO).";
RL Neurology 60:1354-1356(2003).
RN [16]
RP VARIANT HYPERTROPHIC CARDIOMYOPATHY ASP-123.
RX PubMed=16155110; DOI=10.1093/hmg/ddi341;
RA Palmieri L., Alberio S., Pisano I., Lodi T., Meznaric-Petrusa M.,
RA Zidar J., Santoro A., Scarcia P., Fontanesi F., Lamantea E.,
RA Ferrero I., Zeviani M.;
RT "Complete loss-of-function of the heart/muscle-specific adenine
RT nucleotide translocator is associated with mitochondrial myopathy and
RT cardiomyopathy.";
RL Hum. Mol. Genet. 14:3079-3088(2005).
RN [17]
RP VARIANT PEOA2 ASP-90.
RX PubMed=15792871; DOI=10.1016/j.nmd.2004.12.004;
RA Deschauer M., Hudson G., Mueller T., Taylor R.W., Chinnery P.F.,
RA Zierz S.;
RT "A novel ANT1 gene mutation with probable germline mosaicism in
RT autosomal dominant progressive external ophthalmoplegia.";
RL Neuromuscul. Disord. 15:311-315(2005).
RN [18]
RP VARIANTS PEOA2 PRO-98 AND PRO-114.
RX PubMed=18575922; DOI=10.1007/s00415-008-0926-3;
RA Virgilio R., Ronchi D., Hadjigeorgiou G.M., Bordoni A., Saladino F.,
RA Moggio M., Adobbati L., Kafetsouli D., Tsironi E., Previtali S.,
RA Papadimitriou A., Bresolin N., Comi G.P.;
RT "Novel Twinkle (PEO1) gene mutations in Mendelian progressive external
RT ophthalmoplegia.";
RL J. Neurol. 255:1384-1391(2008).
CC -!- FUNCTION: Catalyzes the exchange of cytoplasmic ADP with
CC mitochondrial ATP across the mitochondrial inner membrane.
CC -!- SUBUNIT: Found in a complex with ARL2, ARL2BP and SLC25A4.
CC Interacts with ARL2BP (By similarity). Homodimer. Interacts with
CC HIV-1 Vpr.
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane; Multi-pass
CC membrane protein.
CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial
CC DNA deletions, autosomal dominant, 2 (PEOA2) [MIM:609283]: A
CC disorder characterized by progressive weakness of ocular muscles
CC and levator muscle of the upper eyelid. In a minority of cases, it
CC is associated with skeletal myopathy, which predominantly involves
CC axial or proximal muscles and which causes abnormal fatigability
CC and even permanent muscle weakness. Ragged-red fibers and atrophy
CC are found on muscle biopsy. A large proportion of chronic
CC ophthalmoplegias are associated with other symptoms, leading to a
CC multisystemic pattern of this disease. Additional symptoms are
CC variable, and may include cataracts, hearing loss, sensory axonal
CC neuropathy, ataxia, depression, hypogonadism, and parkinsonism.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- MISCELLANEOUS: The transmembrane helices are not perpendicular to
CC the plane of the membrane, but cross the membrane at an angle.
CC Odd-numbered transmembrane helices exhibit a sharp kink, due to
CC the presence of a conserved proline residue (By similarity).
CC -!- SIMILARITY: Belongs to the mitochondrial carrier (TC 2.A.29)
CC family.
CC -!- SIMILARITY: Contains 3 Solcar repeats.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/SLC25A4";
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DR EMBL; J02966; AAA61223.1; -; mRNA.
DR EMBL; J04982; AAA51736.1; -; Genomic_DNA.
DR EMBL; HQ206346; ADP92294.1; -; Genomic_DNA.
DR EMBL; HQ206347; ADP92295.1; -; Genomic_DNA.
DR EMBL; HQ206348; ADP92296.1; -; Genomic_DNA.
DR EMBL; HQ206349; ADP92297.1; -; Genomic_DNA.
DR EMBL; HQ206350; ADP92298.1; -; Genomic_DNA.
DR EMBL; HQ206351; ADP92299.1; -; Genomic_DNA.
DR EMBL; HQ206352; ADP92300.1; -; Genomic_DNA.
DR EMBL; HQ206353; ADP92301.1; -; Genomic_DNA.
DR EMBL; HQ206354; ADP92302.1; -; Genomic_DNA.
DR EMBL; HQ206355; ADP92303.1; -; Genomic_DNA.
DR EMBL; HQ206356; ADP92304.1; -; Genomic_DNA.
DR EMBL; HQ206357; ADP92305.1; -; Genomic_DNA.
DR EMBL; HQ206358; ADP92306.1; -; Genomic_DNA.
DR EMBL; HQ206359; ADP92307.1; -; Genomic_DNA.
DR EMBL; HQ206360; ADP92308.1; -; Genomic_DNA.
DR EMBL; HQ206361; ADP92309.1; -; Genomic_DNA.
DR EMBL; HQ206362; ADP92310.1; -; Genomic_DNA.
DR EMBL; HQ206363; ADP92311.1; -; Genomic_DNA.
DR EMBL; HQ206364; ADP92312.1; -; Genomic_DNA.
DR EMBL; HQ206365; ADP92313.1; -; Genomic_DNA.
DR EMBL; HQ206366; ADP92314.1; -; Genomic_DNA.
DR EMBL; HQ206367; ADP92315.1; -; Genomic_DNA.
DR EMBL; HQ206368; ADP92316.1; -; Genomic_DNA.
DR EMBL; HQ206369; ADP92317.1; -; Genomic_DNA.
DR EMBL; HQ206370; ADP92318.1; -; Genomic_DNA.
DR EMBL; HQ206371; ADP92319.1; -; Genomic_DNA.
DR EMBL; HQ206372; ADP92320.1; -; Genomic_DNA.
DR EMBL; HQ206373; ADP92321.1; -; Genomic_DNA.
DR EMBL; HQ206374; ADP92322.1; -; Genomic_DNA.
DR EMBL; HQ206375; ADP92323.1; -; Genomic_DNA.
DR EMBL; HQ206376; ADP92324.1; -; Genomic_DNA.
DR EMBL; HQ206377; ADP92325.1; -; Genomic_DNA.
DR EMBL; HQ206378; ADP92326.1; -; Genomic_DNA.
DR EMBL; HQ206379; ADP92327.1; -; Genomic_DNA.
DR EMBL; HQ206380; ADP92328.1; -; Genomic_DNA.
DR EMBL; HQ206381; ADP92329.1; -; Genomic_DNA.
DR EMBL; HQ206382; ADP92330.1; -; Genomic_DNA.
DR EMBL; HQ206383; ADP92331.1; -; Genomic_DNA.
DR EMBL; HQ206384; ADP92332.1; -; Genomic_DNA.
DR EMBL; HQ206385; ADP92333.1; -; Genomic_DNA.
DR EMBL; CH471056; EAX04655.1; -; Genomic_DNA.
DR EMBL; CH471056; EAX04656.1; -; Genomic_DNA.
DR EMBL; BC008664; AAH08664.1; -; mRNA.
DR EMBL; BC061589; AAH61589.1; -; mRNA.
DR EMBL; BC063643; AAH63643.1; -; mRNA.
DR EMBL; J03593; AAA36751.1; -; mRNA.
DR PIR; A44778; A44778.
DR RefSeq; NP_001142.2; NM_001151.3.
DR UniGene; Hs.246506; -.
DR ProteinModelPortal; P12235; -.
DR SMR; P12235; 3-294.
DR IntAct; P12235; 13.
DR MINT; MINT-196037; -.
DR STRING; 9606.ENSP00000281456; -.
DR DrugBank; DB00171; Adenosine triphosphate.
DR DrugBank; DB00720; Clodronate.
DR GuidetoPHARMACOLOGY; 1062; -.
DR TCDB; 2.A.29.1.2; the mitochondrial carrier (mc) family.
DR PhosphoSite; P12235; -.
DR DMDM; 113455; -.
DR PaxDb; P12235; -.
DR PRIDE; P12235; -.
DR DNASU; 291; -.
DR Ensembl; ENST00000281456; ENSP00000281456; ENSG00000151729.
DR GeneID; 291; -.
DR KEGG; hsa:291; -.
DR UCSC; uc003ixd.3; human.
DR CTD; 291; -.
DR GeneCards; GC04P186064; -.
DR HGNC; HGNC:10990; SLC25A4.
DR MIM; 103220; gene.
DR MIM; 609283; phenotype.
DR neXtProt; NX_P12235; -.
DR Orphanet; 254892; Autosomal dominant progressive external ophthalmoplegia.
DR Orphanet; 1369; Congenital cataract - hypertrophic cardiomyopathy - mitochondrial myopathy.
DR Orphanet; 269; Facioscapulohumeral dystrophy.
DR Orphanet; 155; Familial isolated hypertrophic cardiomyopathy.
DR PharmGKB; PA35866; -.
DR eggNOG; NOG238123; -.
DR HOGENOM; HOG000165727; -.
DR HOVERGEN; HBG108348; -.
DR InParanoid; P12235; -.
DR KO; K05863; -.
DR OMA; VECFKRT; -.
DR OrthoDB; EOG7T1RBR; -.
DR PhylomeDB; P12235; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_17015; Metabolism of proteins.
DR GeneWiki; SLC25A4; -.
DR GenomeRNAi; 291; -.
DR NextBio; 1187; -.
DR PRO; PR:P12235; -.
DR Bgee; P12235; -.
DR CleanEx; HS_SLC25A4; -.
DR Genevestigator; P12235; -.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0005743; C:mitochondrial inner membrane; TAS:Reactome.
DR GO; GO:0015207; F:adenine transmembrane transporter activity; TAS:ProtInc.
DR GO; GO:0008637; P:apoptotic mitochondrial changes; IEA:Ensembl.
DR GO; GO:0006112; P:energy reserve metabolic process; TAS:Reactome.
DR GO; GO:0000002; P:mitochondrial genome maintenance; TAS:ProtInc.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0060547; P:negative regulation of necrotic cell death; IMP:BHF-UCL.
DR GO; GO:0050796; P:regulation of insulin secretion; TAS:Reactome.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0016032; P:viral process; TAS:Reactome.
DR Gene3D; 1.50.40.10; -; 1.
DR InterPro; IPR002113; Aden_trnslctor.
DR InterPro; IPR002067; Mit_carrier.
DR InterPro; IPR018108; Mitochondrial_sb/sol_carrier.
DR InterPro; IPR023395; Mt_carrier_dom.
DR Pfam; PF00153; Mito_carr; 3.
DR PRINTS; PR00927; ADPTRNSLCASE.
DR PRINTS; PR00926; MITOCARRIER.
DR SUPFAM; SSF103506; SSF103506; 1.
DR PROSITE; PS50920; SOLCAR; 3.
PE 1: Evidence at protein level;
KW Acetylation; Complete proteome; Direct protein sequencing;
KW Disease mutation; Host-virus interaction; Isopeptide bond; Membrane;
KW Mitochondrion; Mitochondrion inner membrane;
KW Progressive external ophthalmoplegia; Reference proteome; Repeat;
KW Transmembrane; Transmembrane helix; Transport; Ubl conjugation.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 298 ADP/ATP translocase 1.
FT /FTId=PRO_0000090574.
FT TRANSMEM 5 39 Helical; Name=1; (By similarity).
FT TRANSMEM 75 100 Helical; Name=2; (By similarity).
FT TRANSMEM 109 143 Helical; Name=3; (By similarity).
FT TRANSMEM 176 202 Helical; Name=4; (By similarity).
FT TRANSMEM 207 241 Helical; Name=5; (By similarity).
FT TRANSMEM 273 298 Helical; Name=6; (By similarity).
FT REPEAT 6 98 Solcar 1.
FT REPEAT 111 201 Solcar 2.
FT REPEAT 212 297 Solcar 3.
FT MOTIF 235 240 Substrate recognition (By similarity).
FT BINDING 80 80 Nucleotide (By similarity).
FT MOD_RES 2 2 N-acetylglycine.
FT CROSSLNK 10 10 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin) (By
FT similarity).
FT VARIANT 90 90 A -> D (in PEOA2).
FT /FTId=VAR_038814.
FT VARIANT 98 98 L -> P (in PEOA2).
FT /FTId=VAR_022459.
FT VARIANT 104 104 D -> G (in PEOA2; dbSNP:rs28999114).
FT /FTId=VAR_022460.
FT VARIANT 114 114 A -> P (in PEOA2).
FT /FTId=VAR_012111.
FT VARIANT 123 123 A -> D (in hypertrophic cardiomyopathy;
FT sporadic patient with mild myopathy,
FT exercise intolerance and lactic acidosis
FT but no ophthalmoplegia).
FT /FTId=VAR_038815.
FT VARIANT 289 289 V -> M (in PEOA2; also found in a
FT sporadic case affected by PEO).
FT /FTId=VAR_012112.
FT CONFLICT 16 16 G -> A (in Ref. 1; AAA61223).
FT CONFLICT 147 149 KGA -> RR (in Ref. 1; AAA61223).
FT CONFLICT 227 227 V -> L (in Ref. 1; AAA61223).
SQ SEQUENCE 298 AA; 33064 MW; 59F0DFAEC4E7CFBB CRC64;
MGDHAWSFLK DFLAGGVAAA VSKTAVAPIE RVKLLLQVQH ASKQISAEKQ YKGIIDCVVR
IPKEQGFLSF WRGNLANVIR YFPTQALNFA FKDKYKQLFL GGVDRHKQFW RYFAGNLASG
GAAGATSLCF VYPLDFARTR LAADVGKGAA QREFHGLGDC IIKIFKSDGL RGLYQGFNVS
VQGIIIYRAA YFGVYDTAKG MLPDPKNVHI FVSWMIAQSV TAVAGLVSYP FDTVRRRMMM
QSGRKGADIM YTGTVDCWRK IAKDEGAKAF FKGAWSNVLR GMGGAFVLVL YDEIKKYV
//

MIM 103220
*RECORD*
*FIELD* NO
103220
*FIELD* TI
*103220 SOLUTE CARRIER FAMILY 25 (MITOCHONDRIAL CARRIER, ADENINE NUCLEOTIDE
TRANSLOCATOR), MEMBER 4; SLC25A4
read more;;ADENINE NUCLEOTIDE TRANSLOCATOR 1; ANT1;;
ADP/ATP TRANSLOCATOR OF SKELETAL MUSCLE; ANT;;
ADP/ATP TRANSLOCASE 1;;
ADP/ATP CARRIER 1; AAC1
*FIELD* TX

DESCRIPTION

The SLC25A4 gene encodes the mitochondrial ADP/ATP, or adenine
nucleotide, translocator, which is a homodimer of 30-kD subunits
embedded in the mitochondrial inner membrane. The dimer forms a gated
pore through which ADP is moved across the inner membrane into the
mitochondrial matrix and ATP is moved from the matrix into the cytoplasm
(summary by Neckelmann et al., 1987).

CLONING

Neckelmann et al. (1987) characterized a 1,400-nucleotide cDNA for human
skeletal muscle ANT. They compared the sequence with that of the human
fibroblast ANT cognate as reported by Battini et al. (1987). This showed
that the 2 distinct ANTs diverged about 275 million years ago. The
skeletal muscle ANT is expressed in heart, kidney, liver, skeletal
muscle, and HeLa cells. The rate of evolution of the skeletal muscle ANT
is 10 to 12 times slower than that of the mitochondrial Ox/Phos genes.
Mitochondrial energy production varies greatly among human tissues.
Because the ANT determines the rate of ADP/ATP flux between the
mitochondrion and the cytosol, it is a logical candidate for regulator
of cellular dependence on oxidative energy metabolism.

Li et al. (1989) reported the cloning of the human ANT1 locus. The mRNA
is 1.4 kb and most abundant in heart and skeletal muscle, but barely
detectable in liver, kidney, or brain. A second full-length ANT cDNA,
ANT2 (300150), derived from fibroblasts is present in all of the
above-mentioned tissues at relatively constant levels. A third cDNA,
ANT3 (300151), has been cloned from human liver (Houldsworth and
Attardi, 1988). ANT1, ANT2, and ANT3 are approximately 90% homologous at
the amino acid level.

GENE STRUCTURE

Li et al. (1989) determined that the ANT1 gene is 5.8 kb long and
contains 4 exons.

GENE FUNCTION

Almost all patients with facioscapulohumeral muscular dystrophy (FSHD;
158900) carry deletions of an integral number of tandem 3.3-kb repeats,
termed D4Z4, on chromosome 4q35. Gabellini et al. (2002) found that in
FSHD muscle, genes located upstream of D4Z4 on 4q35, including FRG1
(601278), FRG2 (609032), and ANT1, are inappropriately overexpressed.
They showed that an element within D4Z4 specifically binds a
multiprotein complex that mediates transcriptional repression of 4q35
genes. Gabellini et al. (2002) proposed that deletion of D4Z4 leads to
the inappropriate transcriptional derepression of 4q35 genes, resulting
in disease.

Forlani et al. (2010) showed that MeCP2 (300005) cooperates with YY1
(600013) in repressing the ANT1 gene, encoding a mitochondrial adenine
nucleotide translocase. Importantly, ANT1 mRNA levels are increased in
human and mouse cell lines devoid of MeCP2, in Rett syndrome (312750)
patient fibroblast, and in the brain of MeCP2-null mice. Forlani et al.
(2010) further demonstrated that ANT1 protein levels are upregulated in
MeCP2-null mice.

MAPPING

Minoshima et al. (1989) used hybridization to flow-sorted human
chromosomes and Southern blot hybridization to mouse/human somatic cell
hybrids to demonstrate that the ANT1 gene localizes to human chromosome
4. Fan et al. (1992) regionalized the ANT1 gene to 4q35 by fluorescence
in situ hybridization. Haraguchi et al. (1993) mapped the ANT1 gene to
4q35-qter using somatic cell hybrids containing various deletions of
chromosome 4. The regional location was further refined through family
studies using ANT1 intron and promoter nucleotide polymorphisms
recognized by 3 different restriction endonucleases. Family studies
suggested that ANT1 is located centromeric to D4S139 which in turn is
centromeric to the locus for FSHD. Wijmenga et al. (1993) likewise
mapped the ANT1 gene to 4q35 to a site proximal to the FSHD gene.
Studies using a polymorphic CA-repeat 5 kb upstream of the ANT1 gene as
a marker in FSHD and CEPH families suggested that the ANT1 gene is
centromeric to FSHD and is separated from it by several markers,
including the factor XI gene (264900).

Mills et al. (1996) demonstrated that the murine homolog Ant1 is located
on chromosome 8 by studies of an interspecific cross. The gene had been
previously localized to chromosome 8 by PCR of a somatic cell hybrid
mapping panel with primers from the cDNA sequence. Only a single
recombination event in 227 chromosomes was observed between Ant1 and the
plasma kallikrein gene Klk3 (KLKB1; 229000) which in the human maps to
4q35 as does also ANT1.

MOLECULAR GENETICS

- Autosomal Dominant Progressive External Ophthalmoplegia
2

Kaukonen et al. (2000) identified a missense mutation in the ANT1 gene
(A114P; 103220.0001) in 5 families with autosomal dominant progressive
external ophthalmoplegia (PEOA2; 609283). The analogous mutation in
yeast caused a respiratory defect. Kaukonen et al. (2000) also
identified a mutations in the ANT1 gene (V289M; 103220.0002) in a
sporadic case of PEO. The A114P mutation is likely to be located either
in the third transmembrane domain of ANT1 or just adjacent to it in the
loop joining the second and third transmembrane domains in the
intermembrane space. The V289M mutation affects the sixth transmembrane
domain. A simulation analysis of the secondary structure of human ANT1
suggested that the adenine-to-proline substitution would cause an
additional bend in the polypeptide, disrupting the local alpha helix.
Because patients with dominant PEO carry 1 wildtype and 1 mutant allele,
defective ANT1 dimers would form in 2 out of 3 dimerization events.

Chen (2002) determined that the A128P mutation of the S. cerevisiae Aac2
protein, equivalent to A114P (103220.0001) in human ANT1, does not
always affect respiratory growth. Rather, expression of A128P resulted
in depolarization, structural swelling, and disintegration of
mitochondria, and ultimately an arrest of cell growth in a
dominant-negative manner. Chen (2002) proposed that the A128P mutation
may induce an unregulated channel, allowing free passage of solutes
across the inner membrane, rather than interfere specifically with
ATP/ADP exchange.

Fontanesi et al. (2004) introduced dominant-acting missense mutations
associated with PEO into AAC2, the yeast ortholog of human ANT1.
Expression of the equivalent mutations in aac2-defective haploid strains
of Saccharomyces cerevisiae resulted in a marked growth defect on
nonfermentable carbon sources, and a concurrent reduction of the amount
of mitochondrial cytochromes, cytochrome c oxidase activity, and
cellular respiration. The AAC2 pathogenic mutants showed a significant
defect in ADP versus ATP transport compared with wildtype AAC2. The aac2
mutant alleles were also inserted in combination with the endogenous
wildtype AAC2 gene. The heteroallelic strains behaved as recessive for
oxidative growth and petite-negative phenotype. In contrast, reduction
in cytochrome content and increased mtDNA instability appeared to behave
as dominant traits in heteroallelic strains.

- Autosomal Recessive Mitochondrial DNA Depletion Syndrome
12

In a 25-year-old Slovenian male with mitochondrial DNA depletion
syndrome-12 (MTDPS12; 615418), manifest as hypertrophic cardiomyopathy
and exercise intolerance, Palmieri et al. (2005) identified homozygosity
for a mutation in the SLC25A4 gene (A123D; 103220.0005). The clinical
and biochemical features were different from those found in dominant
ANT1 mutations, resembling those described in ANT1-knockout mice. No ATP
uptake was measured in proteoliposomes reconstituted with protein
extracts from the patient's muscle. The equivalent mutation in AAC2, the
yeast ortholog of human ANT1, resulted in a complete loss of transport
activity and in the inability to rescue the severe oxidative
phosphorylation phenotype displayed by WB-12, an AAC1/AAC2-defective
yeast strain.

In a 21-year-old Portuguese girl with MTDPS12, Echaniz-Laguna et al.
(2012) identified a homozygous splice site mutation in the ANT1 gene
(103220.0006). The mutant transcript was undetectable in patient cells,
consistent with complete loss of protein expression and function. The
clinically unaffected mother, who was heterozygous for the mutation, had
low levels (less than 2%) of mtDNA rearrangements in skeletal muscle.
The deceased father was reportedly unaffected. The patient had
hypertrophic cardiomyopathy, exercise intolerance with muscle weakness
and atrophy, congenital cataracts, and lactic acidosis. Muscle biopsy
showed ragged red fibers and multiple mtDNA deletions.

BIOCHEMICAL FEATURES

- Crystal Structure

Pebay-Peyroula et al. (2003) solved the bovine ADP/ATP carrier structure
at a resolution of 2.2 angstroms by X-ray crystallography in complex
with an inhibitor, carboxyatractyloside. Six alpha helices form a
compact transmembrane domain, which, at the surface toward the space
between inner and outer mitochondrial membranes, reveals a deep
depression. At its bottom, a hexapeptide carrying the signature of
nucleotide carriers (RRRMMM) is located. Pebay-Peyroula et al. (2003)
concluded that their structure, together with earlier biochemical
results, suggested that transport substrates bind to the bottom of the
cavity and that translocation results from a transient transition from a
'pit' to a 'channel' conformation.

ANIMAL MODEL

Mutations in mitochondrial DNA (mtDNA) involving rearrangements and
point mutations in tRNAs (e.g., 590050, 590045, 590035.0001) are
associated with mitochondrial disease in which myopathy associated with
ragged-red fibers and hypertrophic cardiomyopathy are common features.
Graham et al. (1997) hypothesized that these clinical manifestations may
derive from severe defects in oxidative phosphorylation, resulting in
marked mitochondrial energy deficiency and a compensatory induction of
mitochondrial proliferation. To test this hypothesis, they took
advantage of the presence of tissue-specific isoforms of ANT. They
reasoned that if ATP deficiency were the cause of mitochondrial myopathy
and cardiomyopathy, inactivation of ANT1 would starve the skeletal
muscle and the heart of mitochondrial ATP, resulting in the pathology.
They generated 'knockout' mice deficient in the heart/muscle isoform of
ANT. Histologic and ultrastructural examination of skeletal muscle from
Ant1-null mutants revealed ragged-red muscle fibers a dramatic
proliferation of mitochondria, while examination of the heart revealed
cardiac hypertrophy with mitochondrial proliferation. Mitochondria
isolated from mutant skeletal muscle exhibited a severe defect in
coupled respiration. Ant1-mutant adults also had a resting serum lactate
level 4-fold higher than that of controls, indicative of metabolic
acidosis. Significantly, mutant adults manifested severe exercise
intolerance.

The mitochondrial permeability transition pore (mtPTP), a protein
complex that includes the ANTs, mediates the sudden increase in inner
mitochondrial membrane permeability that is a common feature of
apoptosis. Kokoszka et al. (2004) confirmed that the mouse genome
contains only 2 Ant genes, Ant1 and Ant2. They inactivated both Ant
genes in mouse liver and analyzed mtPTP activation in isolated
mitochondria and the induction of cell death in hepatocytes.
Mitochondria lacking Ant could still undergo inner membrane permeability
transition and release cytochrome c (123970). However, more Ca(2+) than
usual was required to activate mtPTP, and the pore could not be
regulated by Ant ligands, including adenine nucleotides. Hepatocytes
without Ant remained competent to respond to various initiators of cell
death. In addition, mutant mouse liver mitochondria showed respiration
rates that were almost twice that of controls and that were
nonresponsive to the addition of ADP. The mitochondrial membrane
potential was higher than that of controls. The increased respiration
rate was associated with upregulated Cox1 (176805) protein levels.

Halestrap (2004) commented on the observations of Kokoszka et al.
(2004).

*FIELD* AV
.0001
PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS,
AUTOSOMAL DOMINANT, 2
SLC25A4, ALA114PRO

In 5 Italian families with PEOA2 (609283), Kaukonen et al. (2000)
identified a G-to-C transversion in exon 2 of the ANT1 gene, resulting
in an ala114-to-pro (A114P) substitution. The nucleotide change was
present in all affected family members, but not in 860 Finnish or 150
Italian control individuals. Alanine-114 and its flanking sequences are
strictly conserved among species. A common disease haplotype with
identical markers was shared by all patients in 3 Italian families,
suggesting that there is 1 founder mutation and common ancestry,
although this could not be genealogically confirmed. Three families had
been reported by Kaukonen et al. (1996, 1999).

.0002
PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS,
AUTOSOMAL DOMINANT, 2
SLC25A4, VAL289MET

In a sporadic patient with PEOA2 (609283) and multiple mitochondrial DNA
deletions, Kaukonen et al. (2000) identified a missense mutation, a
G-to-A transition in exon 4 of the ANT1 gene resulting in a
val289-to-met (V289M) substitution.

.0003
PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS,
AUTOSOMAL DOMINANT, 2
SLC25A4, LEU98PRO

In 3 members of a Greek family with PEOA2 (609283), Napoli et al. (2001)
identified a heterozygous 293T-C transition in the ANT1 gene, resulting
in a leu98-to-pro (L98P) substitution. The mutation was absent in
several unaffected family members and in Italian and Greek controls.

.0004
PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS,
AUTOSOMAL DOMINANT, 2
SLC25A4, ASP104GLY

In 4 affected members of a Japanese family with PEOA2 (609283), Komaki
et al. (2002) identified a 311A-G heterozygous mutation in exon 2 of the
ANT1 gene, resulting in an asp104-to-gly (D104G) substitution. The
mutation was not detected in 2 unaffected family members or 120 normal
individuals. The authors noted that the mutation converted a highly
conserved aspartic acid into a nonpolar glycine in a side chain.

.0005
MITOCHONDRIAL DNA DEPLETION SYNDROME 12 (CARDIOMYOPATHIC TYPE)
SLC25A4, ALA123ASP

In a 25-year-old Slovenian male with mitochondrial DNA depletion
syndrome-12 (MTDPS12; 615418), Palmieri et al. (2005) identified
homozygosity for a 368C-A transversion in the SLC25A4 gene, resulting in
an ala123-to-asp (A123D) substitution in a conserved residue. The
unaffected mother was heterozygous for the mutation, and the father was
unavailable for testing. The mutation was absent in 500 control
individuals. The patient presented with hypertrophic cardiomyopathy,
mild myopathy with exercise intolerance, and lactic acidosis but no
ophthalmoplegia. Muscle biopsy revealed numerous ragged-red fibers, and
Southern blot analysis disclosed multiple deletions of muscle
mitochondrial DNA. Muscle tissue was unavailable from the patient's
mother, so the presence of subclinical amounts of multiple deletions
could not be ruled out. The clinical and biochemical features were
different from those found in dominant ANT1 mutations, resembling those
described in ANT1-knockout mice. No ATP uptake was measured in
proteoliposomes reconstituted with protein extracts from the patient's
muscle. The equivalent mutation in AAC2, the yeast ortholog of human
ANT1, resulted in a complete loss of transport activity and in the
inability to rescue the severe oxidative phosphorylation phenotype
displayed by WB-12, an AAC1/AAC2-defective yeast strain.

.0006
MITOCHONDRIAL DNA DEPLETION SYNDROME 12 (CARDIOMYOPATHIC TYPE)
SLC25A4, IVS1DS, G-A, +1

In a patient, born of consanguineous Portuguese parents, with MTDPS12
(615418), Echaniz-Laguna et al. (2012) identified a homozygous G-to-A
transition in intron 1 of the SLC25A4 gene (c.111+1G-A). The mutant
transcript was undetectable in patient cells, consistent with complete
loss of protein expression and function. The clinically unaffected
mother, who was heterozygous for the mutation, had low levels (less than
2%) of mtDNA rearrangements in skeletal muscle. The deceased father was
reportedly unaffected. The patient had hypertrophic cardiomyopathy,
exercise intolerance with muscle weakness and atrophy, congenital
cataracts, and lactic acidosis. Muscle biopsy showed ragged red fibers
and multiple mtDNA deletions.

*FIELD* SA
Li et al. (1989); Servidei et al. (1991)
*FIELD* RF
1. Battini, R.; Ferrari, S.; Kaczmarek, L.; Calabretta, B.; Chen,
S.; Baserga, R.: Molecular cloning of a cDNA for a human ADP/ATP
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1987.

2. Chen, X. J.: Induction of an unregulated channel by mutations
in adenine nucleotide translocase suggests an explanation for human
ophthalmoplegia. Hum. Molec. Genet. 11: 1835-1843, 2002.

3. Echaniz-Laguna, A.; Chassagne, M.; Ceresuela, J.; Rouvet, I.; Padet,
S.; Acquaviva, C.; Nataf, S.; Vinzio, S.; Bozon, D.; Mousson de Camaret,
B.: Complete loss of expression of the ANT1 gene causing cardiomyopathy
and myopathy. J. Med. Genet. 49: 146-150, 2012.

4. Fan, Y.-S.; Yang, H.-M.; Lin, C. C.: Assignment of the human muscle
adenine nucleotide translocator gene (ANT1) to 4q35 by fluorescence
in situ hybridization. Cytogenet. Cell Genet. 60: 29-30, 1992.

5. Fontanesi, F.; Palmieri, L.; Scarcia, P.; Lodi, T.; Donnini, C.;
Limongelli, A.; Tiranti, V.; Zeviani, M.; Ferrero, I.; Viola, A. M.
: Mutations in AAC2, equivalent to human adPEO-associated ANT1 mutations,
lead to defective oxidative phosphorylation in Saccharomyces cerevisiae
and affect mitochondrial DNA stability. Hum. Molec. Genet. 13: 923-934,
2004.

6. Forlani, G.; Giarda, E.; Ala, U.; Di Cunto, F.; Salani, M.; Tupler,
R.; Kilstrup-Nielsen, C.; Landsberger, N. The MeCP2/YY1 interaction
regulates ANT1 expression at 4q35: novel hints for Rett syndrome pathogenesis. Hum.
Molec. Genet. 19: 3114-3123, 2010.

7. Gabellini, D.; Green, M. R.; Tupler, R.: Inappropriate gene activation
in FSHD: a repressor complex binds a chromosomal repeat deleted in
dystrophic muscle. Cell 110: 339-348, 2002.

8. Graham, B. H.; Waymire, K. G.; Cottrell, B.; Trounce, I. A.; MacGregor,
G. R.; Wallace, D. C.: A mouse model for mitochondrial myopathy and
cardiomyopathy resulting from a deficiency in the heart/muscle isoform
of the adenine nucleotide translocator. Nature Genet. 16: 226-234,
1997.

9. Halestrap, A. P.: Mitochondrial permeability: dual role for the
ADP/ATP translocator? Comment on 'The ADP/ATP translocator is not
essential for the mitochondrial permeability transition pore'. Nature 430:
984 only, 2004.

10. Haraguchi, Y.; Chung, A. B.; Torroni, A.; Stepien, G.; Shoffner,
J. M.; Wasmuth, J. J.; Costigan, D. A.; Polak, M.; Altherr, M. R.;
Winokur, S. T.; Wallace, D. C.: Genetic mapping of human heart-skeletal
muscle adenine nucleotide translocator and its relationship to the
facioscapulohumeral muscular dystrophy locus. Genomics 16: 479-485,
1993.

11. Houldsworth, J.; Attardi, G.: Two distinct genes for ADP/ATP
translocase are expressed at the mRNA level in adult human liver. Proc.
Nat. Acad. Sci. 85: 377-381, 1988.

12. Kaukonen, J.; Juselius, J. K.; Tiranti, V.; Kyttala, A.; Zeviani,
M.; Comi, G. P.; Keranen, J.; Peltonen, L.; Suomalainen, A.: Role
of adenine nucleotide translocator 1 in mtDNA maintenance. Science 289:
782-785, 2000.

13. Kaukonen, J.; Zeviani, M.; Comi, G. P.; Piscaglia, M.-G.; Peltonen,
L.; Suomalainen, A.: A third locus predisposing to multiple deletions
of mtDNA in autosomal dominant progressive external ophthalmoplegia.
(Letter) Am. J. Hum. Genet. 65: 256-261, 1999.

14. Kaukonen, J. A.; Amati, P.; Suomalainen, A.; Rotig, A.; Piscaglia,
M.-G.; Salvi, F.; Weissenbach, J.; Fratta, G.; Comi, G.; Peltonen,
L.; Zeviani, M.: An autosomal locus predisposing to multiple deletions
of mtDNA on chromosome 3p. Am. J. Hum. Genet. 58: 763-769, 1996.

15. Kokoszka, J. E.; Waymire, K. G.; Levy, S. E.; Sligh, J. E.; Cai,
J.; Jones, D. P.; MacGregor, G. R.; Wallace, D. C.: The ADP/ATP translocator
is not essential for the mitochondrial permeability transition pore. Nature 427:
461-465, 2004.

16. Komaki, H.; Fukazawa, T.; Houzen, H.; Yoshida, K.; Nonaka, I.;
Goto, Y.: A novel D104G mutation in the adenine nucleotide translocator
1 gene in autosomal dominant progressive external ophthalmoplegia
patients with mitochondrial DNA with multiple deletions. Ann. Neurol. 51:
645-648, 2002.

17. Li, K.; Warner, C. K.; Hodge, J. A.; Minoshima, S.; Kudoh, J.;
Fukuyama, R.; Maekawa, M.; Shimizu, Y.; Shimizu, N.; Wallace, D. C.
: A human muscle adenine nucleotide translocator gene has four exons,
is located on chromosome 4, and is differentially expressed. J. Biol.
Chem. 264: 13998-14004, 1989.

18. Li, K.; Warner, C. K.; Hodge, J. A.; Wallace, D. C.: Cloning
and tissue-differential expression of human heart-skeletal muscle
adenine nucleotide translocator gene. (Abstract) Cytogenet. Cell
Genet. 51: 1032-1033, 1989.

19. Mills, K. A.; Ellison, J. W.; Mathews, K. D.: The Ant1 gene maps
near Klk3 on proximal mouse chromosome 8. Mammalian Genome 7: 707
only, 1996.

20. Minoshima, S.; Kudoh, J.; Fukuyama, R.; Maekawa, M.; Shimizu,
Y.; Li, K.; Wallace, D. C.; Shimizu, N.: Mapping of the human muscle
adenine nucleotide translocator gene (ANT1) to chromosome 4. (Abstract) Cytogenet.
Cell Genet. 51: 1044-1045, 1989.

21. Napoli, L.; Bordoni, A.; Zeviani, M.; Hadjigeorgiou, G. M.; Sciacco,
M.; Tiranti, V.; Terentiou, A.; Moggio, M.; Papadimitriou, A.; Scarlato,
G.; Comi, G. P.: A novel missense adenine nucleotide translocator-1
gene mutation in a Greek adPEO family. Neurology 57: 2295-2298,
2001.

22. Neckelmann, N.; Li, K.; Wade, R. P.; Shuster, R.; Wallace, D.
C.: cDNA sequence of a human skeletal muscle ADP/ATP translocator:
lack of a leader peptide, divergence from a fibroblast translocator
cDNA, and coevolution with mitochondrial DNA genes. Proc. Nat. Acad.
Sci. 84: 7580-7584, 1987.

23. Palmieri, L.; Alberio, S.; Pisano, I.; Lodi, T.; Meznaric-Petrusa,
M.; Zidar, J.; Santoro, A.; Scarcia, P.; Fontanesi, F.; Lamantea,
E.; Ferrero, I.; Zeviani, M.: Complete loss-of-function of the heart/muscle-specific
adenine nucleotide translocator is associated with mitochondrial myopathy
and cardiomyopathy. Hum. Molec. Genet. 14: 3079-3088, 2005.

24. Pebay-Peyroula, E.; Dahout-Gonzalez, C.; Kahn, R.; Trezeguet,
V.; Lauquin, G. J.-M.; Brandolin, G.: Structure of mitochondrial
ADP/ATP carrier in complex with carboxyatractyloside. Nature 426:
39-44, 2003.

25. Servidei, S.; Zeviani, M.; Manfredi, G.; Ricci, E.; Silvestri,
G.; Bertini, E.; Gellera, C.; DiMauro, S.; DiDonato, S.; Tonali, P.
: Dominantly inherited mitochondrial myopathy with multiple deletions
of mitochondrial DNA: clinical, morphologic and biochemical studies. Neurology 41:
1053-1059, 1991.

26. Wijmenga, C.; Winokur, S. T.; Padberg, G. W.; Skraastad, M. I.;
Altherr, M. R.; Wasmuth, J. J.; Murray, J. C.; Hofker, M. H.; Frants,
R. R.: The human skeletal muscle adenine nucleotide translocator
gene maps to chromosome 4q35 in the region of the facioscapulohumeral
muscular dystrophy locus. Hum. Genet. 92: 198-203, 1993.

*FIELD* CN
Cassandra L. Kniffin - updated: 9/18/2013
Ada Hamosh - updated: 7/18/2011
George E. Tiller - updated: 5/13/2009
Ada Hamosh - updated: 12/6/2006
George E. Tiller - updated: 9/18/2006
Matthew B. Gross - updated: 11/18/2004
Ada Hamosh - updated: 9/29/2004
Patricia A. Hartz - updated: 2/16/2004
Ada Hamosh - updated: 1/8/2004
George E. Tiller - updated: 7/8/2003
Cassandra L. Kniffin - updated: 12/11/2002
Cassandra L. Kniffin - updated: 5/24/2002
Ada Hamosh - updated: 8/3/2000
Victor A. McKusick - updated: 7/3/1997

*FIELD* CD
Victor A. McKusick: 12/3/1987

*FIELD* ED
carol: 09/30/2013
ckniffin: 9/18/2013
joanna: 6/28/2013
terry: 2/3/2012
terry: 7/25/2011
terry: 7/22/2011
carol: 7/21/2011
alopez: 7/18/2011
terry: 9/10/2009
wwang: 6/25/2009
terry: 5/13/2009
carol: 11/20/2008
mgross: 2/22/2007
alopez: 12/13/2006
terry: 12/6/2006
alopez: 9/18/2006
ckniffin: 3/30/2005
carol: 3/30/2005
ckniffin: 3/29/2005
carol: 3/29/2005
ckniffin: 2/21/2005
mgross: 11/18/2004
alopez: 10/1/2004
terry: 9/29/2004
mgross: 2/16/2004
tkritzer: 1/12/2004
terry: 1/8/2004
cwells: 7/8/2003
carol: 12/16/2002
tkritzer: 12/13/2002
ckniffin: 12/11/2002
carol: 5/24/2002
ckniffin: 5/23/2002
terry: 3/28/2002
carol: 6/28/2001
alopez: 8/4/2000
alopez: 8/3/2000
carol: 3/7/2000
mark: 7/7/1997
terry: 7/3/1997
mark: 10/26/1996
terry: 10/17/1996
carol: 5/10/1994
carol: 10/26/1993
carol: 9/13/1993
carol: 5/26/1993
carol: 4/7/1993
carol: 1/26/1993

MIM 609283
*RECORD*
*FIELD* NO
609283
*FIELD* TI
#609283 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS,
AUTOSOMAL DOMINANT, 2; PEOA2
read more;;PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA, AUTOSOMAL DOMINANT, 2
*FIELD* TX
A number sign (#) is used with this entry because autosomal dominant
progressive external ophthalmoplegia (adPEO) with mitochondrial DNA
(mtDNA) deletions-2 (PEOA2) is caused by heterozygous mutation in the
nuclear-encoded ANT1 gene (SLC25A4; 103220) on chromosome 4q35.

DESCRIPTION

Progressive external ophthalmoplegia is characterized by multiple
mitochondrial DNA deletions in skeletal muscle. The most common clinical
features include adult onset of weakness of the external eye muscles and
exercise intolerance. Both autosomal dominant and autosomal recessive
inheritance can occur; autosomal recessive inheritance is usually more
severe (Filosto et al., 2003; Luoma et al., 2004).

PEO caused by mutations in the POLG gene are associated with more
complicated phenotypes than those forms caused by mutations in the ANT1
or C10ORF2 genes (Lamantea et al., 2002).

For a general phenotypic description and a discussion of genetic
heterogeneity of autosomal dominant progressive external
ophthalmoplegia, see PEOA1 (157640).

CLINICAL FEATURES

Kaukonen et al. (1996, 1999) reported several Italian adPEO families.
All patients had progressive external ophthalmoplegia and ptosis, but no
generalized muscle weakness. Age at onset was approximately 35 years.
Several affected family members had sensorineural hearing loss. Two
subjects had goiter associated with hypo- or hyperthyroidism. Two
elderly subjects suffered from dementia manifesting as impairment of
cognitive functions, with no affective component. An increased serum
lactate level at rest was detected in 1 patient. A typical example of a
patient in this family was a 67-year-old woman with ptosis and
ophthalmoplegia, bilateral hearing loss, and hyperthyroidism with
goiter. Her standard electromyogram was myopathic, and nerve
conduction-velocity studies were normal. Multiple mtDNA deletions were
detected in an analysis of muscle biopsy from the biceps brachialis.
Histologic analysis of her muscle sample showed that 3% of the fibers
were ragged red and 5% showed partial COX deficiency (see 220110). No
elevation of lactic acid was detected at rest or after standard
exercise, and her serum CPK level was within the normal range.
Respiratory chain analysis showed slightly reduced activities of
complexes III and IV (65 to 70% of the mean of controls), whereas
activities of complexes I and II were within the normal range.

MAPPING

In an Italian family with adPEO, Kaukonen et al. (1999) mapped the
disease locus, formerly designated 'PEO3,' to a 13.5-cM interval between
markers D4S2920 and D4S2924 on chromosome 4q34-q35. The results yielded
2-point and multipoint lod scores of 3.51 and 4.7, respectively. In 3
Italian families with autosomal dominant PEO, Kaukonen et al. (1996)
found linkage to a locus on chromosome 3p (formerly designated 'PEO2').
However, in a reanalysis of these families, Kaukonen et al. (2000)
failed to find significant lod scores to the locus on chromosome 3p
(highest new multipoint lod score of 2.85). Further haplotype analysis
did not support the existence of an adPEO locus on chromosome 3, and a
mutation in the ANT1 gene (103220.0001) on 4q35 was later identified in
these families (see Kaukonen et al., 2000).

MOLECULAR GENETICS

In affected members of 5 4q-linked Italian families with adPEO reported
by Kaukonen et al. (1996, 1999), Kaukonen et al. (2000) identified a
heterozygous mutation in the ANT1 gene (103220.0001). The affected
families originated from the Romagna County of Italy, suggesting a
founder effect. Except for a lack of cardiac symptoms, the features of
the patients resembled those in Ant1 knockout mice (Graham et al.,
1997).

In 3 members of a Greek family with PEOA2, Napoli et al. (2001)
identified a heterozygous mutation in the SLC25A4 gene (103220.0003).
The mutation was absent in several unaffected family members and in
Italian and Greek controls.

Hirano and DiMauro (2001) reviewed the molecular genetics of progressive
external ophthalmoplegia and classified the specific disease type
according to mutation in the autosomal ANT1, C10ORF2, and POLG genes as
well as in multiple mitochondrial genes.

Lamantea et al. (2002) stated that mutations in the ANT1 and C10ORF2
gene account for approximately 4% and 35% of familial adPEO cases,
respectively. Mutations in the POLG gene are the most frequent cause of
all forms of familial PEO, accounting for approximately 45% of cases.

HISTORY

Bakker et al. (1993) described an 8-year-old boy with adenine nucleotide
translocator deficiency in muscle who was first investigated at the age
of 3.5 years because of shortness of breath and rapid fatigue. Lactate
levels in serum and cerebrospinal fluid were greatly elevated, and
histochemical and electron-microscopic examination of skeletal muscle
suggested a mitochondrial myopathy. Great clinical improvement was
observed with the administration of vitamin E (Bakker et al., 1993).

*FIELD* RF
1. Bakker, H. D.; Scholte, H. R.; Van den Bogert, C.; Jeneson, J.
A. L.; Ruitenbeek, W.; Wanders, R. J. A.; Abeling, N. G. G. M.; van
Gennip, A. H.: Adenine nucleotide translocator deficiency in muscle:
potential therapeutic value of vitamin E. J. Inherit. Metab. Dis. 16:
548-552, 1993.

2. Bakker, H. D.; Scholte, H. R.; Van den Bogert, C.; Ruitenbeek,
W.; Jeneson, J. A. L.; Wanders, R. J. A.; Abeling, N. G. G. M.; Dorland,
B.; Sengers, R. C. A.; van Gennip, A. H.: Deficiency of the adenine
nucleotide translocator in muscle of a patient with myopathy and lactic
acidosis: a new mitochondrial defect. Pediat. Res. 33: 412-417,
1993.

3. Filosto, M.; Mancuso, M.; Nishigaki, Y.; Pancrudo, J.; Harati,
Y.; Gooch, C.; Mankodi, A.; Bayne, L.; Bonilla, E.; Shanske, S.; Hirano,
M.; DiMauro, S.: Clinical and genetic heterogeneity in progressive
external ophthalmoplegia due to mutations in polymerase-gamma. Arch.
Neurol. 60: 1279-1284, 2003.

4. Graham, B. H.; Waymire, K. G.; Cottrell, B.; Trounce, I. A.; MacGregor,
G. R.; Wallace, D. C.: A mouse model for mitochondrial myopathy and
cardiomyopathy resulting from a deficiency in the heart/muscle isoform
of the adenine nucleotide translocator. Nature Genet. 16: 226-234,
1997.

5. Hirano, M.; DiMauro, S.: ANT1, twinkle, POLG, and TP: new genes
open our eyes to ophthalmoplegia. Neurology 57: 2163-2165, 2001.

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2001.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Ears];
Sensorineural hearing loss has been reported;
[Eyes];
External ophthalmoplegia, progressive (PEO);
Ptosis

MUSCLE, SOFT TISSUE:
Facial muscle weakness;
Generalized muscle weakness (less common);
Exercise intolerance (less common);
EMG shows myopathic changes;
Muscle biopsy shows ragged red fibers;
Muscle biopsy shows multiple mitochondrial DNA (mtDNA) deletions;
Muscle biopsy shows decreased activity of cytochrome c oxidase;
Electron microscopy shows subsarcolemmal accumulations of abnormally
shaped mitochondria

LABORATORY ABNORMALITIES:
Serum lactate is usually normal

MISCELLANEOUS:
Adult onset (before 50 years);
Progressive disorder;
Genetic heterogeneity (see 157640);
SLC25A4 mutations account for approximately 4% of all PEO cases

MOLECULAR BASIS:
Caused by mutation in the solute carrier family 25 (mitochondrial
carrier) member 4 gene (SLC25A4, 103220.0001)

*FIELD* CD
Cassandra L. Kniffin: 3/30/2005

*FIELD* ED
joanna: 10/22/2013
joanna: 3/2/2010
joanna: 12/30/2005
ckniffin: 3/30/2005

*FIELD* CD
Cassandra L. Kniffin: 3/29/2005

*FIELD* ED
carol: 07/21/2011
carol: 1/4/2011
joanna: 3/2/2010
alopez: 5/18/2006
carol: 3/30/2005
ckniffin: 3/29/2005