Full text data of CPT1A
CPT1A
(CPT1)
[Confidence: high (present in two of the MS resources)]
Carnitine O-palmitoyltransferase 1, liver isoform; CPT1-L; 2.3.1.21 (Carnitine O-palmitoyltransferase I, liver isoform; CPT I; CPTI-L; Carnitine palmitoyltransferase 1A)
Carnitine O-palmitoyltransferase 1, liver isoform; CPT1-L; 2.3.1.21 (Carnitine O-palmitoyltransferase I, liver isoform; CPT I; CPTI-L; Carnitine palmitoyltransferase 1A)
hRBCD
IPI00032038
IPI00032038 Carnitine O-palmitoyltransferase I, mitochondrial liver isoform Carnitine O-palmitoyltransferase I, mitochondrial liver isoform membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 1 n/a n/a n/a n/a n/a n/a n/a n/a n/a Mitochondrial outer membrane. n/a found at its expected molecular weight found at molecular weight
IPI00032038 Carnitine O-palmitoyltransferase I, mitochondrial liver isoform Carnitine O-palmitoyltransferase I, mitochondrial liver isoform membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 1 n/a n/a n/a n/a n/a n/a n/a n/a n/a Mitochondrial outer membrane. n/a found at its expected molecular weight found at molecular weight
Comments
Isoform P50416-2 was detected.
Isoform P50416-2 was detected.
UniProt
P50416
ID CPT1A_HUMAN Reviewed; 773 AA.
AC P50416; Q8TCU0; Q9BWK0;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 07-DEC-2004, sequence version 2.
DT 22-JAN-2014, entry version 131.
DE RecName: Full=Carnitine O-palmitoyltransferase 1, liver isoform;
DE Short=CPT1-L;
DE EC=2.3.1.21;
DE AltName: Full=Carnitine O-palmitoyltransferase I, liver isoform;
DE Short=CPT I;
DE Short=CPTI-L;
DE AltName: Full=Carnitine palmitoyltransferase 1A;
GN Name=CPT1A; Synonyms=CPT1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=7892212; DOI=10.1073/pnas.92.6.1984;
RA Britton C.H., Schultz R.A., Zhang B., Esser V., Foster D.W.,
RA McGarry J.D.;
RT "Human liver mitochondrial carnitine palmitoyltransferase I:
RT characterization of its cDNA and chromosomal localization and partial
RT analysis of the gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:1984-1988(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS CPT1AD VAL-414 AND
RP CYS-498, AND VARIANT THR-275.
RX PubMed=12189492; DOI=10.1007/s00439-002-0752-0;
RA Gobin S., Bonnefont J.-P., Prip-Buus C., Mugnier C., Ferrec M.,
RA Demaugre F., Saudubray J.-M., Rostane H., Djouadi F., Wilcox W.,
RA Cederbaum S., Haas R., Nyhan W.L., Green A., Gray G., Girard J.,
RA Thuillier L.;
RT "Organization of the human liver carnitine palmitoyltransferase 1 gene
RT (CPT1A) and identification of novel mutations in hypoketotic
RT hypoglycaemia.";
RL Hum. Genet. 111:179-189(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Eye;
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 [5]
RP INDUCTION BY FATTY ACIDS.
RX PubMed=16271724; DOI=10.1016/j.jmb.2005.09.097;
RA Napal L., Marrero P.F., Haro D.;
RT "An intronic peroxisome proliferator-activated receptor-binding
RT sequence mediates fatty acid induction of the human carnitine
RT palmitoyltransferase 1A.";
RL J. Mol. Biol. 354:751-759(2005).
RN [6]
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 [7]
RP 3D-STRUCTURE MODELING.
RX PubMed=14711372; DOI=10.1042/BJ20031373;
RA Morillas M., Lopez-Vinas E., Valencia A., Serra D., Gomez-Puertas P.,
RA Hegardt F.G., Asins G.;
RT "Structural model of carnitine palmitoyltransferase I based on the
RT carnitine acetyltransferase crystal.";
RL Biochem. J. 379:777-784(2004).
RN [8]
RP STRUCTURE BY NMR OF 1-42, AND DOMAIN.
RX PubMed=21990363; DOI=10.1074/jbc.M111.306951;
RA Rao J.N., Warren G.Z., Estolt-Povedano S., Zammit V.A., Ulmer T.S.;
RT "An environment-dependent structural switch underlies the regulation
RT of carnitine palmitoyltransferase 1A.";
RL J. Biol. Chem. 286:42545-42554(2011).
RN [9]
RP VARIANT CPT1AD GLY-454.
RX PubMed=9691089; DOI=10.1172/JCI2927;
RA IJlst L., Mandel H., Oostheim W., Ruiter J.P.N., Gutman A.,
RA Wanders R.J.;
RT "Molecular basis of hepatic carnitine palmitoyltransferase I
RT deficiency.";
RL J. Clin. Invest. 102:527-531(1998).
RN [10]
RP VARIANTS CPT1AD CYS-123; TRP-304; TRP-357; ARG-395 DEL; LEU-479 AND
RP PRO-484, AND VARIANT THR-275.
RX PubMed=11441142;
RA Brown N.F., Mullur R.S., Subramanian I., Esser V., Bennett M.J.,
RA Saudubray J.-M., Feigenbaum A.S., Kobari J.A., Macleod P.M.,
RA McGarry J.D., Cohen J.C.;
RT "Molecular characterization of L-CPT I deficiency in six patients:
RT insights into function of the native enzyme.";
RL J. Lipid Res. 42:1134-1142(2001).
RN [11]
RP VARIANT CPT1AD GLU-710, CHARACTERIZATION OF VARIANT CPT1AD GLU-710,
RP CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=11350182; DOI=10.1006/mgme.2001.3176;
RA Prip-Buus C., Thuillier L., Abadi N., Prasad C., Dilling L.,
RA Klasing J., Demaugre F., Greenberg C.R., Haworth J.C., Droin V.,
RA Kadhom N., Gobin S., Kamoun P., Girard J., Bonnefont J.-P.;
RT "Molecular and enzymatic characterization of a unique carnitine
RT palmitoyltransferase 1A mutation in the Hutterite community.";
RL Mol. Genet. Metab. 73:46-54(2001).
RN [12]
RP CHARACTERIZATION OF VARIANT CPT1AD GLY-360.
RX PubMed=12111367; DOI=10.1007/s100380200047;
RA Ogawa E., Kanazawa M., Yamamoto S., Ohtsuka S., Ogawa A., Ohtake A.,
RA Takayanagi M., Kohno Y.;
RT "Expression analysis of two mutations in carnitine
RT palmitoyltransferase IA deficiency.";
RL J. Hum. Genet. 47:342-347(2002).
RN [13]
RP VARIANT CPT1AD GLU-709, CHARACTERIZATION OF VARIANTS CPT1AD THR-275;
RP VAL-414; CYS-498; GLU-709 AND GLU-710, SUBCELLULAR LOCATION, CATALYTIC
RP ACTIVITY, AND ENZYME REGULATION.
RX PubMed=14517221; DOI=10.1074/jbc.M310130200;
RA Gobin S., Thuillier L., Jogl G., Faye A., Tong L., Chi M.,
RA Bonnefont J.-P., Girard J., Prip-Buus C.;
RT "Functional and structural basis of carnitine palmitoyltransferase 1A
RT deficiency.";
RL J. Biol. Chem. 278:50428-50434(2003).
RN [14]
RP VARIANT CPT1AD ILE-314.
RX PubMed=15669684; DOI=10.1023/B:BOLI.0000042979.42120.55;
RA Stoler J.M., Sabry M.A., Hanley C., Hoppel C.L., Shih V.E.;
RT "Successful long-term treatment of hepatic carnitine
RT palmitoyltransferase I deficiency and a novel mutation.";
RL J. Inherit. Metab. Dis. 27:679-684(2004).
RN [15]
RP VARIANTS CPT1AD GLY-316; VAL-343 AND TRP-465.
RX PubMed=15110323; DOI=10.1016/j.ymgme.2004.02.004;
RA Bennett M.J., Boriack R.L., Narayan S., Rutledge S.L., Raff M.L.;
RT "Novel mutations in CPT 1A define molecular heterogeneity of hepatic
RT carnitine palmitoyltransferase I deficiency.";
RL Mol. Genet. Metab. 82:59-63(2004).
CC -!- FUNCTION: Catalyzes the transfer of the acyl group of long-chain
CC fatty acid-CoA conjugates onto carnitine, an essential step for
CC the mitochondrial uptake of long-chain fatty acids and their
CC subsequent beta-oxidation in the mitochondrion. Plays an important
CC role in triglyceride metabolism.
CC -!- CATALYTIC ACTIVITY: Palmitoyl-CoA + L-carnitine = CoA + L-
CC palmitoylcarnitine.
CC -!- ENZYME REGULATION: Inhibited by malonyl-CoA.
CC -!- PATHWAY: Lipid metabolism; fatty acid beta-oxidation.
CC -!- SUBUNIT: Homohexamer and homotrimer. Identified in a complex that
CC contains at least CPT1A, ACSL1 and VDAC1. Also identified in
CC complexes with ACSL1 and VDAC2 and VDAC3 (By similarity).
CC -!- SUBCELLULAR LOCATION: Mitochondrion outer membrane; Multi-pass
CC membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P50416-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P50416-2; Sequence=VSP_012167;
CC -!- TISSUE SPECIFICITY: Strong expression in kidney and heart, and
CC lower in liver and skeletal muscle.
CC -!- INDUCTION: Up-regulated by fatty acids.
CC -!- DOMAIN: A conformation change in the N-terminal region spanning
CC the first 42 residues plays an important role in the regulation of
CC enzyme activity by malonyl-CoA.
CC -!- DISEASE: Carnitine palmitoyltransferase 1A deficiency (CPT1AD)
CC [MIM:255120]: Rare autosomal recessive metabolic disorder of long-
CC chain fatty acid oxidation characterized by severe episodes of
CC hypoketotic hypoglycemia usually occurring after fasting or
CC illness. Onset is in infancy or early childhood. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the carnitine/choline acetyltransferase
CC family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CPT1A";
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DR EMBL; L39211; AAC41748.1; -; mRNA.
DR EMBL; AJ420747; CAD12625.1; -; Genomic_DNA.
DR EMBL; AJ420748; CAD59673.1; -; Genomic_DNA.
DR EMBL; BT009791; AAP88793.1; -; mRNA.
DR EMBL; BC000185; AAH00185.1; -; mRNA.
DR PIR; I59351; I59351.
DR RefSeq; NP_001027017.1; NM_001031847.2.
DR RefSeq; NP_001867.2; NM_001876.3.
DR RefSeq; XP_005273821.1; XM_005273764.1.
DR UniGene; Hs.503043; -.
DR PDB; 2LE3; NMR; -; A=1-42.
DR PDBsum; 2LE3; -.
DR ProteinModelPortal; P50416; -.
DR SMR; P50416; 1-42, 180-765.
DR IntAct; P50416; 12.
DR MINT; MINT-3018357; -.
DR STRING; 9606.ENSP00000265641; -.
DR ChEMBL; CHEMBL1293194; -.
DR DrugBank; DB00583; L-Carnitine.
DR DrugBank; DB01074; Perhexiline.
DR PhosphoSite; P50416; -.
DR DMDM; 56405343; -.
DR PaxDb; P50416; -.
DR PeptideAtlas; P50416; -.
DR PRIDE; P50416; -.
DR DNASU; 1374; -.
DR Ensembl; ENST00000265641; ENSP00000265641; ENSG00000110090.
DR Ensembl; ENST00000376618; ENSP00000365803; ENSG00000110090.
DR Ensembl; ENST00000539743; ENSP00000446108; ENSG00000110090.
DR Ensembl; ENST00000540367; ENSP00000439084; ENSG00000110090.
DR GeneID; 1374; -.
DR KEGG; hsa:1374; -.
DR UCSC; uc001oog.4; human.
DR CTD; 1374; -.
DR GeneCards; GC11M068524; -.
DR HGNC; HGNC:2328; CPT1A.
DR HPA; HPA008835; -.
DR MIM; 255120; phenotype.
DR MIM; 600528; gene.
DR neXtProt; NX_P50416; -.
DR Orphanet; 156; Carnitine palmitoyl transferase 1A deficiency.
DR PharmGKB; PA26847; -.
DR eggNOG; NOG70127; -.
DR HOGENOM; HOG000233542; -.
DR HOVERGEN; HBG003458; -.
DR InParanoid; P50416; -.
DR KO; K08765; -.
DR OMA; IASEKHQ; -.
DR OrthoDB; EOG7J17ZQ; -.
DR PhylomeDB; P50416; -.
DR BioCyc; MetaCyc:HS03286-MONOMER; -.
DR BRENDA; 2.3.1.21; 2681.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_24941; Circadian Clock.
DR SABIO-RK; P50416; -.
DR UniPathway; UPA00659; -.
DR ChiTaRS; CPT1A; human.
DR GenomeRNAi; 1374; -.
DR NextBio; 5569; -.
DR PRO; PR:P50416; -.
DR ArrayExpress; P50416; -.
DR Bgee; P50416; -.
DR CleanEx; HS_CPT1A; -.
DR Genevestigator; P50416; -.
DR GO; GO:0031307; C:integral to mitochondrial outer membrane; ISS:UniProtKB.
DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:Ensembl.
DR GO; GO:0004095; F:carnitine O-palmitoyltransferase activity; IDA:UniProtKB.
DR GO; GO:0009437; P:carnitine metabolic process; IDA:UniProtKB.
DR GO; GO:0006853; P:carnitine shuttle; TAS:Reactome.
DR GO; GO:0042755; P:eating behavior; IEA:Ensembl.
DR GO; GO:0006635; P:fatty acid beta-oxidation; TAS:ProtInc.
DR GO; GO:0006006; P:glucose metabolic process; IEA:Ensembl.
DR GO; GO:0001676; P:long-chain fatty acid metabolic process; IDA:UniProtKB.
DR GO; GO:0032000; P:positive regulation of fatty acid beta-oxidation; IEA:Ensembl.
DR GO; GO:0051260; P:protein homooligomerization; IEA:Ensembl.
DR GO; GO:0050796; P:regulation of insulin secretion; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0014070; P:response to organic cyclic compound; IEA:Ensembl.
DR GO; GO:0006641; P:triglyceride metabolic process; IEA:Ensembl.
DR InterPro; IPR000542; Carn_acyl_trans.
DR PANTHER; PTHR22589; PTHR22589; 1.
DR Pfam; PF00755; Carn_acyltransf; 1.
DR PROSITE; PS00439; ACYLTRANSF_C_1; 1.
DR PROSITE; PS00440; ACYLTRANSF_C_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Acyltransferase; Alternative splicing;
KW Complete proteome; Disease mutation; Fatty acid metabolism;
KW Lipid metabolism; Membrane; Mitochondrion;
KW Mitochondrion outer membrane; Nitration; Phosphoprotein; Polymorphism;
KW Reference proteome; Transferase; Transmembrane; Transmembrane helix;
KW Transport.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 773 Carnitine O-palmitoyltransferase 1, liver
FT isoform.
FT /FTId=PRO_0000210159.
FT TOPO_DOM 2 47 Cytoplasmic (Potential).
FT TRANSMEM 48 73 Helical; (Potential).
FT TOPO_DOM 74 102 Mitochondrial intermembrane (Potential).
FT TRANSMEM 103 122 Helical; (Potential).
FT TOPO_DOM 123 773 Cytoplasmic (Potential).
FT REGION 555 567 Coenzyme A binding (By similarity).
FT ACT_SITE 473 473 Proton acceptor (By similarity).
FT BINDING 589 589 Carnitine (By similarity).
FT BINDING 602 602 Carnitine (By similarity).
FT MOD_RES 2 2 N-acetylalanine (By similarity).
FT MOD_RES 282 282 Nitrated tyrosine (By similarity).
FT MOD_RES 588 588 Phosphothreonine (By similarity).
FT MOD_RES 589 589 Nitrated tyrosine (By similarity).
FT MOD_RES 604 604 Phosphothreonine (By similarity).
FT MOD_RES 741 741 Phosphoserine (By similarity).
FT MOD_RES 747 747 Phosphoserine (By similarity).
FT VAR_SEQ 746 773 DSHRFGRHLKEAMTDIITLFGLSSNSKK -> GIISQGPSS
FT DT (in isoform 2).
FT /FTId=VSP_012167.
FT VARIANT 123 123 R -> C (in CPT1AD).
FT /FTId=VAR_020546.
FT VARIANT 275 275 A -> T (in dbSNP:rs2229738).
FT /FTId=VAR_020547.
FT VARIANT 304 304 C -> W (in CPT1AD).
FT /FTId=VAR_020548.
FT VARIANT 314 314 T -> I (in CPT1AD).
FT /FTId=VAR_020549.
FT VARIANT 316 316 R -> G (in CPT1AD).
FT /FTId=VAR_046767.
FT VARIANT 343 343 F -> V (in CPT1AD).
FT /FTId=VAR_046768.
FT VARIANT 357 357 R -> W (in CPT1AD; decreased stability).
FT /FTId=VAR_020550.
FT VARIANT 360 360 E -> G (in CPT1AD; reduced protein
FT levels; dbSNP:rs28936372).
FT /FTId=VAR_020551.
FT VARIANT 395 395 Missing (in CPT1AD; loss of activity).
FT /FTId=VAR_020552.
FT VARIANT 414 414 A -> V (in CPT1AD; decreased activity;
FT dbSNP:rs28936373).
FT /FTId=VAR_020553.
FT VARIANT 454 454 D -> G (in CPT1AD).
FT /FTId=VAR_020554.
FT VARIANT 465 465 G -> W (in CPT1AD).
FT /FTId=VAR_046769.
FT VARIANT 479 479 P -> L (in CPT1AD; decreased activity).
FT /FTId=VAR_020555.
FT VARIANT 484 484 L -> P (in CPT1AD).
FT /FTId=VAR_020556.
FT VARIANT 498 498 Y -> C (in CPT1AD; decreased activity).
FT /FTId=VAR_020557.
FT VARIANT 709 709 G -> E (in CPT1AD; loss of activity;
FT dbSNP:rs28936374).
FT /FTId=VAR_020558.
FT VARIANT 710 710 G -> E (in CPT1AD; loss of activity).
FT /FTId=VAR_020559.
FT CONFLICT 479 479 P -> Q (in Ref. 1; AAC41748).
FT CONFLICT 568 568 A -> T (in Ref. 1; AAC41748).
FT HELIX 4 7
FT STRAND 9 15
FT STRAND 18 23
FT HELIX 25 39
SQ SEQUENCE 773 AA; 88368 MW; E5DC9141B6301947 CRC64;
MAEAHQAVAF QFTVTPDGID LRLSHEALRQ IYLSGLHSWK KKFIRFKNGI ITGVYPASPS
SWLIVVVGVM TTMYAKIDPS LGIIAKINRT LETANCMSSQ TKNVVSGVLF GTGLWVALIV
TMRYSLKVLL SYHGWMFTEH GKMSRATKIW MGMVKIFSGR KPMLYSFQTS LPRLPVPAVK
DTVNRYLQSV RPLMKEEDFK RMTALAQDFA VGLGPRLQWY LKLKSWWATN YVSDWWEEYI
YLRGRGPLMV NSNYYAMDLL YILPTHIQAA RAGNAIHAIL LYRRKLDREE IKPIRLLGST
IPLCSAQWER MFNTSRIPGE ETDTIQHMRD SKHIVVYHRG RYFKVWLYHD GRLLKPREME
QQMQRILDNT SEPQPGEARL AALTAGDRVP WARCRQAYFG RGKNKQSLDA VEKAAFFVTL
DETEEGYRSE DPDTSMDSYA KSLLHGRCYD RWFDKSFTFV VFKNGKMGLN AEHSWADAPI
VAHLWEYVMS IDSLQLGYAE DGHCKGDINP NIPYPTRLQW DIPGECQEVI ETSLNTANLL
ANDVDFHSFP FVAFGKGIIK KCRTSPDAFV QLALQLAHYK DMGKFCLTYE ASMTRLFREG
RTETVRSCTT ESCDFVRAMV DPAQTVEQRL KLFKLASEKH QHMYRLAMTG SGIDRHLFCL
YVVSKYLAVE SPFLKEVLSE PWRLSTSQTP QQQVELFDLE NNPEYVSSGG GFGPVADDGY
GVSYILVGEN LINFHISSKF SCPETDSHRF GRHLKEAMTD IITLFGLSSN SKK
//
ID CPT1A_HUMAN Reviewed; 773 AA.
AC P50416; Q8TCU0; Q9BWK0;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 07-DEC-2004, sequence version 2.
DT 22-JAN-2014, entry version 131.
DE RecName: Full=Carnitine O-palmitoyltransferase 1, liver isoform;
DE Short=CPT1-L;
DE EC=2.3.1.21;
DE AltName: Full=Carnitine O-palmitoyltransferase I, liver isoform;
DE Short=CPT I;
DE Short=CPTI-L;
DE AltName: Full=Carnitine palmitoyltransferase 1A;
GN Name=CPT1A; Synonyms=CPT1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=7892212; DOI=10.1073/pnas.92.6.1984;
RA Britton C.H., Schultz R.A., Zhang B., Esser V., Foster D.W.,
RA McGarry J.D.;
RT "Human liver mitochondrial carnitine palmitoyltransferase I:
RT characterization of its cDNA and chromosomal localization and partial
RT analysis of the gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:1984-1988(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS CPT1AD VAL-414 AND
RP CYS-498, AND VARIANT THR-275.
RX PubMed=12189492; DOI=10.1007/s00439-002-0752-0;
RA Gobin S., Bonnefont J.-P., Prip-Buus C., Mugnier C., Ferrec M.,
RA Demaugre F., Saudubray J.-M., Rostane H., Djouadi F., Wilcox W.,
RA Cederbaum S., Haas R., Nyhan W.L., Green A., Gray G., Girard J.,
RA Thuillier L.;
RT "Organization of the human liver carnitine palmitoyltransferase 1 gene
RT (CPT1A) and identification of novel mutations in hypoketotic
RT hypoglycaemia.";
RL Hum. Genet. 111:179-189(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Eye;
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 [5]
RP INDUCTION BY FATTY ACIDS.
RX PubMed=16271724; DOI=10.1016/j.jmb.2005.09.097;
RA Napal L., Marrero P.F., Haro D.;
RT "An intronic peroxisome proliferator-activated receptor-binding
RT sequence mediates fatty acid induction of the human carnitine
RT palmitoyltransferase 1A.";
RL J. Mol. Biol. 354:751-759(2005).
RN [6]
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 [7]
RP 3D-STRUCTURE MODELING.
RX PubMed=14711372; DOI=10.1042/BJ20031373;
RA Morillas M., Lopez-Vinas E., Valencia A., Serra D., Gomez-Puertas P.,
RA Hegardt F.G., Asins G.;
RT "Structural model of carnitine palmitoyltransferase I based on the
RT carnitine acetyltransferase crystal.";
RL Biochem. J. 379:777-784(2004).
RN [8]
RP STRUCTURE BY NMR OF 1-42, AND DOMAIN.
RX PubMed=21990363; DOI=10.1074/jbc.M111.306951;
RA Rao J.N., Warren G.Z., Estolt-Povedano S., Zammit V.A., Ulmer T.S.;
RT "An environment-dependent structural switch underlies the regulation
RT of carnitine palmitoyltransferase 1A.";
RL J. Biol. Chem. 286:42545-42554(2011).
RN [9]
RP VARIANT CPT1AD GLY-454.
RX PubMed=9691089; DOI=10.1172/JCI2927;
RA IJlst L., Mandel H., Oostheim W., Ruiter J.P.N., Gutman A.,
RA Wanders R.J.;
RT "Molecular basis of hepatic carnitine palmitoyltransferase I
RT deficiency.";
RL J. Clin. Invest. 102:527-531(1998).
RN [10]
RP VARIANTS CPT1AD CYS-123; TRP-304; TRP-357; ARG-395 DEL; LEU-479 AND
RP PRO-484, AND VARIANT THR-275.
RX PubMed=11441142;
RA Brown N.F., Mullur R.S., Subramanian I., Esser V., Bennett M.J.,
RA Saudubray J.-M., Feigenbaum A.S., Kobari J.A., Macleod P.M.,
RA McGarry J.D., Cohen J.C.;
RT "Molecular characterization of L-CPT I deficiency in six patients:
RT insights into function of the native enzyme.";
RL J. Lipid Res. 42:1134-1142(2001).
RN [11]
RP VARIANT CPT1AD GLU-710, CHARACTERIZATION OF VARIANT CPT1AD GLU-710,
RP CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=11350182; DOI=10.1006/mgme.2001.3176;
RA Prip-Buus C., Thuillier L., Abadi N., Prasad C., Dilling L.,
RA Klasing J., Demaugre F., Greenberg C.R., Haworth J.C., Droin V.,
RA Kadhom N., Gobin S., Kamoun P., Girard J., Bonnefont J.-P.;
RT "Molecular and enzymatic characterization of a unique carnitine
RT palmitoyltransferase 1A mutation in the Hutterite community.";
RL Mol. Genet. Metab. 73:46-54(2001).
RN [12]
RP CHARACTERIZATION OF VARIANT CPT1AD GLY-360.
RX PubMed=12111367; DOI=10.1007/s100380200047;
RA Ogawa E., Kanazawa M., Yamamoto S., Ohtsuka S., Ogawa A., Ohtake A.,
RA Takayanagi M., Kohno Y.;
RT "Expression analysis of two mutations in carnitine
RT palmitoyltransferase IA deficiency.";
RL J. Hum. Genet. 47:342-347(2002).
RN [13]
RP VARIANT CPT1AD GLU-709, CHARACTERIZATION OF VARIANTS CPT1AD THR-275;
RP VAL-414; CYS-498; GLU-709 AND GLU-710, SUBCELLULAR LOCATION, CATALYTIC
RP ACTIVITY, AND ENZYME REGULATION.
RX PubMed=14517221; DOI=10.1074/jbc.M310130200;
RA Gobin S., Thuillier L., Jogl G., Faye A., Tong L., Chi M.,
RA Bonnefont J.-P., Girard J., Prip-Buus C.;
RT "Functional and structural basis of carnitine palmitoyltransferase 1A
RT deficiency.";
RL J. Biol. Chem. 278:50428-50434(2003).
RN [14]
RP VARIANT CPT1AD ILE-314.
RX PubMed=15669684; DOI=10.1023/B:BOLI.0000042979.42120.55;
RA Stoler J.M., Sabry M.A., Hanley C., Hoppel C.L., Shih V.E.;
RT "Successful long-term treatment of hepatic carnitine
RT palmitoyltransferase I deficiency and a novel mutation.";
RL J. Inherit. Metab. Dis. 27:679-684(2004).
RN [15]
RP VARIANTS CPT1AD GLY-316; VAL-343 AND TRP-465.
RX PubMed=15110323; DOI=10.1016/j.ymgme.2004.02.004;
RA Bennett M.J., Boriack R.L., Narayan S., Rutledge S.L., Raff M.L.;
RT "Novel mutations in CPT 1A define molecular heterogeneity of hepatic
RT carnitine palmitoyltransferase I deficiency.";
RL Mol. Genet. Metab. 82:59-63(2004).
CC -!- FUNCTION: Catalyzes the transfer of the acyl group of long-chain
CC fatty acid-CoA conjugates onto carnitine, an essential step for
CC the mitochondrial uptake of long-chain fatty acids and their
CC subsequent beta-oxidation in the mitochondrion. Plays an important
CC role in triglyceride metabolism.
CC -!- CATALYTIC ACTIVITY: Palmitoyl-CoA + L-carnitine = CoA + L-
CC palmitoylcarnitine.
CC -!- ENZYME REGULATION: Inhibited by malonyl-CoA.
CC -!- PATHWAY: Lipid metabolism; fatty acid beta-oxidation.
CC -!- SUBUNIT: Homohexamer and homotrimer. Identified in a complex that
CC contains at least CPT1A, ACSL1 and VDAC1. Also identified in
CC complexes with ACSL1 and VDAC2 and VDAC3 (By similarity).
CC -!- SUBCELLULAR LOCATION: Mitochondrion outer membrane; Multi-pass
CC membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P50416-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P50416-2; Sequence=VSP_012167;
CC -!- TISSUE SPECIFICITY: Strong expression in kidney and heart, and
CC lower in liver and skeletal muscle.
CC -!- INDUCTION: Up-regulated by fatty acids.
CC -!- DOMAIN: A conformation change in the N-terminal region spanning
CC the first 42 residues plays an important role in the regulation of
CC enzyme activity by malonyl-CoA.
CC -!- DISEASE: Carnitine palmitoyltransferase 1A deficiency (CPT1AD)
CC [MIM:255120]: Rare autosomal recessive metabolic disorder of long-
CC chain fatty acid oxidation characterized by severe episodes of
CC hypoketotic hypoglycemia usually occurring after fasting or
CC illness. Onset is in infancy or early childhood. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the carnitine/choline acetyltransferase
CC family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CPT1A";
CC -----------------------------------------------------------------------
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DR EMBL; L39211; AAC41748.1; -; mRNA.
DR EMBL; AJ420747; CAD12625.1; -; Genomic_DNA.
DR EMBL; AJ420748; CAD59673.1; -; Genomic_DNA.
DR EMBL; BT009791; AAP88793.1; -; mRNA.
DR EMBL; BC000185; AAH00185.1; -; mRNA.
DR PIR; I59351; I59351.
DR RefSeq; NP_001027017.1; NM_001031847.2.
DR RefSeq; NP_001867.2; NM_001876.3.
DR RefSeq; XP_005273821.1; XM_005273764.1.
DR UniGene; Hs.503043; -.
DR PDB; 2LE3; NMR; -; A=1-42.
DR PDBsum; 2LE3; -.
DR ProteinModelPortal; P50416; -.
DR SMR; P50416; 1-42, 180-765.
DR IntAct; P50416; 12.
DR MINT; MINT-3018357; -.
DR STRING; 9606.ENSP00000265641; -.
DR ChEMBL; CHEMBL1293194; -.
DR DrugBank; DB00583; L-Carnitine.
DR DrugBank; DB01074; Perhexiline.
DR PhosphoSite; P50416; -.
DR DMDM; 56405343; -.
DR PaxDb; P50416; -.
DR PeptideAtlas; P50416; -.
DR PRIDE; P50416; -.
DR DNASU; 1374; -.
DR Ensembl; ENST00000265641; ENSP00000265641; ENSG00000110090.
DR Ensembl; ENST00000376618; ENSP00000365803; ENSG00000110090.
DR Ensembl; ENST00000539743; ENSP00000446108; ENSG00000110090.
DR Ensembl; ENST00000540367; ENSP00000439084; ENSG00000110090.
DR GeneID; 1374; -.
DR KEGG; hsa:1374; -.
DR UCSC; uc001oog.4; human.
DR CTD; 1374; -.
DR GeneCards; GC11M068524; -.
DR HGNC; HGNC:2328; CPT1A.
DR HPA; HPA008835; -.
DR MIM; 255120; phenotype.
DR MIM; 600528; gene.
DR neXtProt; NX_P50416; -.
DR Orphanet; 156; Carnitine palmitoyl transferase 1A deficiency.
DR PharmGKB; PA26847; -.
DR eggNOG; NOG70127; -.
DR HOGENOM; HOG000233542; -.
DR HOVERGEN; HBG003458; -.
DR InParanoid; P50416; -.
DR KO; K08765; -.
DR OMA; IASEKHQ; -.
DR OrthoDB; EOG7J17ZQ; -.
DR PhylomeDB; P50416; -.
DR BioCyc; MetaCyc:HS03286-MONOMER; -.
DR BRENDA; 2.3.1.21; 2681.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_24941; Circadian Clock.
DR SABIO-RK; P50416; -.
DR UniPathway; UPA00659; -.
DR ChiTaRS; CPT1A; human.
DR GenomeRNAi; 1374; -.
DR NextBio; 5569; -.
DR PRO; PR:P50416; -.
DR ArrayExpress; P50416; -.
DR Bgee; P50416; -.
DR CleanEx; HS_CPT1A; -.
DR Genevestigator; P50416; -.
DR GO; GO:0031307; C:integral to mitochondrial outer membrane; ISS:UniProtKB.
DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:Ensembl.
DR GO; GO:0004095; F:carnitine O-palmitoyltransferase activity; IDA:UniProtKB.
DR GO; GO:0009437; P:carnitine metabolic process; IDA:UniProtKB.
DR GO; GO:0006853; P:carnitine shuttle; TAS:Reactome.
DR GO; GO:0042755; P:eating behavior; IEA:Ensembl.
DR GO; GO:0006635; P:fatty acid beta-oxidation; TAS:ProtInc.
DR GO; GO:0006006; P:glucose metabolic process; IEA:Ensembl.
DR GO; GO:0001676; P:long-chain fatty acid metabolic process; IDA:UniProtKB.
DR GO; GO:0032000; P:positive regulation of fatty acid beta-oxidation; IEA:Ensembl.
DR GO; GO:0051260; P:protein homooligomerization; IEA:Ensembl.
DR GO; GO:0050796; P:regulation of insulin secretion; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0014070; P:response to organic cyclic compound; IEA:Ensembl.
DR GO; GO:0006641; P:triglyceride metabolic process; IEA:Ensembl.
DR InterPro; IPR000542; Carn_acyl_trans.
DR PANTHER; PTHR22589; PTHR22589; 1.
DR Pfam; PF00755; Carn_acyltransf; 1.
DR PROSITE; PS00439; ACYLTRANSF_C_1; 1.
DR PROSITE; PS00440; ACYLTRANSF_C_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Acyltransferase; Alternative splicing;
KW Complete proteome; Disease mutation; Fatty acid metabolism;
KW Lipid metabolism; Membrane; Mitochondrion;
KW Mitochondrion outer membrane; Nitration; Phosphoprotein; Polymorphism;
KW Reference proteome; Transferase; Transmembrane; Transmembrane helix;
KW Transport.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 773 Carnitine O-palmitoyltransferase 1, liver
FT isoform.
FT /FTId=PRO_0000210159.
FT TOPO_DOM 2 47 Cytoplasmic (Potential).
FT TRANSMEM 48 73 Helical; (Potential).
FT TOPO_DOM 74 102 Mitochondrial intermembrane (Potential).
FT TRANSMEM 103 122 Helical; (Potential).
FT TOPO_DOM 123 773 Cytoplasmic (Potential).
FT REGION 555 567 Coenzyme A binding (By similarity).
FT ACT_SITE 473 473 Proton acceptor (By similarity).
FT BINDING 589 589 Carnitine (By similarity).
FT BINDING 602 602 Carnitine (By similarity).
FT MOD_RES 2 2 N-acetylalanine (By similarity).
FT MOD_RES 282 282 Nitrated tyrosine (By similarity).
FT MOD_RES 588 588 Phosphothreonine (By similarity).
FT MOD_RES 589 589 Nitrated tyrosine (By similarity).
FT MOD_RES 604 604 Phosphothreonine (By similarity).
FT MOD_RES 741 741 Phosphoserine (By similarity).
FT MOD_RES 747 747 Phosphoserine (By similarity).
FT VAR_SEQ 746 773 DSHRFGRHLKEAMTDIITLFGLSSNSKK -> GIISQGPSS
FT DT (in isoform 2).
FT /FTId=VSP_012167.
FT VARIANT 123 123 R -> C (in CPT1AD).
FT /FTId=VAR_020546.
FT VARIANT 275 275 A -> T (in dbSNP:rs2229738).
FT /FTId=VAR_020547.
FT VARIANT 304 304 C -> W (in CPT1AD).
FT /FTId=VAR_020548.
FT VARIANT 314 314 T -> I (in CPT1AD).
FT /FTId=VAR_020549.
FT VARIANT 316 316 R -> G (in CPT1AD).
FT /FTId=VAR_046767.
FT VARIANT 343 343 F -> V (in CPT1AD).
FT /FTId=VAR_046768.
FT VARIANT 357 357 R -> W (in CPT1AD; decreased stability).
FT /FTId=VAR_020550.
FT VARIANT 360 360 E -> G (in CPT1AD; reduced protein
FT levels; dbSNP:rs28936372).
FT /FTId=VAR_020551.
FT VARIANT 395 395 Missing (in CPT1AD; loss of activity).
FT /FTId=VAR_020552.
FT VARIANT 414 414 A -> V (in CPT1AD; decreased activity;
FT dbSNP:rs28936373).
FT /FTId=VAR_020553.
FT VARIANT 454 454 D -> G (in CPT1AD).
FT /FTId=VAR_020554.
FT VARIANT 465 465 G -> W (in CPT1AD).
FT /FTId=VAR_046769.
FT VARIANT 479 479 P -> L (in CPT1AD; decreased activity).
FT /FTId=VAR_020555.
FT VARIANT 484 484 L -> P (in CPT1AD).
FT /FTId=VAR_020556.
FT VARIANT 498 498 Y -> C (in CPT1AD; decreased activity).
FT /FTId=VAR_020557.
FT VARIANT 709 709 G -> E (in CPT1AD; loss of activity;
FT dbSNP:rs28936374).
FT /FTId=VAR_020558.
FT VARIANT 710 710 G -> E (in CPT1AD; loss of activity).
FT /FTId=VAR_020559.
FT CONFLICT 479 479 P -> Q (in Ref. 1; AAC41748).
FT CONFLICT 568 568 A -> T (in Ref. 1; AAC41748).
FT HELIX 4 7
FT STRAND 9 15
FT STRAND 18 23
FT HELIX 25 39
SQ SEQUENCE 773 AA; 88368 MW; E5DC9141B6301947 CRC64;
MAEAHQAVAF QFTVTPDGID LRLSHEALRQ IYLSGLHSWK KKFIRFKNGI ITGVYPASPS
SWLIVVVGVM TTMYAKIDPS LGIIAKINRT LETANCMSSQ TKNVVSGVLF GTGLWVALIV
TMRYSLKVLL SYHGWMFTEH GKMSRATKIW MGMVKIFSGR KPMLYSFQTS LPRLPVPAVK
DTVNRYLQSV RPLMKEEDFK RMTALAQDFA VGLGPRLQWY LKLKSWWATN YVSDWWEEYI
YLRGRGPLMV NSNYYAMDLL YILPTHIQAA RAGNAIHAIL LYRRKLDREE IKPIRLLGST
IPLCSAQWER MFNTSRIPGE ETDTIQHMRD SKHIVVYHRG RYFKVWLYHD GRLLKPREME
QQMQRILDNT SEPQPGEARL AALTAGDRVP WARCRQAYFG RGKNKQSLDA VEKAAFFVTL
DETEEGYRSE DPDTSMDSYA KSLLHGRCYD RWFDKSFTFV VFKNGKMGLN AEHSWADAPI
VAHLWEYVMS IDSLQLGYAE DGHCKGDINP NIPYPTRLQW DIPGECQEVI ETSLNTANLL
ANDVDFHSFP FVAFGKGIIK KCRTSPDAFV QLALQLAHYK DMGKFCLTYE ASMTRLFREG
RTETVRSCTT ESCDFVRAMV DPAQTVEQRL KLFKLASEKH QHMYRLAMTG SGIDRHLFCL
YVVSKYLAVE SPFLKEVLSE PWRLSTSQTP QQQVELFDLE NNPEYVSSGG GFGPVADDGY
GVSYILVGEN LINFHISSKF SCPETDSHRF GRHLKEAMTD IITLFGLSSN SKK
//
MIM
255120
*RECORD*
*FIELD* NO
255120
*FIELD* TI
#255120 CARNITINE PALMITOYLTRANSFERASE I DEFICIENCY
;;CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY;;
read moreCPT I DEFICIENCY;;
CPT DEFICIENCY, HEPATIC, TYPE I
*FIELD* TX
A number sign (#) is used with this entry because carnitine
palmitoyltransferase deficiency I is caused by mutation in the gene
encoding carnitine palmitoyltransferase IA (CPT1A; 600528).
DESCRIPTION
CPT I deficiency is an autosomal recessive metabolic disorder of
long-chain fatty acid oxidation characterized by severe episodes of
hypoketotic hypoglycemia usually occurring after fasting or illness.
Onset is in infancy or early childhood (Bougneres et al., 1981)
CLINICAL FEATURES
Bougneres et al. (1981) reported 2 sisters who developed severe
hypoketotic hypoglycemia at age 8 months, resulting in death in 1 of
them. Other features included hepatomegaly, nonketotic hypoglycemia, and
coma. Liver CPT activity was absent in the patient who was tested.
Demaugre et al. (1988) reported 2 patients with carnitine
palmitoyltransferase deficiency and hepatic symptoms. Biochemical
analysis of fibroblasts showed a decrease in CPT1 activity which
resulted in impaired long-chain fatty acid oxidation. Bonnefont et al.
(1989) reported a patient who presented at age 14 months with seizures
and hypoketotic hypoglycemia. Administration of medium-chain
triglycerides relieved the hypoglycemia and generated a brisk
ketogenesis. Biochemical analysis showed decreased CPT I activity
(approximately 10% of controls) in fibroblasts; oxidation of palmitate
was about 5% of controls.
Falik-Borenstein et al. (1989) reported a 26-month-old Mexican female
born to parents from a sparsely populated genetic isolate. Beginning at
1 year of age, she had suffered 3 severe Reye syndrome-like episodes
precipitated by mild viral illnesses. These episodes were characterized
by coma, aketotic hypoglycemia, mild hyperammonemia, elevated serum
transaminases, elevated plasma free fatty acids, and hepatomegaly with
fatty infiltration. Recovery with glucose treatment and other
nonspecific measures was accompanied by severe hypertriglyceridemia.
Renal tubular acidosis, both proximal and distal, was noted. Within 20
minutes of administration of medium-chain triglycerides, plasma glucose
rose to 75 mg/% without hypertriglyceridemia. After 2 months of
treatment with medium-chain triglycerides, renal tubular acidosis
completely resolved. Falik-Borenstein et al. (1992) reported a girl with
CPT I deficiency in whom clinical manifestations began at 14 months of
age and were followed by renal tubular acidosis. Therapy with
medium-chain triglycerides resulted in the disappearance of the renal
defects, catch-up growth within 2 months, and the ability to tolerate
viral infections without developing hypoglycemia or other problems.
In a boy with CPT I deficiency, Stanley et al. (1992) found that plasma
carnitine levels were twice the normal levels. Urinary dicarboxylic
acids were not elevated.
Haworth et al. (1991, 1992) described this disorder in a brother and
sister and a female second cousin in an extended Hutterite family. The
patients were first seen between 8 and 18 months of age with recurrent
episodes of hypoketotic hypoglycemia accompanied by a decreased level of
consciousness and hepatomegaly. One patient had 2 Reye syndrome-like
episodes. The patients were successfully treated with medium-chain
triglycerides and avoidance of fasting.
IJlst et al. (1998) reported a child, born of consanguineous parents,
who presented at age 15 months with diarrhea and feeding difficulties.
She was hypotonic and lethargic, and physical examination showed
hepatomegaly, hypoketotic hypoglycemia, and elevated liver function
tests. Biochemical studies showed decreased beta-oxidation of long-chain
fatty acids and decreased CPT Ia activity and protein levels.
Innes et al. (2000) reported a 19-year-old Inuit woman who presented in
pregnancy with acute fatty liver of pregnancy and hyperemesis
gravidarum. Laboratory analysis showed elevated liver enzymes, direct
hyperbilirubinemia, and ultrasound findings consistent with fatty liver.
After induced labor and delivery, the mother's illness resolved. A
second pregnancy was complicated by hyperemesis without documented liver
disease. Biochemical analysis showed decreased fibroblast palmitate
oxidation in both offspring (34% and 14% of control, respectively) and
in the mother (50% of control). Both offspring had complete absence of
CPT I activity. Innes et al. (2000) postulated that the defect in
long-chain fatty acid oxidation in the fetus produced abnormal
metabolites that entered the maternal circulation, leading to liver
toxicity, hepatocellular necrosis, and acute fatty liver. The findings
increased the spectrum of disorders of the fetus causing maternal liver
disease in pregnancy.
Olpin et al. (2001) reported 4 cases of CPT I deficiency in 3 families
showing variable renal tubular acidosis, transient hyperlipidemia, and,
paradoxically, myopathy with elevated creatine kinase or cardiac
involvement in the neonatal period.
DIAGNOSIS
Sim et al. (2001) described a neonate at risk for hepatic CPT I
deficiency who was investigated from birth. The free carnitine and
acylcarnitine profile in dried whole blood filter paper samples
collected at ages 1 and 4 days showed a markedly elevated concentration
of free carnitine (141 and 142 micromoles per liter), normal
concentrations of acetyl- and propionylcarnitine, with the near absence
of all other species. The newborn population distribution of free
carnitine (n = 143,981) showed that only 3 samples had free carnitine of
greater than 140 micromoles per liter, 2 from CPT I-deficient neonates
and 1 from a baby with sepsis. Sim et al. (2001) concluded that whereas
there are other conditions that can cause elevated concentrations of
free carnitine, an isolated elevation of free carnitine in an apparently
healthy term neonate warrants further investigation to exclude CPT I
deficiency.
Roomets et al. (2006) reported brain proton MR spectroscopy (MRS)
findings in an infant with CPT I deficiency. At age 11 months, she
presented with coma after fasting and showed hepatomegaly and metabolic
acidosis. Brain MRI was normal, but MRS showed a high N-acetyl
aspartate/choline ratio, excess of glutamine/glutamate, and large lipid
peaks in the thalamus, white matter, and cortex. Biochemical and genetic
analysis confirmed the diagnosis.
MOLECULAR GENETICS
In a patient with CPT I deficiency, IJlst et al. (1998) identified a
homozygous mutation in the CPT1A gene (600528.0001).
Gobin et al. (2002) characterized 6 novel mutations in 4 CPT1A-deficient
patients (600528.0003-600528.0008).
*FIELD* RF
1. Bonnefont, J. P.; Haas, R.; Wolff, J.; Thuy, L. P.; Buchta, R.;
Carroll, J. E.; Saudubray, J.-M.; Demaugre, F.; Nyhan, W. L.: Deficiency
of carnitine palmitoyltransferase I. J. Child Neurol. 4: 197-202,
1989.
2. Bougneres, P. F.; Saudubray, J. M.; Marsac, C.; Bernard, O.; Odievre,
M.; Girard, J.: Fasting hypoglycemia resulting from hepatic carnitine
palmitoyl transferase deficiency. J. Pediat. 98: 742-746, 1981.
3. Demaugre, F.; Bonnefont, J.-P.; Mitchell, G.; Nguyen-Hoang, N.;
Pelet, A.; Rimoldi, M.; Di Donato, S.; Saudubray, J.-M.: Hepatic
and muscular presentations of carnitine palmitoyl transferase deficiency:
two distinct entities. Pediat. Res. 24: 308-311, 1988.
4. Falik-Borenstein, T. C.; Jordan, S. C.; Saudubray, J. M.; Edmond,
J.; Cederbaum, S. D.: Carnitine palmitoyl transferase I deficiency
(CPT I). (Abstract) Am. J. Hum. Genet. 45 (suppl.): A5, 1989.
5. Falik-Borenstein, Z. C.; Jordan, S. C.; Saudubray, J.-M.; Brivet,
M.; Demaugre, F.; Edmond, J.; Cederbaum, S. D.: Renal tubular acidosis
in carnitine palmitoyltransferase type I deficiency. New Eng. J.
Med. 327: 24-27, 1992.
6. Gobin, S.; Bonnefont, J.-P.; Prip-Buus, C.; Mugnier, C.; Ferrec,
M.; Demaugre, F.; Saudubray, J.-M.; Rostane, H.; Djouadi, F.; Wilcox,
W.; Cederbaum, S.; Haas, R.; Nyhan, W. L.; Green, A.; Gray, G.; Girard,
J.; Thuillier, L.: Organization of the human liver carnitine palmitoyltransferase
1 gene (CPT1A) and identification of novel mutations in hypoketotic
hypoglycaemia. Hum. Genet. 111: 179-189, 2002.
7. Haworth, J. C.; Coates, P. M.; Demaugre, F.; Dilling, L. A.; Seargeant,
L. E.; Moroz, S. P.; Booth, F. A.; Seshia, S. S.: Hepatic carnitine
palmityltransferase (CPT I) deficiency: 3 patients in a Hutterite
family. (Abstract) Pediat. Res. 29: 130A, 1991.
8. Haworth, J. C.; Demaugre, F.; Booth, F. A.; Dilling, L. A.; Moroz,
S. P.; Seshia, S. S.; Seargeant, L. E.; Coates, P. M.: Atypical features
of the hepatic form of carnitine palmitoyltransferase deficiency in
a Hutterite family. J. Pediat. 121: 553-557, 1992.
9. IJlst, L.; Mandel, H.; Oostheim, W.; Ruiter, J. P. N.; Gutman,
A.; Wanders, R. J. A.: Molecular basis of hepatic carnitine palmitoyltransferase
I deficiency. J. Clin. Invest. 102: 527-531, 1998.
10. Innes, A. M.; Seargeant, L. E.; Balachandra, K.; Roe, C. R.; Wanders,
R. J. A.; Ruiter, J. P. N.; Casiro, O.; Grewar, D. A.; Greenberg,
C. R.: Hepatic carnitine palmitoyltransferase I deficiency presenting
as maternal illness in pregnancy. Pediat. Res. 47: 43-45, 2000.
11. Olpin, S. E.; Allen, J.; Bonham, J. R.; Clark, S.; Clayton, P.
T.; Calvin, J.; Downing, M.; Ives, K.; Jones, S.; Manning, N. J.;
Pollitt, R. J.; Standing, S. J.; Tanner, M. S.: Features of carnitine
palmitoyltransferase type I deficiency. J. Inherit. Metab. Dis. 24:
35-42, 2001.
12. Roomets, E.; Lundbom, N.; Pihko, H.; Heikkinen, S.; Tyni, T.:
Lipids detected by brain MRS during coma caused by carnitine palmitoyltransferase
1 deficiency. Neurology 67: 1516-1517, 2006.
13. Sim, K. G.; Wiley, V.; Carpenter, K.; Wilcken, B.: Carnitine
palmitoyltransferase I deficiency in neonate identified by dried blood
spot free carnitine and acylcarnitine profile. J. Inherit. Metab.
Dis. 24: 51-59, 2001.
14. Stanley, C. A.; Sunaryo, F.; Hale, D. E.; Bonnefont, J.-P.; Demaugre,
F.; Saudubray, J.-M.: Elevated plasma carnitine in the hepatic form
of carnitine palmitoyltransferase-1 deficiency. J. Inherit. Metab.
Dis. 15: 785-789, 1992.
*FIELD* CS
INHERITANCE:
Autosomal recessive
CARDIOVASCULAR:
[Heart];
Cardiomegaly;
Cardiac rhythm disturbances
ABDOMEN:
[Liver];
Hepatomegaly;
[Gastrointestinal];
Poor feeding;
Diarrhea
MUSCLE, SOFT TISSUE:
Muscle weakness is not a feature
NEUROLOGIC:
[Central nervous system];
Hypotonia;
Lethargy;
Seizures;
Coma;
Encephalopathy, recurrent
METABOLIC FEATURES:
Hypoketotic hypoglycemia;
Renal tubular acidosis
PRENATAL MANIFESTATIONS:
[Maternal];
Acute fatty liver in pregnancy (fetus with carnitine palmitoyltransferase
I (CPT1) deficiency);
HELLP syndrome
LABORATORY ABNORMALITIES:
Mild to moderate hyperammonemia;
Transient hyperlipidemia;
Elevated creatine kinase;
Elevated transaminases;
No dicarboxylic aciduria;
No ketonuria;
Normal to elevated total plasma carnitine;
Elevated free carnitine;
Carnitine palmitoyltransferase I deficiency (fibroblast, liver, leukocytes);
Decreased CPT1 activity;
Decreased long-chain fatty acid oxidation
MISCELLANEOUS:
Onset <30 months;
Precipitated by infection, fasting, or intercurrent illness
MOLECULAR BASIS:
Caused by mutation in the carnitine palmitoyltransferase IA gene (CPT1A,
600528.0001)
*FIELD* CN
Kelly A. Przylepa - revised: 10/5/2004
Cassandra L. Kniffin - revised: 8/19/2004
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 12/20/2007
joanna: 8/1/2005
joanna: 10/6/2004
joanna: 10/5/2004
ckniffin: 8/19/2004
*FIELD* CN
Cassandra L. Kniffin - updated: 9/14/2007
Cassandra L. Kniffin - reorganized: 8/23/2004
Cassandra L. Kniffin - updated: 8/19/2004
Victor A. McKusick - updated: 10/10/2002
Victor A. McKusick - updated: 8/7/2002
Ada Hamosh - updated: 4/17/2001
Victor A. McKusick - updated: 10/1/1998
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
wwang: 09/21/2007
ckniffin: 9/14/2007
terry: 3/23/2006
carol: 8/1/2005
carol: 8/23/2004
ckniffin: 8/19/2004
ckniffin: 8/17/2004
tkritzer: 10/10/2002
carol: 8/7/2002
tkritzer: 8/7/2002
alopez: 4/17/2001
carol: 10/6/1998
terry: 10/1/1998
mimman: 2/8/1996
mark: 10/2/1995
carol: 7/13/1995
terry: 6/3/1995
davew: 6/6/1994
pfoster: 5/12/1994
carol: 9/23/1993
*RECORD*
*FIELD* NO
255120
*FIELD* TI
#255120 CARNITINE PALMITOYLTRANSFERASE I DEFICIENCY
;;CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY;;
read moreCPT I DEFICIENCY;;
CPT DEFICIENCY, HEPATIC, TYPE I
*FIELD* TX
A number sign (#) is used with this entry because carnitine
palmitoyltransferase deficiency I is caused by mutation in the gene
encoding carnitine palmitoyltransferase IA (CPT1A; 600528).
DESCRIPTION
CPT I deficiency is an autosomal recessive metabolic disorder of
long-chain fatty acid oxidation characterized by severe episodes of
hypoketotic hypoglycemia usually occurring after fasting or illness.
Onset is in infancy or early childhood (Bougneres et al., 1981)
CLINICAL FEATURES
Bougneres et al. (1981) reported 2 sisters who developed severe
hypoketotic hypoglycemia at age 8 months, resulting in death in 1 of
them. Other features included hepatomegaly, nonketotic hypoglycemia, and
coma. Liver CPT activity was absent in the patient who was tested.
Demaugre et al. (1988) reported 2 patients with carnitine
palmitoyltransferase deficiency and hepatic symptoms. Biochemical
analysis of fibroblasts showed a decrease in CPT1 activity which
resulted in impaired long-chain fatty acid oxidation. Bonnefont et al.
(1989) reported a patient who presented at age 14 months with seizures
and hypoketotic hypoglycemia. Administration of medium-chain
triglycerides relieved the hypoglycemia and generated a brisk
ketogenesis. Biochemical analysis showed decreased CPT I activity
(approximately 10% of controls) in fibroblasts; oxidation of palmitate
was about 5% of controls.
Falik-Borenstein et al. (1989) reported a 26-month-old Mexican female
born to parents from a sparsely populated genetic isolate. Beginning at
1 year of age, she had suffered 3 severe Reye syndrome-like episodes
precipitated by mild viral illnesses. These episodes were characterized
by coma, aketotic hypoglycemia, mild hyperammonemia, elevated serum
transaminases, elevated plasma free fatty acids, and hepatomegaly with
fatty infiltration. Recovery with glucose treatment and other
nonspecific measures was accompanied by severe hypertriglyceridemia.
Renal tubular acidosis, both proximal and distal, was noted. Within 20
minutes of administration of medium-chain triglycerides, plasma glucose
rose to 75 mg/% without hypertriglyceridemia. After 2 months of
treatment with medium-chain triglycerides, renal tubular acidosis
completely resolved. Falik-Borenstein et al. (1992) reported a girl with
CPT I deficiency in whom clinical manifestations began at 14 months of
age and were followed by renal tubular acidosis. Therapy with
medium-chain triglycerides resulted in the disappearance of the renal
defects, catch-up growth within 2 months, and the ability to tolerate
viral infections without developing hypoglycemia or other problems.
In a boy with CPT I deficiency, Stanley et al. (1992) found that plasma
carnitine levels were twice the normal levels. Urinary dicarboxylic
acids were not elevated.
Haworth et al. (1991, 1992) described this disorder in a brother and
sister and a female second cousin in an extended Hutterite family. The
patients were first seen between 8 and 18 months of age with recurrent
episodes of hypoketotic hypoglycemia accompanied by a decreased level of
consciousness and hepatomegaly. One patient had 2 Reye syndrome-like
episodes. The patients were successfully treated with medium-chain
triglycerides and avoidance of fasting.
IJlst et al. (1998) reported a child, born of consanguineous parents,
who presented at age 15 months with diarrhea and feeding difficulties.
She was hypotonic and lethargic, and physical examination showed
hepatomegaly, hypoketotic hypoglycemia, and elevated liver function
tests. Biochemical studies showed decreased beta-oxidation of long-chain
fatty acids and decreased CPT Ia activity and protein levels.
Innes et al. (2000) reported a 19-year-old Inuit woman who presented in
pregnancy with acute fatty liver of pregnancy and hyperemesis
gravidarum. Laboratory analysis showed elevated liver enzymes, direct
hyperbilirubinemia, and ultrasound findings consistent with fatty liver.
After induced labor and delivery, the mother's illness resolved. A
second pregnancy was complicated by hyperemesis without documented liver
disease. Biochemical analysis showed decreased fibroblast palmitate
oxidation in both offspring (34% and 14% of control, respectively) and
in the mother (50% of control). Both offspring had complete absence of
CPT I activity. Innes et al. (2000) postulated that the defect in
long-chain fatty acid oxidation in the fetus produced abnormal
metabolites that entered the maternal circulation, leading to liver
toxicity, hepatocellular necrosis, and acute fatty liver. The findings
increased the spectrum of disorders of the fetus causing maternal liver
disease in pregnancy.
Olpin et al. (2001) reported 4 cases of CPT I deficiency in 3 families
showing variable renal tubular acidosis, transient hyperlipidemia, and,
paradoxically, myopathy with elevated creatine kinase or cardiac
involvement in the neonatal period.
DIAGNOSIS
Sim et al. (2001) described a neonate at risk for hepatic CPT I
deficiency who was investigated from birth. The free carnitine and
acylcarnitine profile in dried whole blood filter paper samples
collected at ages 1 and 4 days showed a markedly elevated concentration
of free carnitine (141 and 142 micromoles per liter), normal
concentrations of acetyl- and propionylcarnitine, with the near absence
of all other species. The newborn population distribution of free
carnitine (n = 143,981) showed that only 3 samples had free carnitine of
greater than 140 micromoles per liter, 2 from CPT I-deficient neonates
and 1 from a baby with sepsis. Sim et al. (2001) concluded that whereas
there are other conditions that can cause elevated concentrations of
free carnitine, an isolated elevation of free carnitine in an apparently
healthy term neonate warrants further investigation to exclude CPT I
deficiency.
Roomets et al. (2006) reported brain proton MR spectroscopy (MRS)
findings in an infant with CPT I deficiency. At age 11 months, she
presented with coma after fasting and showed hepatomegaly and metabolic
acidosis. Brain MRI was normal, but MRS showed a high N-acetyl
aspartate/choline ratio, excess of glutamine/glutamate, and large lipid
peaks in the thalamus, white matter, and cortex. Biochemical and genetic
analysis confirmed the diagnosis.
MOLECULAR GENETICS
In a patient with CPT I deficiency, IJlst et al. (1998) identified a
homozygous mutation in the CPT1A gene (600528.0001).
Gobin et al. (2002) characterized 6 novel mutations in 4 CPT1A-deficient
patients (600528.0003-600528.0008).
*FIELD* RF
1. Bonnefont, J. P.; Haas, R.; Wolff, J.; Thuy, L. P.; Buchta, R.;
Carroll, J. E.; Saudubray, J.-M.; Demaugre, F.; Nyhan, W. L.: Deficiency
of carnitine palmitoyltransferase I. J. Child Neurol. 4: 197-202,
1989.
2. Bougneres, P. F.; Saudubray, J. M.; Marsac, C.; Bernard, O.; Odievre,
M.; Girard, J.: Fasting hypoglycemia resulting from hepatic carnitine
palmitoyl transferase deficiency. J. Pediat. 98: 742-746, 1981.
3. Demaugre, F.; Bonnefont, J.-P.; Mitchell, G.; Nguyen-Hoang, N.;
Pelet, A.; Rimoldi, M.; Di Donato, S.; Saudubray, J.-M.: Hepatic
and muscular presentations of carnitine palmitoyl transferase deficiency:
two distinct entities. Pediat. Res. 24: 308-311, 1988.
4. Falik-Borenstein, T. C.; Jordan, S. C.; Saudubray, J. M.; Edmond,
J.; Cederbaum, S. D.: Carnitine palmitoyl transferase I deficiency
(CPT I). (Abstract) Am. J. Hum. Genet. 45 (suppl.): A5, 1989.
5. Falik-Borenstein, Z. C.; Jordan, S. C.; Saudubray, J.-M.; Brivet,
M.; Demaugre, F.; Edmond, J.; Cederbaum, S. D.: Renal tubular acidosis
in carnitine palmitoyltransferase type I deficiency. New Eng. J.
Med. 327: 24-27, 1992.
6. Gobin, S.; Bonnefont, J.-P.; Prip-Buus, C.; Mugnier, C.; Ferrec,
M.; Demaugre, F.; Saudubray, J.-M.; Rostane, H.; Djouadi, F.; Wilcox,
W.; Cederbaum, S.; Haas, R.; Nyhan, W. L.; Green, A.; Gray, G.; Girard,
J.; Thuillier, L.: Organization of the human liver carnitine palmitoyltransferase
1 gene (CPT1A) and identification of novel mutations in hypoketotic
hypoglycaemia. Hum. Genet. 111: 179-189, 2002.
7. Haworth, J. C.; Coates, P. M.; Demaugre, F.; Dilling, L. A.; Seargeant,
L. E.; Moroz, S. P.; Booth, F. A.; Seshia, S. S.: Hepatic carnitine
palmityltransferase (CPT I) deficiency: 3 patients in a Hutterite
family. (Abstract) Pediat. Res. 29: 130A, 1991.
8. Haworth, J. C.; Demaugre, F.; Booth, F. A.; Dilling, L. A.; Moroz,
S. P.; Seshia, S. S.; Seargeant, L. E.; Coates, P. M.: Atypical features
of the hepatic form of carnitine palmitoyltransferase deficiency in
a Hutterite family. J. Pediat. 121: 553-557, 1992.
9. IJlst, L.; Mandel, H.; Oostheim, W.; Ruiter, J. P. N.; Gutman,
A.; Wanders, R. J. A.: Molecular basis of hepatic carnitine palmitoyltransferase
I deficiency. J. Clin. Invest. 102: 527-531, 1998.
10. Innes, A. M.; Seargeant, L. E.; Balachandra, K.; Roe, C. R.; Wanders,
R. J. A.; Ruiter, J. P. N.; Casiro, O.; Grewar, D. A.; Greenberg,
C. R.: Hepatic carnitine palmitoyltransferase I deficiency presenting
as maternal illness in pregnancy. Pediat. Res. 47: 43-45, 2000.
11. Olpin, S. E.; Allen, J.; Bonham, J. R.; Clark, S.; Clayton, P.
T.; Calvin, J.; Downing, M.; Ives, K.; Jones, S.; Manning, N. J.;
Pollitt, R. J.; Standing, S. J.; Tanner, M. S.: Features of carnitine
palmitoyltransferase type I deficiency. J. Inherit. Metab. Dis. 24:
35-42, 2001.
12. Roomets, E.; Lundbom, N.; Pihko, H.; Heikkinen, S.; Tyni, T.:
Lipids detected by brain MRS during coma caused by carnitine palmitoyltransferase
1 deficiency. Neurology 67: 1516-1517, 2006.
13. Sim, K. G.; Wiley, V.; Carpenter, K.; Wilcken, B.: Carnitine
palmitoyltransferase I deficiency in neonate identified by dried blood
spot free carnitine and acylcarnitine profile. J. Inherit. Metab.
Dis. 24: 51-59, 2001.
14. Stanley, C. A.; Sunaryo, F.; Hale, D. E.; Bonnefont, J.-P.; Demaugre,
F.; Saudubray, J.-M.: Elevated plasma carnitine in the hepatic form
of carnitine palmitoyltransferase-1 deficiency. J. Inherit. Metab.
Dis. 15: 785-789, 1992.
*FIELD* CS
INHERITANCE:
Autosomal recessive
CARDIOVASCULAR:
[Heart];
Cardiomegaly;
Cardiac rhythm disturbances
ABDOMEN:
[Liver];
Hepatomegaly;
[Gastrointestinal];
Poor feeding;
Diarrhea
MUSCLE, SOFT TISSUE:
Muscle weakness is not a feature
NEUROLOGIC:
[Central nervous system];
Hypotonia;
Lethargy;
Seizures;
Coma;
Encephalopathy, recurrent
METABOLIC FEATURES:
Hypoketotic hypoglycemia;
Renal tubular acidosis
PRENATAL MANIFESTATIONS:
[Maternal];
Acute fatty liver in pregnancy (fetus with carnitine palmitoyltransferase
I (CPT1) deficiency);
HELLP syndrome
LABORATORY ABNORMALITIES:
Mild to moderate hyperammonemia;
Transient hyperlipidemia;
Elevated creatine kinase;
Elevated transaminases;
No dicarboxylic aciduria;
No ketonuria;
Normal to elevated total plasma carnitine;
Elevated free carnitine;
Carnitine palmitoyltransferase I deficiency (fibroblast, liver, leukocytes);
Decreased CPT1 activity;
Decreased long-chain fatty acid oxidation
MISCELLANEOUS:
Onset <30 months;
Precipitated by infection, fasting, or intercurrent illness
MOLECULAR BASIS:
Caused by mutation in the carnitine palmitoyltransferase IA gene (CPT1A,
600528.0001)
*FIELD* CN
Kelly A. Przylepa - revised: 10/5/2004
Cassandra L. Kniffin - revised: 8/19/2004
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 12/20/2007
joanna: 8/1/2005
joanna: 10/6/2004
joanna: 10/5/2004
ckniffin: 8/19/2004
*FIELD* CN
Cassandra L. Kniffin - updated: 9/14/2007
Cassandra L. Kniffin - reorganized: 8/23/2004
Cassandra L. Kniffin - updated: 8/19/2004
Victor A. McKusick - updated: 10/10/2002
Victor A. McKusick - updated: 8/7/2002
Ada Hamosh - updated: 4/17/2001
Victor A. McKusick - updated: 10/1/1998
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
wwang: 09/21/2007
ckniffin: 9/14/2007
terry: 3/23/2006
carol: 8/1/2005
carol: 8/23/2004
ckniffin: 8/19/2004
ckniffin: 8/17/2004
tkritzer: 10/10/2002
carol: 8/7/2002
tkritzer: 8/7/2002
alopez: 4/17/2001
carol: 10/6/1998
terry: 10/1/1998
mimman: 2/8/1996
mark: 10/2/1995
carol: 7/13/1995
terry: 6/3/1995
davew: 6/6/1994
pfoster: 5/12/1994
carol: 9/23/1993
MIM
600528
*RECORD*
*FIELD* NO
600528
*FIELD* TI
*600528 CARNITINE PALMITOYLTRANSFERASE I, LIVER; CPT1A
;;CPT IA;;
CPT I, LIVER;;
CPT1
read more*FIELD* TX
DESCRIPTION
The CPT1A gene encodes carnitine palmitoyltransferase IA, a liver enzyme
involved in fatty acid oxidation. The carnitine palmitoyltransferase
(CPT; EC 2.3.1.21) enzyme system, in conjunction with acyl-CoA
synthetase and carnitine/acylcarnitine translocase (613698), provides
the mechanism whereby long-chain fatty acids are transferred from the
cytosol to the mitochondrial matrix to undergo beta-oxidation for energy
production. The CPT I isozymes (CPT1A and CPT1B; 601987) are located in
the mitochondrial outer membrane and are detergent-labile, whereas CPT
II (600650) is located in the inner mitochondrial membrane and is
detergent-stable (Bieber, 1988; Murthy and Pande, 1987).
CLONING
From a rat liver cDNA library, Esser et al. (1993) isolated a cDNA
corresponding to carnitine palmitoyltransferase I. The deduced 773-amino
acid protein has a molecular mass of 88 kD. A 4.7-kb mRNA was detected
in rat liver. The authors suggested that the de novo synthesized enzyme
is targeted to the mitochondrial outer membrane by a leader peptide, and
that the mature protein anchors to the membrane through a 20-amino acid
region near the N terminus. The findings established that CPT I and CPT
II are distinct proteins and that inhibitors of CPT I interact within
the catalytic domain, not with an associated regulatory component.
Britton et al. (1995) used the cDNA for rat liver mitochondrial CPT I as
a probe to isolate its counterpart from a human liver cDNA library. The
predicted 773-amino acid protein shares 86% identity with the rat
enzyme. Northern blot analysis detected a 4.7-kb mRNA in human liver.
GENE STRUCTURE
Gobin et al. (2002) used the working draft data of the human genome
sequence to characterize the organization of the CPT1A gene. They showed
the existence of 20 exons, spanning 60 kb of DNA. Two alternate
promoters and numerous transcription factor-binding sites were
identified within the 5-prime upstream region of the gene. In the
3-prime untranslated region, the major polyA signal was suggested to lie
about 2 kb downstream of the stop codon.
MAPPING
Britton et al. (1995) assigned the human liver CPT1 gene to 11q by
testing of oligonucleotide primers specific to upstream and downstream
regions of one of the exon-intron junctions in PCRs with DNA from a
panel of somatic cell hybrids. One of the somatic cell hybrids that
contained only a small portion of chromosome 11 (11q22-q23) gave
negative results.
By fluorescence in situ hybridization, Britton et al. (1997) mapped the
CPT1A gene to chromosome 11q13.1-q13.5.
GENE FUNCTION
Major control over fatty acid oxidation process is exerted at the level
of CPT I by virtue of the unique inhibitability of this enzyme by
malonyl-CoA. This fuel 'cross talk' was first recognized in the context
of hepatic ketogenesis and its regulation and thereafter emerged as a
central component of metabolism in a variety of tissues.
For many years, it was unclear whether or not there were 2 distinct CPT
proteins associated with mitochondrial beta-oxidation. Bergstrom and
Reitz (1980) showed that CPT I and CPT II have similar physical
characteristics, including molecular mass and kinetic properties, and
that antibodies raised against each enzyme crossreacted with the other.
Slama et al. (1996) demonstrated complementation between cells from CPT
I- and CPT II-deficient (255110) individuals, indicating that the
respective causative mutations of CPT I and CPT II deficiencies reside
in distinct genes.
Britton et al. (1997) established that liver and fibroblast express the
same isoform of mitochondrial CPT1, legitimizing the use of fibroblast
assays in the differential diagnosis of the 'muscle' (255110) and
'hepatic' (255120) forms of CPT deficiency. The findings established
unequivocally that carnitine palmitoyltransferases I and II are distinct
proteins encoded by separate genes.
To investigate the mechanism by which central metabolism of lipids can
modulate energy balance, Obici et al. (2003) selectively reduced lipid
oxidation in the hypothalamus. The activity of CPT1 was decreased in
rats either by administration of a ribozyme-containing plasmid designed
specifically to decrease the expression of this enzyme, or by infusion
of pharmacologic inhibitors of its activity into the third cerebral
ventricle. Either genetic or biochemical inhibition of hypothalamic CPT1
activity was sufficient to diminish food intake and endogenous glucose
production substantially. Obici et al. (2003) concluded that changes in
the rate of lipid oxidation in selective hypothalamic neurons signaled
nutrient availability to the hypothalamus, which in turn modulated the
exogenous and endogenous inputs of nutrients into the circulation.
MOLECULAR GENETICS
In an infant with CPT IA deficiency (255120), IJlst et al. (1998)
identified a homozygous mutation in the CPT1A gene (600528.0001).
Yamamoto et al. (2000) reported 3 nonsense mutations, 1 missense
mutation, and 2 splicing mutations in 4 Japanese patients with CPT IA
deficiency.
Ogawa et al. (2002) stated that 19 patients with CPT IA deficiency and 9
CPT1A mutations had been reported. Gobin et al. (2002) pointed out that
while more than 200 families with CPT II deficiencies were known, fewer
than 30 families with CPT IA deficiency had been reported prior to their
report.
Gobin et al. (2002) characterized 6 novel mutations in 4 CPT1A-deficient
patients (600528.0003-600528.0008).
*FIELD* AV
.0001
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, ASP454GLY
IJlst et al. (1998) described homozygosity for an asp454-to-gly (D454G)
missense mutation of the CPT1A gene in a patient with CPT IA deficiency
(255120), the offspring of consanguineous parents. She presented at 15
months of age with diarrhea and feeding difficulties. On admission, she
was severely hypotonic and lethargic. Physical examination showed
hepatomegaly and decreased tendon reflexes. Hypoketotic hypoglycemia was
demonstrated.
.0002
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, GLU360GLY
In a Japanese patient with CPT IA deficiency (255120), Yamamoto et al.
(2000) identified a 1079A-G mutation in the CPT1A gene, resulting in a
glu360-to-gly (E360G) substitution. By functional expression studies in
SV40 transformed fibroblasts, Ogawa et al. (2002) found that the E360G
mutation caused decreased enzyme activity and protein levels, indicating
that it is pathogenic.
.0003
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, GLN100TER
In a patient with CPT IA deficiency (255120), Gobin et al. (2002)
identified a homozygous 298C-T substitution in exon 4 of the CPT1A gene,
resulting in a gln100-to-ter (Q100X) mutation. The mutation truncated
the protein by 671 amino acids.
.0004
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, ALA414VAL
In a patient with CPT IA deficiency (255120), Gobin et al. (2002)
identified a 1241C-T substitution in exon 11 of the CPT1A gene,
resulting in an ala414-to-val (A414V) mutation. Both the proband and the
proband's father were heterozygous for the mutation. The same patient
also had a 1493A-G substitution in exon 13 which produced a
tyr498-to-cys (Y498C) mutation (600528.0005). Both the proband and the
proband's mother were heterozygous for the mutation.
Using functional and structural analysis, Gobin et al. (2003) found that
the A414V mutation results in a severe decrease in protein expression
(20- to 30-fold lower than wildtype), indicating protein instability, as
well as a 98% decrease in catalytic activity of the CPT I enzyme.
Modeling studies suggested that the mutation introduces a conformational
change in the protein.
.0005
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, TYR498CYS
See 600528.0004 and Gobin et al. (2002).
Using functional and structural analysis, Gobin et al. (2003) found that
the Y498C mutation results in slight protein instability and a 3-fold
decrease in enzyme activity. The affected residue is located at some
distance from the active site of the enzyme and may cause indirect
effects via a conformational change.
.0006
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, 153-BP DEL
In a patient with CPT IA deficiency (255120), Gobin et al. (2002)
identified a 153-bp deletion at nucleotide 1876 of the CPT1A gene
resulting from a G-to-A substitution at the intron 15 splice acceptor
site. The patient's mother was heterozygous for the mutation, which was
not detected in the patient's father nor in 20 healthy controls. The
mutation deleted 51 amino acids, from codons 626 to 676. The patient
also had a 113-bp intronic insertion at nucleotide 1575 of the cDNA
(600528.0007) resulting from retention of part of intron 13.
.0007
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, 113-BP INS
See 600528.0006 and Gobin et al. (2002).
.0008
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, 8-KB DEL
In a patient with CPT IA deficiency (255120), Gobin et al. (2002)
identified homozygosity for an 8-kb deletion in the CPT1A gene spanning
the distal two-thirds of intron 14 to nucleotide 2107 in exon 17. The
rearrangement deleted amino acids 581 to 702.
.0009
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, GLY709GLU
In a patient with CPT IA deficiency (255120) reported by Schaefer et al.
(1997), Gobin et al. (2003) identified compound heterozygosity for 2
mutations in the CPT1A gene: a 2126G-A transition, resulting in a
gly709-to-glu (G709E) substitution, and a 1-bp deletion (948delG),
resulting in a premature termination signal in exon 10 (600528.0010).
Using functional and structural analysis, Gobin et al. (2003) found that
the G709E mutation resulted in significant protein instability and
complete loss of enzyme function. The authors suggested that the
mutation introduces a bulky and negatively charged group into the
hydrophobic core of the enzyme, causing steric repulsions and
unfavorable electrostatic interactions.
.0010
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, 1-BP DEL, 948G
See 600528.0009 and Gobin et al. (2003).
.0011
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, GLY710GLU
In affected members of a large Hutterite kindred with CPT IA deficiency
(255120), Prip-Buus et al. (2001) identified a homozygous 2129G-A
transition in the CPT1A gene, resulting in a gly710-to-glu (G710E)
substitution. Expression studies showed that the G710E mutation alters
neither mitochondrial targeting nor stability of the protein, but
kinetic studies showed that the mutant enzyme is completely
catalytically inactive. The authors suspected a founder effect.
*FIELD* SA
Zierz and Engel (1985)
*FIELD* RF
1. Bergstrom, J. P.; Reitz, R. C.: Studies on carnitine palmitoyl
transferase: the similar nature of CPTi (inner form) and CPTo (outer
form). Arch. Biochem. Biophys. 204: 71-78, 1980.
2. Bieber, L. L.: Carnitine. Annu. Rev. Biochem. 57: 261-283, 1988.
3. Britton, C. H.; Mackey, D. W.; Esser, V.; Foster, D. W.; Burns,
D. K.; Yarnall, D. P.; Froguel, P.; McGarry, J. D.: Fine chromosome
mapping of the genes for human liver and muscle carnitine palmitoyltransferase
I (CPT1A and CPT1B). Genomics 40: 209-211, 1997.
4. Britton, C. H.; Schultz, R. A.; Zhang, B.; Esser, V.; Foster, D.
W.; McGarry, J. D.: Human liver mitochondrial carnitine palmitoyltransferase
I: characterization of its cDNA and chromosomal localization and partial
analysis of the gene. Proc. Nat. Acad. Sci. 92: 1984-1988, 1995.
5. Esser, V.; Britton, C. H.; Weis, B. C.; Foster, D. W.; McGarry,
J. D.: Cloning, sequencing, and expression of a cDNA encoding rat
liver carnitine palmitoyltransferase I: direct evidence that a single
polypeptide is involved in inhibitor interaction and catalytic function. J.
Biol. Chem. 268: 5817-5822, 1993.
6. Gobin, S.; Bonnefont, J.-P.; Prip-Buus, C.; Mugnier, C.; Ferrec,
M.; Demaugre, F.; Saudubray, J.-M.; Rostane, H.; Djouadi, F.; Wilcox,
W.; Cederbaum, S.; Haas, R.; Nyhan, W. L.; Green, A.; Gray, G.; Girard,
J.; Thuillier, L.: Organization of the human liver carnitine palmitoyltransferase
1 gene (CPT1A) and identification of novel mutations in hypoketotic
hypoglycaemia. Hum. Genet. 111: 179-189, 2002.
7. Gobin, S.; Thuillier, L.; Jogl, G.; Faye, A.; Tong, L.; Chi, M.;
Bonnefont, J.-P.; Girard, J.; Prip-Buus, C.: Functional and structural
basis of carnitine palmitoyltransferase 1A deficiency. J. Biol. Chem. 278:
50428-50434, 2003.
8. IJlst, L.; Mandel, H.; Oostheim, W.; Ruiter, J. P. N.; Gutman,
A.; Wanders, R. J. A.: Molecular basis of hepatic carnitine palmitoyltransferase
I deficiency. J. Clin. Invest. 102: 527-531, 1998.
9. Murthy, M. S. R.; Pande, S. V.: Malonyl-CoA binding site and the
overt carnitine palmitoyltransferase activity reside on the opposite
sides of the outer mitochondrial membrane. Proc. Nat. Acad. Sci. 84:
378-382, 1987.
10. Obici, S.; Feng, Z.; Arduini, A.; Conti, R.; Rossetti, L.: Inhibition
of hypothalamic carnitine palmitoyltransferase-1 decreases food intake
and glucose production. Nature Med. 9: 756-761, 2003.
11. Ogawa, E.; Kanazawa, M.; Yamamoto, S.; Ohtsuka, S.; Ogawa, A.;
Ohtake, A.; Takayanagi, M.; Kohno, Y.: Expression analysis of two
mutations in carnitine palmitoyltransferase IA deficiency. J. Hum.
Genet. 47: 342-347, 2002.
12. Prip-Buus, C.; Thuillier, L.; Abadi, N.; Prasad, C.; Dilling,
L.; Klasing, J.; Demaugre, F.; Greenberg, C. R.; Haworth, J. C.; Droin,
V.; Kadhom, N.; Gobin, S.; Kamoun, P.; Girard, J.; Bonnefont, J.-P.
: Molecular and enzymatic characterization of a unique carnitine palmitoyltransferase
1A mutation in the Hutterite community. Molec. Genet. Metab. 73:
46-54, 2001.
13. Schaefer, J.; Jackson, S.; Taroni, F.; Swift, P.; Turnbull, D.
M.: Characterisation of carnitine palmitoyltransferases in patients
with a carnitine palmitoyltransferase deficiency: implications for
diagnosis and therapy. J. Neurol. Neurosurg. Psychiat. 62: 169-176,
1997.
14. Slama, A.; Brivet, M.; Boutron, A.; Legrand, A.; Saudubray, J.-M.;
Demaugre, F.: Complementation analysis of carnitine palmitoyltransferase
I and II defects. Pediat. Res. 40: 542-546, 1996.
15. Yamamoto, S.; Kanazawa, M.; Ogawa, A.; Takayanagi, M.; Ohtake,
A.; Kohono, Y.: Molecular analysis of hepatic carnitine palmitoyltransferase
I deficiency (1): cDNA and genomic DNA analysis of infants presenting
with Reye-like illness.In: Proceedings of the VIII International Congress
Inborn Errors of Metabolism. Cambridge, U.K. 13Sept: 2000.
16. Zierz, S.; Engel, A. G.: Regulatory properties of a mutant carnitine
palmitoyl transferase in human skeletal muscle. Europ. J. Biochem. 149:
207-214, 1985.
*FIELD* CN
Cassandra L. Kniffin - reorganized: 8/23/2004
Cassandra L. Kniffin - updated: 8/19/2004
Ada Hamosh - updated: 9/15/2003
Victor A. McKusick - updated: 10/2/2002
Victor A. McKusick - updated: 8/5/2002
Victor A. McKusick - updated: 10/1/1998
Victor A. McKusick - updated: 3/27/1998
Lori M. Kelman - updated: 1/30/1998
*FIELD* CD
Victor A. McKusick: 5/12/1995
*FIELD* ED
carol: 01/19/2011
terry: 3/22/2006
carol: 8/23/2004
ckniffin: 8/19/2004
cwells: 11/10/2003
alopez: 9/15/2003
tkritzer: 10/10/2002
tkritzer: 10/4/2002
terry: 10/2/2002
tkritzer: 8/8/2002
tkritzer: 8/7/2002
tkritzer: 8/6/2002
terry: 8/5/2002
alopez: 4/17/2001
terry: 4/12/2001
carol: 10/6/1998
terry: 10/1/1998
psherman: 3/27/1998
dholmes: 3/6/1998
dholmes: 1/30/1998
mark: 9/11/1997
terry: 9/4/1997
mark: 7/14/1995
mark: 5/12/1995
*RECORD*
*FIELD* NO
600528
*FIELD* TI
*600528 CARNITINE PALMITOYLTRANSFERASE I, LIVER; CPT1A
;;CPT IA;;
CPT I, LIVER;;
CPT1
read more*FIELD* TX
DESCRIPTION
The CPT1A gene encodes carnitine palmitoyltransferase IA, a liver enzyme
involved in fatty acid oxidation. The carnitine palmitoyltransferase
(CPT; EC 2.3.1.21) enzyme system, in conjunction with acyl-CoA
synthetase and carnitine/acylcarnitine translocase (613698), provides
the mechanism whereby long-chain fatty acids are transferred from the
cytosol to the mitochondrial matrix to undergo beta-oxidation for energy
production. The CPT I isozymes (CPT1A and CPT1B; 601987) are located in
the mitochondrial outer membrane and are detergent-labile, whereas CPT
II (600650) is located in the inner mitochondrial membrane and is
detergent-stable (Bieber, 1988; Murthy and Pande, 1987).
CLONING
From a rat liver cDNA library, Esser et al. (1993) isolated a cDNA
corresponding to carnitine palmitoyltransferase I. The deduced 773-amino
acid protein has a molecular mass of 88 kD. A 4.7-kb mRNA was detected
in rat liver. The authors suggested that the de novo synthesized enzyme
is targeted to the mitochondrial outer membrane by a leader peptide, and
that the mature protein anchors to the membrane through a 20-amino acid
region near the N terminus. The findings established that CPT I and CPT
II are distinct proteins and that inhibitors of CPT I interact within
the catalytic domain, not with an associated regulatory component.
Britton et al. (1995) used the cDNA for rat liver mitochondrial CPT I as
a probe to isolate its counterpart from a human liver cDNA library. The
predicted 773-amino acid protein shares 86% identity with the rat
enzyme. Northern blot analysis detected a 4.7-kb mRNA in human liver.
GENE STRUCTURE
Gobin et al. (2002) used the working draft data of the human genome
sequence to characterize the organization of the CPT1A gene. They showed
the existence of 20 exons, spanning 60 kb of DNA. Two alternate
promoters and numerous transcription factor-binding sites were
identified within the 5-prime upstream region of the gene. In the
3-prime untranslated region, the major polyA signal was suggested to lie
about 2 kb downstream of the stop codon.
MAPPING
Britton et al. (1995) assigned the human liver CPT1 gene to 11q by
testing of oligonucleotide primers specific to upstream and downstream
regions of one of the exon-intron junctions in PCRs with DNA from a
panel of somatic cell hybrids. One of the somatic cell hybrids that
contained only a small portion of chromosome 11 (11q22-q23) gave
negative results.
By fluorescence in situ hybridization, Britton et al. (1997) mapped the
CPT1A gene to chromosome 11q13.1-q13.5.
GENE FUNCTION
Major control over fatty acid oxidation process is exerted at the level
of CPT I by virtue of the unique inhibitability of this enzyme by
malonyl-CoA. This fuel 'cross talk' was first recognized in the context
of hepatic ketogenesis and its regulation and thereafter emerged as a
central component of metabolism in a variety of tissues.
For many years, it was unclear whether or not there were 2 distinct CPT
proteins associated with mitochondrial beta-oxidation. Bergstrom and
Reitz (1980) showed that CPT I and CPT II have similar physical
characteristics, including molecular mass and kinetic properties, and
that antibodies raised against each enzyme crossreacted with the other.
Slama et al. (1996) demonstrated complementation between cells from CPT
I- and CPT II-deficient (255110) individuals, indicating that the
respective causative mutations of CPT I and CPT II deficiencies reside
in distinct genes.
Britton et al. (1997) established that liver and fibroblast express the
same isoform of mitochondrial CPT1, legitimizing the use of fibroblast
assays in the differential diagnosis of the 'muscle' (255110) and
'hepatic' (255120) forms of CPT deficiency. The findings established
unequivocally that carnitine palmitoyltransferases I and II are distinct
proteins encoded by separate genes.
To investigate the mechanism by which central metabolism of lipids can
modulate energy balance, Obici et al. (2003) selectively reduced lipid
oxidation in the hypothalamus. The activity of CPT1 was decreased in
rats either by administration of a ribozyme-containing plasmid designed
specifically to decrease the expression of this enzyme, or by infusion
of pharmacologic inhibitors of its activity into the third cerebral
ventricle. Either genetic or biochemical inhibition of hypothalamic CPT1
activity was sufficient to diminish food intake and endogenous glucose
production substantially. Obici et al. (2003) concluded that changes in
the rate of lipid oxidation in selective hypothalamic neurons signaled
nutrient availability to the hypothalamus, which in turn modulated the
exogenous and endogenous inputs of nutrients into the circulation.
MOLECULAR GENETICS
In an infant with CPT IA deficiency (255120), IJlst et al. (1998)
identified a homozygous mutation in the CPT1A gene (600528.0001).
Yamamoto et al. (2000) reported 3 nonsense mutations, 1 missense
mutation, and 2 splicing mutations in 4 Japanese patients with CPT IA
deficiency.
Ogawa et al. (2002) stated that 19 patients with CPT IA deficiency and 9
CPT1A mutations had been reported. Gobin et al. (2002) pointed out that
while more than 200 families with CPT II deficiencies were known, fewer
than 30 families with CPT IA deficiency had been reported prior to their
report.
Gobin et al. (2002) characterized 6 novel mutations in 4 CPT1A-deficient
patients (600528.0003-600528.0008).
*FIELD* AV
.0001
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, ASP454GLY
IJlst et al. (1998) described homozygosity for an asp454-to-gly (D454G)
missense mutation of the CPT1A gene in a patient with CPT IA deficiency
(255120), the offspring of consanguineous parents. She presented at 15
months of age with diarrhea and feeding difficulties. On admission, she
was severely hypotonic and lethargic. Physical examination showed
hepatomegaly and decreased tendon reflexes. Hypoketotic hypoglycemia was
demonstrated.
.0002
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, GLU360GLY
In a Japanese patient with CPT IA deficiency (255120), Yamamoto et al.
(2000) identified a 1079A-G mutation in the CPT1A gene, resulting in a
glu360-to-gly (E360G) substitution. By functional expression studies in
SV40 transformed fibroblasts, Ogawa et al. (2002) found that the E360G
mutation caused decreased enzyme activity and protein levels, indicating
that it is pathogenic.
.0003
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, GLN100TER
In a patient with CPT IA deficiency (255120), Gobin et al. (2002)
identified a homozygous 298C-T substitution in exon 4 of the CPT1A gene,
resulting in a gln100-to-ter (Q100X) mutation. The mutation truncated
the protein by 671 amino acids.
.0004
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, ALA414VAL
In a patient with CPT IA deficiency (255120), Gobin et al. (2002)
identified a 1241C-T substitution in exon 11 of the CPT1A gene,
resulting in an ala414-to-val (A414V) mutation. Both the proband and the
proband's father were heterozygous for the mutation. The same patient
also had a 1493A-G substitution in exon 13 which produced a
tyr498-to-cys (Y498C) mutation (600528.0005). Both the proband and the
proband's mother were heterozygous for the mutation.
Using functional and structural analysis, Gobin et al. (2003) found that
the A414V mutation results in a severe decrease in protein expression
(20- to 30-fold lower than wildtype), indicating protein instability, as
well as a 98% decrease in catalytic activity of the CPT I enzyme.
Modeling studies suggested that the mutation introduces a conformational
change in the protein.
.0005
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, TYR498CYS
See 600528.0004 and Gobin et al. (2002).
Using functional and structural analysis, Gobin et al. (2003) found that
the Y498C mutation results in slight protein instability and a 3-fold
decrease in enzyme activity. The affected residue is located at some
distance from the active site of the enzyme and may cause indirect
effects via a conformational change.
.0006
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, 153-BP DEL
In a patient with CPT IA deficiency (255120), Gobin et al. (2002)
identified a 153-bp deletion at nucleotide 1876 of the CPT1A gene
resulting from a G-to-A substitution at the intron 15 splice acceptor
site. The patient's mother was heterozygous for the mutation, which was
not detected in the patient's father nor in 20 healthy controls. The
mutation deleted 51 amino acids, from codons 626 to 676. The patient
also had a 113-bp intronic insertion at nucleotide 1575 of the cDNA
(600528.0007) resulting from retention of part of intron 13.
.0007
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, 113-BP INS
See 600528.0006 and Gobin et al. (2002).
.0008
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, 8-KB DEL
In a patient with CPT IA deficiency (255120), Gobin et al. (2002)
identified homozygosity for an 8-kb deletion in the CPT1A gene spanning
the distal two-thirds of intron 14 to nucleotide 2107 in exon 17. The
rearrangement deleted amino acids 581 to 702.
.0009
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, GLY709GLU
In a patient with CPT IA deficiency (255120) reported by Schaefer et al.
(1997), Gobin et al. (2003) identified compound heterozygosity for 2
mutations in the CPT1A gene: a 2126G-A transition, resulting in a
gly709-to-glu (G709E) substitution, and a 1-bp deletion (948delG),
resulting in a premature termination signal in exon 10 (600528.0010).
Using functional and structural analysis, Gobin et al. (2003) found that
the G709E mutation resulted in significant protein instability and
complete loss of enzyme function. The authors suggested that the
mutation introduces a bulky and negatively charged group into the
hydrophobic core of the enzyme, causing steric repulsions and
unfavorable electrostatic interactions.
.0010
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, 1-BP DEL, 948G
See 600528.0009 and Gobin et al. (2003).
.0011
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1A, GLY710GLU
In affected members of a large Hutterite kindred with CPT IA deficiency
(255120), Prip-Buus et al. (2001) identified a homozygous 2129G-A
transition in the CPT1A gene, resulting in a gly710-to-glu (G710E)
substitution. Expression studies showed that the G710E mutation alters
neither mitochondrial targeting nor stability of the protein, but
kinetic studies showed that the mutant enzyme is completely
catalytically inactive. The authors suspected a founder effect.
*FIELD* SA
Zierz and Engel (1985)
*FIELD* RF
1. Bergstrom, J. P.; Reitz, R. C.: Studies on carnitine palmitoyl
transferase: the similar nature of CPTi (inner form) and CPTo (outer
form). Arch. Biochem. Biophys. 204: 71-78, 1980.
2. Bieber, L. L.: Carnitine. Annu. Rev. Biochem. 57: 261-283, 1988.
3. Britton, C. H.; Mackey, D. W.; Esser, V.; Foster, D. W.; Burns,
D. K.; Yarnall, D. P.; Froguel, P.; McGarry, J. D.: Fine chromosome
mapping of the genes for human liver and muscle carnitine palmitoyltransferase
I (CPT1A and CPT1B). Genomics 40: 209-211, 1997.
4. Britton, C. H.; Schultz, R. A.; Zhang, B.; Esser, V.; Foster, D.
W.; McGarry, J. D.: Human liver mitochondrial carnitine palmitoyltransferase
I: characterization of its cDNA and chromosomal localization and partial
analysis of the gene. Proc. Nat. Acad. Sci. 92: 1984-1988, 1995.
5. Esser, V.; Britton, C. H.; Weis, B. C.; Foster, D. W.; McGarry,
J. D.: Cloning, sequencing, and expression of a cDNA encoding rat
liver carnitine palmitoyltransferase I: direct evidence that a single
polypeptide is involved in inhibitor interaction and catalytic function. J.
Biol. Chem. 268: 5817-5822, 1993.
6. Gobin, S.; Bonnefont, J.-P.; Prip-Buus, C.; Mugnier, C.; Ferrec,
M.; Demaugre, F.; Saudubray, J.-M.; Rostane, H.; Djouadi, F.; Wilcox,
W.; Cederbaum, S.; Haas, R.; Nyhan, W. L.; Green, A.; Gray, G.; Girard,
J.; Thuillier, L.: Organization of the human liver carnitine palmitoyltransferase
1 gene (CPT1A) and identification of novel mutations in hypoketotic
hypoglycaemia. Hum. Genet. 111: 179-189, 2002.
7. Gobin, S.; Thuillier, L.; Jogl, G.; Faye, A.; Tong, L.; Chi, M.;
Bonnefont, J.-P.; Girard, J.; Prip-Buus, C.: Functional and structural
basis of carnitine palmitoyltransferase 1A deficiency. J. Biol. Chem. 278:
50428-50434, 2003.
8. IJlst, L.; Mandel, H.; Oostheim, W.; Ruiter, J. P. N.; Gutman,
A.; Wanders, R. J. A.: Molecular basis of hepatic carnitine palmitoyltransferase
I deficiency. J. Clin. Invest. 102: 527-531, 1998.
9. Murthy, M. S. R.; Pande, S. V.: Malonyl-CoA binding site and the
overt carnitine palmitoyltransferase activity reside on the opposite
sides of the outer mitochondrial membrane. Proc. Nat. Acad. Sci. 84:
378-382, 1987.
10. Obici, S.; Feng, Z.; Arduini, A.; Conti, R.; Rossetti, L.: Inhibition
of hypothalamic carnitine palmitoyltransferase-1 decreases food intake
and glucose production. Nature Med. 9: 756-761, 2003.
11. Ogawa, E.; Kanazawa, M.; Yamamoto, S.; Ohtsuka, S.; Ogawa, A.;
Ohtake, A.; Takayanagi, M.; Kohno, Y.: Expression analysis of two
mutations in carnitine palmitoyltransferase IA deficiency. J. Hum.
Genet. 47: 342-347, 2002.
12. Prip-Buus, C.; Thuillier, L.; Abadi, N.; Prasad, C.; Dilling,
L.; Klasing, J.; Demaugre, F.; Greenberg, C. R.; Haworth, J. C.; Droin,
V.; Kadhom, N.; Gobin, S.; Kamoun, P.; Girard, J.; Bonnefont, J.-P.
: Molecular and enzymatic characterization of a unique carnitine palmitoyltransferase
1A mutation in the Hutterite community. Molec. Genet. Metab. 73:
46-54, 2001.
13. Schaefer, J.; Jackson, S.; Taroni, F.; Swift, P.; Turnbull, D.
M.: Characterisation of carnitine palmitoyltransferases in patients
with a carnitine palmitoyltransferase deficiency: implications for
diagnosis and therapy. J. Neurol. Neurosurg. Psychiat. 62: 169-176,
1997.
14. Slama, A.; Brivet, M.; Boutron, A.; Legrand, A.; Saudubray, J.-M.;
Demaugre, F.: Complementation analysis of carnitine palmitoyltransferase
I and II defects. Pediat. Res. 40: 542-546, 1996.
15. Yamamoto, S.; Kanazawa, M.; Ogawa, A.; Takayanagi, M.; Ohtake,
A.; Kohono, Y.: Molecular analysis of hepatic carnitine palmitoyltransferase
I deficiency (1): cDNA and genomic DNA analysis of infants presenting
with Reye-like illness.In: Proceedings of the VIII International Congress
Inborn Errors of Metabolism. Cambridge, U.K. 13Sept: 2000.
16. Zierz, S.; Engel, A. G.: Regulatory properties of a mutant carnitine
palmitoyl transferase in human skeletal muscle. Europ. J. Biochem. 149:
207-214, 1985.
*FIELD* CN
Cassandra L. Kniffin - reorganized: 8/23/2004
Cassandra L. Kniffin - updated: 8/19/2004
Ada Hamosh - updated: 9/15/2003
Victor A. McKusick - updated: 10/2/2002
Victor A. McKusick - updated: 8/5/2002
Victor A. McKusick - updated: 10/1/1998
Victor A. McKusick - updated: 3/27/1998
Lori M. Kelman - updated: 1/30/1998
*FIELD* CD
Victor A. McKusick: 5/12/1995
*FIELD* ED
carol: 01/19/2011
terry: 3/22/2006
carol: 8/23/2004
ckniffin: 8/19/2004
cwells: 11/10/2003
alopez: 9/15/2003
tkritzer: 10/10/2002
tkritzer: 10/4/2002
terry: 10/2/2002
tkritzer: 8/8/2002
tkritzer: 8/7/2002
tkritzer: 8/6/2002
terry: 8/5/2002
alopez: 4/17/2001
terry: 4/12/2001
carol: 10/6/1998
terry: 10/1/1998
psherman: 3/27/1998
dholmes: 3/6/1998
dholmes: 1/30/1998
mark: 9/11/1997
terry: 9/4/1997
mark: 7/14/1995
mark: 5/12/1995