Full text data of SLC16A1
SLC16A1
(MCT1)
[Confidence: high (present in two of the MS resources)]
Monocarboxylate transporter 1; MCT 1 (Solute carrier family 16 member 1)
Monocarboxylate transporter 1; MCT 1 (Solute carrier family 16 member 1)
hRBCD
IPI00024650
IPI00024650 Monocarboxylate transporter 1 Monocarboxylate transporter 1 membrane n/a n/a n/a n/a n/a n/a n/a 1 n/a n/a 1 n/a n/a n/a n/a 1 n/a n/a n/a n/a integral membrane protein n/a found at its expected molecular weight found at molecular weight
IPI00024650 Monocarboxylate transporter 1 Monocarboxylate transporter 1 membrane n/a n/a n/a n/a n/a n/a n/a 1 n/a n/a 1 n/a n/a n/a n/a 1 n/a n/a n/a n/a integral membrane protein n/a found at its expected molecular weight found at molecular weight
UniProt
P53985
ID MOT1_HUMAN Reviewed; 500 AA.
AC P53985; Q5T8R6; Q9NSJ9;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 30-NOV-2010, sequence version 3.
DT 22-JAN-2014, entry version 137.
DE RecName: Full=Monocarboxylate transporter 1;
DE Short=MCT 1;
DE AltName: Full=Solute carrier family 16 member 1;
GN Name=SLC16A1; Synonyms=MCT1;
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], AND VARIANT GLU-490.
RC TISSUE=Heart;
RX PubMed=7835905; DOI=10.1006/geno.1994.1532;
RA Garcia C.K., Li X., Luna J., Francke U.;
RT "cDNA cloning of the human monocarboxylate transporter 1 and
RT chromosomal localization of the SLC16A1 locus to 1p13.2-p12.";
RL Genomics 23:500-503(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Colon;
RX PubMed=11944921; DOI=10.1006/bbrc.2002.6763;
RA Cuff M.A., Shirazi-Beechey S.P.;
RT "The human monocarboxylate transporter, MCT1: genomic organization and
RT promoter analysis.";
RL Biochem. Biophys. Res. Commun. 292:1048-1056(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT GLU-490.
RC TISSUE=Melanoma;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-213 AND SER-498, VARIANT
RP [LARGE SCALE ANALYSIS] GLU-490, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-461 AND SER-498, VARIANT
RP [LARGE SCALE ANALYSIS] GLU-490, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-461; SER-467; SER-483
RP AND SER-498, VARIANT [LARGE SCALE ANALYSIS] GLU-490, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-461, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-213; SER-483 AND
RP SER-498, VARIANT [LARGE SCALE ANALYSIS] GLU-490, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-213; THR-466; SER-483
RP AND SER-498, VARIANT [LARGE SCALE ANALYSIS] GLU-490, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [14]
RP VARIANTS SDLT GLU-204 AND ARG-472, AND VARIANT GLU-490.
RX PubMed=10590411;
RX DOI=10.1002/(SICI)1097-4598(200001)23:1<90::AID-MUS12>3.0.CO;2-M;
RA Merezhinskaya N., Fishbein W.N., Davis J.I., Foellmer J.W.;
RT "Mutations in MCT1 cDNA in patients with symptomatic deficiency in
RT lactate transport.";
RL Muscle Nerve 23:90-97(2000).
RN [15]
RP INVOLVEMENT IN HHF7.
RX PubMed=17701893; DOI=10.1086/520960;
RA Otonkoski T., Jiao H., Kaminen-Ahola N., Tapia-Paez I., Ullah M.S.,
RA Parton L.E., Schuit F., Quintens R., Sipilae I., Mayatepek E.,
RA Meissner T., Halestrap A.P., Rutter G.A., Kere J.;
RT "Physical exercise-induced hypoglycemia caused by failed silencing of
RT monocarboxylate transporter 1 in pancreatic beta cells.";
RL Am. J. Hum. Genet. 81:467-474(2007).
RN [16]
RP VARIANT [LARGE SCALE ANALYSIS] GLU-490, AND MASS SPECTROMETRY.
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).
CC -!- FUNCTION: Proton-linked monocarboxylate transporter. Catalyzes the
CC rapid transport across the plasma membrane of many
CC monocarboxylates such as lactate, pyruvate, branched-chain oxo
CC acids derived from leucine, valine and isoleucine, and the ketone
CC bodies acetoacetate, beta-hydroxybutyrate and acetate.
CC -!- INTERACTION:
CC P61966:AP1S1; NbExp=1; IntAct=EBI-1054708, EBI-516199;
CC O15121:DEGS1; NbExp=1; IntAct=EBI-1054708, EBI-1052713;
CC Q13530:SERINC3; NbExp=1; IntAct=EBI-1054708, EBI-1045571;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.
CC -!- TISSUE SPECIFICITY: Widely expressed in normal and in cancer
CC cells.
CC -!- DISEASE: Symptomatic deficiency in lactate transport (SDLT)
CC [MIM:245340]: Deficiency of lactate transporter may result in an
CC acidic intracellular environment created by muscle activity with
CC consequent degeneration of muscle and release of myoglobin and
CC creatine kinase. This defect might compromise extreme performance
CC in otherwise healthy individuals. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Familial hyperinsulinemic hypoglycemia 7 (HHF7)
CC [MIM:610021]: Dominantly inherited hypoglycemic disorder
CC characterized by inappropriate insulin secretion during anaerobic
CC exercise or on pyruvate load. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the major facilitator superfamily.
CC Monocarboxylate porter (TC 2.A.1.13) family.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/SLC16A1ID44046ch1p13.html";
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DR EMBL; L31801; AAC41707.1; -; mRNA.
DR EMBL; AJ438945; CAD27707.1; -; Genomic_DNA.
DR EMBL; AL162079; CAB82412.1; -; mRNA.
DR EMBL; AL158844; CAI21872.1; -; Genomic_DNA.
DR EMBL; CH471122; EAW56552.1; -; Genomic_DNA.
DR EMBL; BC026317; AAH26317.1; -; mRNA.
DR PIR; A55568; A55568.
DR RefSeq; NP_001159968.1; NM_001166496.1.
DR RefSeq; NP_003042.3; NM_003051.3.
DR RefSeq; XP_005271207.1; XM_005271150.1.
DR UniGene; Hs.75231; -.
DR ProteinModelPortal; P53985; -.
DR IntAct; P53985; 4.
DR MINT; MINT-5004345; -.
DR STRING; 9606.ENSP00000358640; -.
DR BindingDB; P53985; -.
DR ChEMBL; CHEMBL4360; -.
DR DrugBank; DB00119; Pyruvic acid.
DR TCDB; 2.A.1.13.1; the major facilitator superfamily (mfs).
DR PhosphoSite; P53985; -.
DR DMDM; 13432183; -.
DR PaxDb; P53985; -.
DR PRIDE; P53985; -.
DR DNASU; 6566; -.
DR Ensembl; ENST00000369626; ENSP00000358640; ENSG00000155380.
DR Ensembl; ENST00000538576; ENSP00000441065; ENSG00000155380.
DR GeneID; 6566; -.
DR KEGG; hsa:6566; -.
DR UCSC; uc001ecx.3; human.
DR CTD; 6566; -.
DR GeneCards; GC01M113454; -.
DR H-InvDB; HIX0000897; -.
DR HGNC; HGNC:10922; SLC16A1.
DR HPA; CAB017489; -.
DR HPA; HPA003324; -.
DR MIM; 245340; phenotype.
DR MIM; 600682; gene.
DR MIM; 610021; phenotype.
DR neXtProt; NX_P53985; -.
DR Orphanet; 165991; Exercise-induced hyperinsulinism.
DR Orphanet; 171690; Metabolic myopathy due to lactate transporter defect.
DR PharmGKB; PA35813; -.
DR eggNOG; NOG314865; -.
DR HOGENOM; HOG000280688; -.
DR HOVERGEN; HBG006384; -.
DR InParanoid; P53985; -.
DR KO; K08179; -.
DR OMA; QYFFAIS; -.
DR OrthoDB; EOG7W9RTN; -.
DR PhylomeDB; P53985; -.
DR BioCyc; MetaCyc:ENSG00000155380-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR Reactome; REACT_20633; Bile salt and organic anion SLC transporters.
DR Reactome; REACT_604; Hemostasis.
DR SABIO-RK; P53985; -.
DR ChiTaRS; SLC16A1; human.
DR GenomeRNAi; 6566; -.
DR NextBio; 25547; -.
DR PMAP-CutDB; P53985; -.
DR PRO; PR:P53985; -.
DR ArrayExpress; P53985; -.
DR Bgee; P53985; -.
DR CleanEx; HS_SLC16A1; -.
DR Genevestigator; P53985; -.
DR GO; GO:0016021; C:integral to membrane; TAS:ProtInc.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0015130; F:mevalonate transmembrane transporter activity; TAS:ProtInc.
DR GO; GO:0015355; F:secondary active monocarboxylate transmembrane transporter activity; IEA:InterPro.
DR GO; GO:0015293; F:symporter activity; IEA:UniProtKB-KW.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome.
DR GO; GO:0006090; P:pyruvate metabolic process; TAS:Reactome.
DR InterPro; IPR011701; MFS.
DR InterPro; IPR020846; MFS_dom.
DR InterPro; IPR016196; MFS_dom_general_subst_transpt.
DR InterPro; IPR004743; Monocarb_transpt.
DR Pfam; PF07690; MFS_1; 1.
DR SUPFAM; SSF103473; SSF103473; 2.
DR TIGRFAMs; TIGR00892; 2A0113; 1.
DR PROSITE; PS50850; MFS; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Complete proteome; Disease mutation; Membrane;
KW Phosphoprotein; Polymorphism; Reference proteome; Symport;
KW Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1 500 Monocarboxylate transporter 1.
FT /FTId=PRO_0000211381.
FT TOPO_DOM 1 15 Cytoplasmic (Potential).
FT TRANSMEM 16 36 Helical; (Potential).
FT TOPO_DOM 37 59 Extracellular (Potential).
FT TRANSMEM 60 80 Helical; (Potential).
FT TOPO_DOM 81 86 Cytoplasmic (Potential).
FT TRANSMEM 87 107 Helical; (Potential).
FT TOPO_DOM 108 111 Extracellular (Potential).
FT TRANSMEM 112 132 Helical; (Potential).
FT TOPO_DOM 133 143 Cytoplasmic (Potential).
FT TRANSMEM 144 164 Helical; (Potential).
FT TOPO_DOM 165 166 Extracellular (Potential).
FT TRANSMEM 167 187 Helical; (Potential).
FT TOPO_DOM 188 262 Cytoplasmic (Potential).
FT TRANSMEM 263 283 Helical; (Potential).
FT TOPO_DOM 284 298 Extracellular (Potential).
FT TRANSMEM 299 319 Helical; (Potential).
FT TOPO_DOM 320 328 Cytoplasmic (Potential).
FT TRANSMEM 329 349 Helical; (Potential).
FT TOPO_DOM 350 353 Extracellular (Potential).
FT TRANSMEM 354 374 Helical; (Potential).
FT TOPO_DOM 375 389 Cytoplasmic (Potential).
FT TRANSMEM 390 410 Helical; (Potential).
FT TOPO_DOM 411 422 Extracellular (Potential).
FT TRANSMEM 423 443 Helical; (Potential).
FT TOPO_DOM 444 500 Cytoplasmic (Potential).
FT MOD_RES 210 210 Phosphoserine (By similarity).
FT MOD_RES 213 213 Phosphoserine.
FT MOD_RES 231 231 Phosphothreonine (By similarity).
FT MOD_RES 461 461 Phosphoserine.
FT MOD_RES 466 466 Phosphothreonine.
FT MOD_RES 467 467 Phosphoserine.
FT MOD_RES 483 483 Phosphoserine.
FT MOD_RES 498 498 Phosphoserine.
FT VARIANT 85 85 S -> G (in dbSNP:rs11551867).
FT /FTId=VAR_054804.
FT VARIANT 204 204 K -> E (in SDLT).
FT /FTId=VAR_010434.
FT VARIANT 472 472 G -> R (in SDLT; dbSNP:rs72552271).
FT /FTId=VAR_010435.
FT VARIANT 490 490 D -> E (in dbSNP:rs1049434).
FT /FTId=VAR_010436.
FT CONFLICT 480 480 A -> T (in Ref. 1; AAC41707).
SQ SEQUENCE 500 AA; 53944 MW; 3F5B048CB962ECC8 CRC64;
MPPAVGGPVG YTPPDGGWGW AVVIGAFISI GFSYAFPKSI TVFFKEIEGI FHATTSEVSW
ISSIMLAVMY GGGPISSILV NKYGSRIVMI VGGCLSGCGL IAASFCNTVQ QLYVCIGVIG
GLGLAFNLNP ALTMIGKYFY KRRPLANGLA MAGSPVFLCT LAPLNQVFFG IFGWRGSFLI
LGGLLLNCCV AGALMRPIGP KPTKAGKDKS KASLEKAGKS GVKKDLHDAN TDLIGRHPKQ
EKRSVFQTIN QFLDLTLFTH RGFLLYLSGN VIMFFGLFAP LVFLSSYGKS QHYSSEKSAF
LLSILAFVDM VARPSMGLVA NTKPIRPRIQ YFFAASVVAN GVCHMLAPLS TTYVGFCVYA
GFFGFAFGWL SSVLFETLMD LVGPQRFSSA VGLVTIVECC PVLLGPPLLG RLNDMYGDYK
YTYWACGVVL IISGIYLFIG MGINYRLLAK EQKANEQKKE SKEEETSIDV AGKPNEVTKA
AESPDQKDTD GGPKEEESPV
//
ID MOT1_HUMAN Reviewed; 500 AA.
AC P53985; Q5T8R6; Q9NSJ9;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 30-NOV-2010, sequence version 3.
DT 22-JAN-2014, entry version 137.
DE RecName: Full=Monocarboxylate transporter 1;
DE Short=MCT 1;
DE AltName: Full=Solute carrier family 16 member 1;
GN Name=SLC16A1; Synonyms=MCT1;
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], AND VARIANT GLU-490.
RC TISSUE=Heart;
RX PubMed=7835905; DOI=10.1006/geno.1994.1532;
RA Garcia C.K., Li X., Luna J., Francke U.;
RT "cDNA cloning of the human monocarboxylate transporter 1 and
RT chromosomal localization of the SLC16A1 locus to 1p13.2-p12.";
RL Genomics 23:500-503(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Colon;
RX PubMed=11944921; DOI=10.1006/bbrc.2002.6763;
RA Cuff M.A., Shirazi-Beechey S.P.;
RT "The human monocarboxylate transporter, MCT1: genomic organization and
RT promoter analysis.";
RL Biochem. Biophys. Res. Commun. 292:1048-1056(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT GLU-490.
RC TISSUE=Melanoma;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-213 AND SER-498, VARIANT
RP [LARGE SCALE ANALYSIS] GLU-490, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-461 AND SER-498, VARIANT
RP [LARGE SCALE ANALYSIS] GLU-490, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-461; SER-467; SER-483
RP AND SER-498, VARIANT [LARGE SCALE ANALYSIS] GLU-490, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-461, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-213; SER-483 AND
RP SER-498, VARIANT [LARGE SCALE ANALYSIS] GLU-490, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-213; THR-466; SER-483
RP AND SER-498, VARIANT [LARGE SCALE ANALYSIS] GLU-490, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [14]
RP VARIANTS SDLT GLU-204 AND ARG-472, AND VARIANT GLU-490.
RX PubMed=10590411;
RX DOI=10.1002/(SICI)1097-4598(200001)23:1<90::AID-MUS12>3.0.CO;2-M;
RA Merezhinskaya N., Fishbein W.N., Davis J.I., Foellmer J.W.;
RT "Mutations in MCT1 cDNA in patients with symptomatic deficiency in
RT lactate transport.";
RL Muscle Nerve 23:90-97(2000).
RN [15]
RP INVOLVEMENT IN HHF7.
RX PubMed=17701893; DOI=10.1086/520960;
RA Otonkoski T., Jiao H., Kaminen-Ahola N., Tapia-Paez I., Ullah M.S.,
RA Parton L.E., Schuit F., Quintens R., Sipilae I., Mayatepek E.,
RA Meissner T., Halestrap A.P., Rutter G.A., Kere J.;
RT "Physical exercise-induced hypoglycemia caused by failed silencing of
RT monocarboxylate transporter 1 in pancreatic beta cells.";
RL Am. J. Hum. Genet. 81:467-474(2007).
RN [16]
RP VARIANT [LARGE SCALE ANALYSIS] GLU-490, AND MASS SPECTROMETRY.
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).
CC -!- FUNCTION: Proton-linked monocarboxylate transporter. Catalyzes the
CC rapid transport across the plasma membrane of many
CC monocarboxylates such as lactate, pyruvate, branched-chain oxo
CC acids derived from leucine, valine and isoleucine, and the ketone
CC bodies acetoacetate, beta-hydroxybutyrate and acetate.
CC -!- INTERACTION:
CC P61966:AP1S1; NbExp=1; IntAct=EBI-1054708, EBI-516199;
CC O15121:DEGS1; NbExp=1; IntAct=EBI-1054708, EBI-1052713;
CC Q13530:SERINC3; NbExp=1; IntAct=EBI-1054708, EBI-1045571;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.
CC -!- TISSUE SPECIFICITY: Widely expressed in normal and in cancer
CC cells.
CC -!- DISEASE: Symptomatic deficiency in lactate transport (SDLT)
CC [MIM:245340]: Deficiency of lactate transporter may result in an
CC acidic intracellular environment created by muscle activity with
CC consequent degeneration of muscle and release of myoglobin and
CC creatine kinase. This defect might compromise extreme performance
CC in otherwise healthy individuals. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Familial hyperinsulinemic hypoglycemia 7 (HHF7)
CC [MIM:610021]: Dominantly inherited hypoglycemic disorder
CC characterized by inappropriate insulin secretion during anaerobic
CC exercise or on pyruvate load. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the major facilitator superfamily.
CC Monocarboxylate porter (TC 2.A.1.13) family.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/SLC16A1ID44046ch1p13.html";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; L31801; AAC41707.1; -; mRNA.
DR EMBL; AJ438945; CAD27707.1; -; Genomic_DNA.
DR EMBL; AL162079; CAB82412.1; -; mRNA.
DR EMBL; AL158844; CAI21872.1; -; Genomic_DNA.
DR EMBL; CH471122; EAW56552.1; -; Genomic_DNA.
DR EMBL; BC026317; AAH26317.1; -; mRNA.
DR PIR; A55568; A55568.
DR RefSeq; NP_001159968.1; NM_001166496.1.
DR RefSeq; NP_003042.3; NM_003051.3.
DR RefSeq; XP_005271207.1; XM_005271150.1.
DR UniGene; Hs.75231; -.
DR ProteinModelPortal; P53985; -.
DR IntAct; P53985; 4.
DR MINT; MINT-5004345; -.
DR STRING; 9606.ENSP00000358640; -.
DR BindingDB; P53985; -.
DR ChEMBL; CHEMBL4360; -.
DR DrugBank; DB00119; Pyruvic acid.
DR TCDB; 2.A.1.13.1; the major facilitator superfamily (mfs).
DR PhosphoSite; P53985; -.
DR DMDM; 13432183; -.
DR PaxDb; P53985; -.
DR PRIDE; P53985; -.
DR DNASU; 6566; -.
DR Ensembl; ENST00000369626; ENSP00000358640; ENSG00000155380.
DR Ensembl; ENST00000538576; ENSP00000441065; ENSG00000155380.
DR GeneID; 6566; -.
DR KEGG; hsa:6566; -.
DR UCSC; uc001ecx.3; human.
DR CTD; 6566; -.
DR GeneCards; GC01M113454; -.
DR H-InvDB; HIX0000897; -.
DR HGNC; HGNC:10922; SLC16A1.
DR HPA; CAB017489; -.
DR HPA; HPA003324; -.
DR MIM; 245340; phenotype.
DR MIM; 600682; gene.
DR MIM; 610021; phenotype.
DR neXtProt; NX_P53985; -.
DR Orphanet; 165991; Exercise-induced hyperinsulinism.
DR Orphanet; 171690; Metabolic myopathy due to lactate transporter defect.
DR PharmGKB; PA35813; -.
DR eggNOG; NOG314865; -.
DR HOGENOM; HOG000280688; -.
DR HOVERGEN; HBG006384; -.
DR InParanoid; P53985; -.
DR KO; K08179; -.
DR OMA; QYFFAIS; -.
DR OrthoDB; EOG7W9RTN; -.
DR PhylomeDB; P53985; -.
DR BioCyc; MetaCyc:ENSG00000155380-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR Reactome; REACT_20633; Bile salt and organic anion SLC transporters.
DR Reactome; REACT_604; Hemostasis.
DR SABIO-RK; P53985; -.
DR ChiTaRS; SLC16A1; human.
DR GenomeRNAi; 6566; -.
DR NextBio; 25547; -.
DR PMAP-CutDB; P53985; -.
DR PRO; PR:P53985; -.
DR ArrayExpress; P53985; -.
DR Bgee; P53985; -.
DR CleanEx; HS_SLC16A1; -.
DR Genevestigator; P53985; -.
DR GO; GO:0016021; C:integral to membrane; TAS:ProtInc.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0015130; F:mevalonate transmembrane transporter activity; TAS:ProtInc.
DR GO; GO:0015355; F:secondary active monocarboxylate transmembrane transporter activity; IEA:InterPro.
DR GO; GO:0015293; F:symporter activity; IEA:UniProtKB-KW.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome.
DR GO; GO:0006090; P:pyruvate metabolic process; TAS:Reactome.
DR InterPro; IPR011701; MFS.
DR InterPro; IPR020846; MFS_dom.
DR InterPro; IPR016196; MFS_dom_general_subst_transpt.
DR InterPro; IPR004743; Monocarb_transpt.
DR Pfam; PF07690; MFS_1; 1.
DR SUPFAM; SSF103473; SSF103473; 2.
DR TIGRFAMs; TIGR00892; 2A0113; 1.
DR PROSITE; PS50850; MFS; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Complete proteome; Disease mutation; Membrane;
KW Phosphoprotein; Polymorphism; Reference proteome; Symport;
KW Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1 500 Monocarboxylate transporter 1.
FT /FTId=PRO_0000211381.
FT TOPO_DOM 1 15 Cytoplasmic (Potential).
FT TRANSMEM 16 36 Helical; (Potential).
FT TOPO_DOM 37 59 Extracellular (Potential).
FT TRANSMEM 60 80 Helical; (Potential).
FT TOPO_DOM 81 86 Cytoplasmic (Potential).
FT TRANSMEM 87 107 Helical; (Potential).
FT TOPO_DOM 108 111 Extracellular (Potential).
FT TRANSMEM 112 132 Helical; (Potential).
FT TOPO_DOM 133 143 Cytoplasmic (Potential).
FT TRANSMEM 144 164 Helical; (Potential).
FT TOPO_DOM 165 166 Extracellular (Potential).
FT TRANSMEM 167 187 Helical; (Potential).
FT TOPO_DOM 188 262 Cytoplasmic (Potential).
FT TRANSMEM 263 283 Helical; (Potential).
FT TOPO_DOM 284 298 Extracellular (Potential).
FT TRANSMEM 299 319 Helical; (Potential).
FT TOPO_DOM 320 328 Cytoplasmic (Potential).
FT TRANSMEM 329 349 Helical; (Potential).
FT TOPO_DOM 350 353 Extracellular (Potential).
FT TRANSMEM 354 374 Helical; (Potential).
FT TOPO_DOM 375 389 Cytoplasmic (Potential).
FT TRANSMEM 390 410 Helical; (Potential).
FT TOPO_DOM 411 422 Extracellular (Potential).
FT TRANSMEM 423 443 Helical; (Potential).
FT TOPO_DOM 444 500 Cytoplasmic (Potential).
FT MOD_RES 210 210 Phosphoserine (By similarity).
FT MOD_RES 213 213 Phosphoserine.
FT MOD_RES 231 231 Phosphothreonine (By similarity).
FT MOD_RES 461 461 Phosphoserine.
FT MOD_RES 466 466 Phosphothreonine.
FT MOD_RES 467 467 Phosphoserine.
FT MOD_RES 483 483 Phosphoserine.
FT MOD_RES 498 498 Phosphoserine.
FT VARIANT 85 85 S -> G (in dbSNP:rs11551867).
FT /FTId=VAR_054804.
FT VARIANT 204 204 K -> E (in SDLT).
FT /FTId=VAR_010434.
FT VARIANT 472 472 G -> R (in SDLT; dbSNP:rs72552271).
FT /FTId=VAR_010435.
FT VARIANT 490 490 D -> E (in dbSNP:rs1049434).
FT /FTId=VAR_010436.
FT CONFLICT 480 480 A -> T (in Ref. 1; AAC41707).
SQ SEQUENCE 500 AA; 53944 MW; 3F5B048CB962ECC8 CRC64;
MPPAVGGPVG YTPPDGGWGW AVVIGAFISI GFSYAFPKSI TVFFKEIEGI FHATTSEVSW
ISSIMLAVMY GGGPISSILV NKYGSRIVMI VGGCLSGCGL IAASFCNTVQ QLYVCIGVIG
GLGLAFNLNP ALTMIGKYFY KRRPLANGLA MAGSPVFLCT LAPLNQVFFG IFGWRGSFLI
LGGLLLNCCV AGALMRPIGP KPTKAGKDKS KASLEKAGKS GVKKDLHDAN TDLIGRHPKQ
EKRSVFQTIN QFLDLTLFTH RGFLLYLSGN VIMFFGLFAP LVFLSSYGKS QHYSSEKSAF
LLSILAFVDM VARPSMGLVA NTKPIRPRIQ YFFAASVVAN GVCHMLAPLS TTYVGFCVYA
GFFGFAFGWL SSVLFETLMD LVGPQRFSSA VGLVTIVECC PVLLGPPLLG RLNDMYGDYK
YTYWACGVVL IISGIYLFIG MGINYRLLAK EQKANEQKKE SKEEETSIDV AGKPNEVTKA
AESPDQKDTD GGPKEEESPV
//
MIM
245340
*RECORD*
*FIELD* NO
245340
*FIELD* TI
#245340 ERYTHROCYTE LACTATE TRANSPORTER DEFECT
;;LACTATE TRANSPORTER DEFECT, MYOPATHY DUE TO
read more*FIELD* TX
A number sign (#) is used with this entry because erythrocyte lactate
transporter defect is caused by mutation in the SLC16A1 gene (600682).
CLINICAL FEATURES
Fishbein (1986) described the case of a 26-year-old military drill
instructor in 'superb physical condition' who had experienced 3 brief
episodes of severe, diffuse anterior chest pain after exercise during
the previous 5 years. The chest pain was at first considered cardiac in
origin; after further studies, it was attributed to the metabolic
myopathy of chest wall musculature. Using a clinical assay for the human
erythrocyte lactate transporter and an ischemic exercise test suitable
for evaluating muscle lactate transport, Fishbein (1986) demonstrated a
deficiency of lactate transporter in both striated muscles and red blood
cells from the patient. As a result, an acidic intracellular environment
was created by muscle activity with consequent degeneration of muscle
and release of myoglobin and creatine kinase. Fishbein (1986) noted that
there are a number of enzymes which, although not essential for muscular
activity, are important perquisites for maximal performance. One of
these is myoadenylate deaminase (AMPD1; 102770). Fishbein (1986)
referred to these enzymes as 'perquisitory' catalysts and suggested that
defects in such catalysts may be expected to produce 'diseases of
healthy people.' Most patients whose major complaint is of muscle pain
or weakness are never identified with a specific disease or pathologic
diagnosis.
Fishbein et al. (1988) developed a physiologic assay for the human
erythrocyte lactate transporter. With this test, the authors identified
8 males, aged 14 to 56 years, in good general health but with elevated
serum creatine kinase levels and evidence of lactate transporter defect.
Two patients had episodes of rhabdomyolysis and myoglobinuria after
exercise, 3 had bouts of muscle cramping on exercise, 2 had such bouts
as well as progressive muscle stiffness over 5 to 7 years, and 1 had
minimal symptoms. The deficiency of enzyme was partial (50-75% loss) in
all cases. Fishbein (1989) suggested that such defects may be a common
cause of metabolic myopathy, fitness-failure, and postexertional
rhabdomyolysis.
Merezhinskaya et al. (2000) reported 5 unrelated males with subnormal
erythrocyte lactate transport and symptoms and signs of muscle injury on
exercise and heat exposure. One of the patients had previously been
reported by Fishbein (1986). Clinical features included muscle cramping
or stiffness, increased serum creatine kinase, normal EMG, and normal
muscle biopsies. One patient demonstrated delayed lactate decline in
exercised muscle.
MOLECULAR GENETICS
In a patient with erythrocyte lactate transporter defect originally
reported by Fishbein (1986), Merezhinskaya et al. (2000) identified a
heterozygous mutation in the SLC16A1 gene (600682.0001). Two additional
patients were found to be heterozygous for another SLC16A1 mutation
(600682.0002). All 3 patients had erythrocyte lactate clearance rates
that were 40 to 50% of normal control values. The authors suggested that
homozygous individuals would be more severely compromised.
*FIELD* SA
Fishbein et al. (1988)
*FIELD* RF
1. Fishbein, W. N.: Metabolic myopathy due to lactate transporter
defect. (Abstract) Neurology 39: 258 only, 1989.
2. Fishbein, W. N.: Lactate transporter defect: a new disease of
muscle. Science 234: 1254-1256, 1986.
3. Fishbein, W. N.; Davis, J. I.; Foellmer, J. W.; Casey, M. R.:
Clinical assay of the human erythrocyte lactate transporter. II. Analysis
and display of normal human data. Biochem. Med. Metab. Biol. 39:
351-359, 1988.
4. Fishbein, W. N.; Foellmer, J. W.; Davis, J. I.; Fishbein, T. M.;
Armbrustmacher, P.: Clinical assay of the human erythrocyte lactate
transporter. I. Principles, procedure, and validation. Biochem. Med.
Metab. Biol. 39: 338-350, 1988.
5. Merezhinskaya, N.; Fishbein, W. N.; Davis, J. I.; Foellmer, J.
W.: Mutations in MCT1 cDNA in patients with symptomatic deficiency
in lactate transport. Muscle Nerve 23: 90-97, 2000.
*FIELD* CS
INHERITANCE:
Autosomal dominant
MUSCLE, SOFT TISSUE:
Exercise-induced muscle cramping;
Exercise-induced muscle stiffness;
Exercise-induced muscle fatigue;
Symptoms may be induced by heat;
Decreased lactate clearance from muscle after exercise (reported in
1 patient);
Normal muscle biopsy;
Normal EMG
LABORATORY ABNORMALITIES:
Increased serum creatine kinase;
Decreased erythrocyte lactate clearance (transport), 40 to 50% of
normal values
MISCELLANEOUS:
Mild phenotype;
Mildly progressive;
Symptoms are not apparent at rest
MOLECULAR BASIS:
Caused by mutations in the solute carrier family 16, monocarboxylic
acid transporter, member 1 gene (SLC16A1, 600682.0001).
*FIELD* CN
Cassandra L. Kniffin - revised: 5/1/2006
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 06/06/2006
ckniffin: 5/1/2006
*FIELD* CN
Cassandra L. Kniffin - updated: 5/1/2006
*FIELD* CD
Victor A. McKusick: 12/17/1986
*FIELD* ED
carol: 05/03/2006
ckniffin: 5/1/2006
warfield: 4/15/1994
mimadm: 2/19/1994
supermim: 3/16/1992
carol: 7/6/1990
supermim: 3/20/1990
supermim: 1/13/1990
*RECORD*
*FIELD* NO
245340
*FIELD* TI
#245340 ERYTHROCYTE LACTATE TRANSPORTER DEFECT
;;LACTATE TRANSPORTER DEFECT, MYOPATHY DUE TO
read more*FIELD* TX
A number sign (#) is used with this entry because erythrocyte lactate
transporter defect is caused by mutation in the SLC16A1 gene (600682).
CLINICAL FEATURES
Fishbein (1986) described the case of a 26-year-old military drill
instructor in 'superb physical condition' who had experienced 3 brief
episodes of severe, diffuse anterior chest pain after exercise during
the previous 5 years. The chest pain was at first considered cardiac in
origin; after further studies, it was attributed to the metabolic
myopathy of chest wall musculature. Using a clinical assay for the human
erythrocyte lactate transporter and an ischemic exercise test suitable
for evaluating muscle lactate transport, Fishbein (1986) demonstrated a
deficiency of lactate transporter in both striated muscles and red blood
cells from the patient. As a result, an acidic intracellular environment
was created by muscle activity with consequent degeneration of muscle
and release of myoglobin and creatine kinase. Fishbein (1986) noted that
there are a number of enzymes which, although not essential for muscular
activity, are important perquisites for maximal performance. One of
these is myoadenylate deaminase (AMPD1; 102770). Fishbein (1986)
referred to these enzymes as 'perquisitory' catalysts and suggested that
defects in such catalysts may be expected to produce 'diseases of
healthy people.' Most patients whose major complaint is of muscle pain
or weakness are never identified with a specific disease or pathologic
diagnosis.
Fishbein et al. (1988) developed a physiologic assay for the human
erythrocyte lactate transporter. With this test, the authors identified
8 males, aged 14 to 56 years, in good general health but with elevated
serum creatine kinase levels and evidence of lactate transporter defect.
Two patients had episodes of rhabdomyolysis and myoglobinuria after
exercise, 3 had bouts of muscle cramping on exercise, 2 had such bouts
as well as progressive muscle stiffness over 5 to 7 years, and 1 had
minimal symptoms. The deficiency of enzyme was partial (50-75% loss) in
all cases. Fishbein (1989) suggested that such defects may be a common
cause of metabolic myopathy, fitness-failure, and postexertional
rhabdomyolysis.
Merezhinskaya et al. (2000) reported 5 unrelated males with subnormal
erythrocyte lactate transport and symptoms and signs of muscle injury on
exercise and heat exposure. One of the patients had previously been
reported by Fishbein (1986). Clinical features included muscle cramping
or stiffness, increased serum creatine kinase, normal EMG, and normal
muscle biopsies. One patient demonstrated delayed lactate decline in
exercised muscle.
MOLECULAR GENETICS
In a patient with erythrocyte lactate transporter defect originally
reported by Fishbein (1986), Merezhinskaya et al. (2000) identified a
heterozygous mutation in the SLC16A1 gene (600682.0001). Two additional
patients were found to be heterozygous for another SLC16A1 mutation
(600682.0002). All 3 patients had erythrocyte lactate clearance rates
that were 40 to 50% of normal control values. The authors suggested that
homozygous individuals would be more severely compromised.
*FIELD* SA
Fishbein et al. (1988)
*FIELD* RF
1. Fishbein, W. N.: Metabolic myopathy due to lactate transporter
defect. (Abstract) Neurology 39: 258 only, 1989.
2. Fishbein, W. N.: Lactate transporter defect: a new disease of
muscle. Science 234: 1254-1256, 1986.
3. Fishbein, W. N.; Davis, J. I.; Foellmer, J. W.; Casey, M. R.:
Clinical assay of the human erythrocyte lactate transporter. II. Analysis
and display of normal human data. Biochem. Med. Metab. Biol. 39:
351-359, 1988.
4. Fishbein, W. N.; Foellmer, J. W.; Davis, J. I.; Fishbein, T. M.;
Armbrustmacher, P.: Clinical assay of the human erythrocyte lactate
transporter. I. Principles, procedure, and validation. Biochem. Med.
Metab. Biol. 39: 338-350, 1988.
5. Merezhinskaya, N.; Fishbein, W. N.; Davis, J. I.; Foellmer, J.
W.: Mutations in MCT1 cDNA in patients with symptomatic deficiency
in lactate transport. Muscle Nerve 23: 90-97, 2000.
*FIELD* CS
INHERITANCE:
Autosomal dominant
MUSCLE, SOFT TISSUE:
Exercise-induced muscle cramping;
Exercise-induced muscle stiffness;
Exercise-induced muscle fatigue;
Symptoms may be induced by heat;
Decreased lactate clearance from muscle after exercise (reported in
1 patient);
Normal muscle biopsy;
Normal EMG
LABORATORY ABNORMALITIES:
Increased serum creatine kinase;
Decreased erythrocyte lactate clearance (transport), 40 to 50% of
normal values
MISCELLANEOUS:
Mild phenotype;
Mildly progressive;
Symptoms are not apparent at rest
MOLECULAR BASIS:
Caused by mutations in the solute carrier family 16, monocarboxylic
acid transporter, member 1 gene (SLC16A1, 600682.0001).
*FIELD* CN
Cassandra L. Kniffin - revised: 5/1/2006
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 06/06/2006
ckniffin: 5/1/2006
*FIELD* CN
Cassandra L. Kniffin - updated: 5/1/2006
*FIELD* CD
Victor A. McKusick: 12/17/1986
*FIELD* ED
carol: 05/03/2006
ckniffin: 5/1/2006
warfield: 4/15/1994
mimadm: 2/19/1994
supermim: 3/16/1992
carol: 7/6/1990
supermim: 3/20/1990
supermim: 1/13/1990
MIM
600682
*RECORD*
*FIELD* NO
600682
*FIELD* TI
*600682 SOLUTE CARRIER FAMILY 16 (MONOCARBOXYLIC ACID TRANSPORTER), MEMBER
1; SLC16A1
read more;;MONOCARBOXYLATE TRANSPORTER 1; MCT1
*FIELD* TX
DESCRIPTION
The SLC16A1 gene encodes a monocarboxylate transporter (MCT1) that
mediates the movement of lactate and pyruvate across cell membranes
Import and export of these substrates by tissues such as erythrocytes,
muscle, intestine, and kidney are ascribed largely to the action of a
proton-coupled MCT (Garcia et al., 1994).
CLONING
In a Chinese hamster ovary (CHO) cell line, Kim et al. (1992) identified
a mutant protein, designated Mev, that acted as a mevalonate
transporter. The corresponding cDNA was isolated by an expression
cloning strategy and found to encode a protein with 12 putative
membrane-spanning regions. The cloned mutant 'mevalonate transporter'
differed from its wildtype progenitor by 1 amino acid in the tenth
membrane-spanning region, which changed a phenylalanine (wildtype) to a
cysteine (mutant). The mutant cells were heterozygous for this dominant
gain-of-function mutation. The finding that the wildtype cDNA did not
elicit increased mevalonate transport in transfected cells suggested
that the wildtype protein is a transporter for a molecule other than
mevalonate (i.e., lactate). The mRNA transcribed from the wildtype gene
was expressed in highest levels in heart. Subsequent studies by Garcia
et al. (1994) showed that the wildtype protein, which they designated
MCT1, could transport lactate, pyruvate, and related monocarboxylates.
MCT1 exhibited properties resembling those of the erythrocyte MCT,
including proton symport, transacceleration, and sensitivity to
alpha-cyanocinnamates. The amino acid sequence of MCT1 did not resemble
that of any known protein, suggesting that MCT1 may represent a new
class of solute carriers (solute carrier family 16).
Garcia et al. (1994) isolated cDNA clones corresponding to human MCT1
from a heart cDNA library. The deduced 500-residue protein showed 86%
identity to the hamster protein.
Using primers derived from the human heart MCT1 cDNA isolated by Garcia
et al. (1994), Ritzhaupt et al. (1998) cloned MCT1 from human colon
mRNA. The heart and colon MCT1 cDNAs are identical. Northern blot
analysis detected a 3.3-kb transcript in ileal and colonic RNA. Western
blot analysis detected MCT1 at an apparent molecular mass of 40 kD in
colonic luminal membrane vesicles.
GENE STRUCTURE
Cuff and Shirazi-Beechey (2002) determined that the SLC16A1 gene
contains 5 exons and spans about 44 kb. The first exon is noncoding, and
the first intron is more than 26 kb long. The promoter region lacks a
TATA box, but it contains potential binding sites for several
transcription factors.
MAPPING
Garcia et al. (1994) mapped the SLC16A1 gene to chromosome 1p13.2-p12 by
PCR analysis of panels of human/rodent cell hybrid lines and by
fluorescence in situ hybridization.
GENE FUNCTION
Using radiolabeled lactate, Ritzhaupt et al. (1998) examined the
properties of the L-lactate transporter in human and pig colonic luminal
membrane vesicles. L-lactate uptake was stimulated in the presence of an
outward-directed anion gradient at an extravesicular pH of 5.5.
Transport of L-lactate into anion-loaded colonic membrane vesicles
appeared to be via a proton-activated, anion exchange mechanism.
L-lactate uptake was competitively inhibited by pyruvate, butyrate,
propionate, and acetate, but not by Cl- or SO4(2-), and it was
pharmacologically inhibited by several mercurial compounds. Based on
these findings, Ritzhaupt et al. (1998) concluded that MCT1 is the
protein responsible for L-lactate transport into colonic luminal
membrane vesicles.
Lee et al. (2012) showed that the most abundant lactate transporter in
the central nervous system, MCT1 (also known as SLC16A1), is highly
enriched within oligodendroglia and that disruption of this transporter
produces axon damage and neuron loss in animal and cell culture models.
In addition, this same transporter is reduced in patients with, and in
mouse models of, amyotrophic lateral sclerosis (ALS; see 105400),
suggesting a role for oligodendroglial MCT1 in pathogenesis. Lee et al.
(2012) concluded that the role of oligodendroglia in axon function and
neuron survival has been elusive; this study defines a new fundamental
mechanism by which oligodendroglia support neurons and axons.
In a genomewide haploid genetics screen to identify resistance
mechanisms to 3-bromopyruvate (3-BrPA), a cancer drug candidate that
inhibits glycolysis, Birsoy et al. (2013) identified the SLC16A1 gene
product, MCT1, as the main determinant of 3-BrPA sensitivity. MCT1 is
necessary and sufficient for 3-BrPA uptake by cancer cells. Breast
cancer cell lines with high amounts of MCT1 protein were sensitive to
3-BrPA, whereas those with low or no MCT1 concentration were resistant
to even high concentrations of 3-BrPA. SLC16A1 mRNA levels were most
elevated in glycolytic cancer cells. Forced MCT1 expression in
3-BrPA-resistant cancer cells sensitized tumor xenografts to 3-BrPA
treatment in vivo.
MOLECULAR GENETICS
- Erythrocyte Lactate Transporter Defect
In a patient with erythrocyte lactate transporter defect (245340)
originally reported by Fishbein (1986), Merezhinskaya et al. (2000)
identified a heterozygous mutation in the SLC16A1 gene (600682.0001).
Two additional patients were found to be heterozygous for another
SLC16A1 mutation (600682.0002). All 3 patients had erythrocyte lactate
clearance rates that were 40 to 50% of normal control values. The
authors suggested that homozygous individuals would be more severely
compromised.
- Hyperinsulinemic Hypoglycemia 7
In affected members of 2 Finnish families, previously examined by
Otonkoski et al. (2003) and segregating autosomal dominant
exercise-induced hyperinsulinemic hypoglycemia (610021) mapping to
chromosome 1p, Otonkoski et al. (2007) identified a 163G-A transition
(600682.0003) in the noncoding exon 1 and a 25-bp duplication
(600682.0004), in the promoter region of the SLC16A1 gene, respectively.
In a German proband previously reported by Meissner et al. (2001), they
identified several sequence variants, including a 2-bp insertion. All 3
mutations were located within the binding sites of several transcription
factors; patient fibroblasts displayed abnormally high SLC16A1
transcript levels, although monocarboxylate transport activities were
not changed in those cells, reflecting additional posttranscriptional
control of MCT1 levels in extrapancreatic tissues. In contrast,
functional studies in beta cells demonstrated that these mutations
resulted in increased protein binding to the corresponding promoter
elements and a marked (3- to 10-fold) increase in transcription. Thus,
promoter-activating mutations in patients with hyperinsulinemic
hypoglycemia induce SLC16A1 expression in beta cells, where this gene is
not usually transcribed, permitting pyruvate uptake and
pyruvate-stimulated insulin release despite ensuing hypoglycemia.
Otonkoski et al. (2007) stated that this represented a novel disease
mechanism based on the failure of cell-specific transcriptional
silencing of a gene that is highly expressed in other tissues.
Quintens et al. (2008) noted that repression of certain ubiquitously
expressed housekeeping genes is necessary in pancreatic beta cells, in
order to prevent the insulin toxicity that might result from exocytosis
under conditions when circulating insulin is unwanted, citing low-K(m)
hexokinases (see HK1, 142600) and monocarboxylic acid transporters
(MCTs) as examples. The absence of MCTs in beta cells explains the
so-called 'pyruvate paradox' whereby pyruvate, despite being an
excellent substrate for mitochondrial ATP production, does not stimulate
insulin release when added to beta cells. The importance of this
disallowance is exemplified by patients who have gain-of-function MCT1
promoter mutations and loss of the pyruvate paradox, with resultant
exercise-induced inappropriate insulin release.
*FIELD* AV
.0001
ERYTHROCYTE LACTATE TRANSPORTER DEFECT
SLC16A1, LYS204GLU
In a patient with erythrocyte lactate transporter defect (245340)
originally reported by Fishbein (1986), Merezhinskaya et al. (2000)
identified a heterozygous 610A-G transition in the SLC16A1 gene,
resulting in a lys204-to-glu (K204E) substitution in a highly conserved
residue. The substitution occurs in the early part of the large central
cytoplasmic loop between transmembrane segments 6 and 7. The
substitution was not identified in 90 healthy control individuals.
Erythrocyte lactate clearance was 40 to 50% that of normal control
values.
.0002
ERYTHROCYTE LACTATE TRANSPORTER DEFECT
SLC16A1, GLY472ARG
In 2 unrelated male patients with erythrocyte lactate transporter defect
(245340), Merezhinskaya et al. (2000) identified a heterozygous 1414G-A
transition in the SLC16A1 gene, resulting in a gly472-to-arg (G472R)
substitution halfway along the cytoplasmic C-terminal chain. The
substitution is not conserved, but was not identified in 90 healthy
control individuals. Erythrocyte lactate clearance was 40 to 50% that of
normal control values.
.0003
HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 7
SLC16A1, 163G-A, 5-PRIME UTR
In affected members of a Finnish family segregating autosomal dominant
exercise-induced hyperinsulinemic hypoglycemia (610021), including the
female patient originally reported by Meissner et al. (2001), Otonkoski
et al. (2007) identified heterozygosity for a 163G-A transition in exon
1 of the SLC16A1 gene, located within a binding site for nuclear matrix
protein-1 (RAD21; 606462) and predicted to disrupt the binding sites of
2 potential transcriptional repressors. The mutation was not found in 92
Finnish and German controls. Functional studies in beta cells
demonstrated increased protein binding to the corresponding promoter
elements, resulting in a 3-fold increase in transcription.
.0004
HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 7
SLC16A1, 25-BP INS, NT-24
In affected members of a Finnish family segregating autosomal dominant
exercise-induced hyperinsulinemic hypoglycemia (610021), Otonkoski et
al. (2007) identified heterozygosity for a 25-bp insertion at nucleotide
-24 of the SLC16A1 gene, introducing additional binding sites for the
ubiquitous transcription factors SP1 (189906), USF (see 191523), and
MXF1 (194550). The mutation was not found in 92 Finnish and German
controls. Functional studies in beta cells demonstrated increased
protein binding to the corresponding promoter elements, resulting in a
10-fold increase in transcription.
*FIELD* RF
1. Birsoy, K.; Wang, T.; Possemato, R.; Yilmaz, O. H.; Koch, C. E.;
Chen, W. W.; Hutchins, A. W.; Gultekin, Y.; Peterson, T. R.; Carette,
J. E.; Brummelkamp, T. R.; Clish, C. B.; Sabatini, D. M.: MCT1-mediated
transport of a toxic molecule is an effective strategy for targeting
glycolytic tumors. Nature Genet. 45: 104-108, 2013.
2. Cuff, M. A.; Shirazi-Beechey, S. P.: The human monocarboxylate
transporter, MCT1: genomic organization and promoter analysis. Biochem.
Biophys. Res. Commun. 292: 1048-1056, 2002.
3. Fishbein, W. N.: Lactate transporter defect: a new disease of
muscle. Science 234: 1254-1256, 1986.
4. Garcia, C. K.; Goldstein, J. L.; Pathak, R. K.; Anderson, R. G.
W.; Brown, M. S.: Molecular characterization of a membrane transporter
for lactate, pyruvate, and other monocarboxylates: implications for
the Cori cycle. Cell 76: 865-873, 1994.
5. Garcia, C. K.; Li, X.; Luna, J.; Francke, U.: cDNA cloning of
the human monocarboxylate transporter 1 and chromosomal localization
of the SLC16A1 locus to 1p13.2-p12. Genomics 23: 500-503, 1994.
6. Kim, C. M.; Goldstein, J. L.; Brown, M. S.: cDNA cloning of mev,
a mutant protein that facilitates cellular uptake of mevalonate, and
identification of the point mutation responsible for its gain of function. J.
Biol. Chem. 267: 23113-23121, 1992.
7. Lee, Y.; Morrison, B. M.; Li, Y.; Lengacher, S.; Farah, M. H.;
Hoffman, P. N.; Liu, Y.; Tsingalia, A.; Jin, L.; Zhang, P.-W.; Pellerin,
L.; Magistretti, P. J.; Rothstein, J. D.: Oligodendroglia metabolically
support axons and contribute to neurodegeneration. Nature 487: 443-448,
2012.
8. Meissner, T.; Otonkoski, T.; Feneberg, R.; Beinbrech, B.; Apostolidou,
S.; Sipila, I.; Schaefer, F.; Mayatepek, E.: Exercise induced hypoglycaemic
hyperinsulinism. Arch. Dis. Child. 84: 254-257, 2001.
9. Merezhinskaya, N.; Fishbein, W. N.; Davis, J. I.; Foellmer, J.
W.: Mutations in MCT1 cDNA in patients with symptomatic deficiency
in lactate transport. Muscle Nerve 23: 90-97, 2000.
10. Otonkoski, T.; Jiao, H.; Kaminen-Ahola, N.; Tapia-Paez, I.; Ullah,
M. S.; Parton, L. E.; Schuit, F.; Quintens, R.; Sipila, I.; Mayatepek,
E.; Meissner, T.; Halestrap, A. P.; Rutter, G. A.; Kere, J.: Physical
exercise-induced hypoglycemia caused by failed silencing of monocarboxylate
transporter 1 in pancreatic beta cells. Am. J. Hum. Genet. 81: 467-474,
2007.
11. Otonkoski, T.; Kaminen, N.; Ustinov, J.; Lapatto, R.; Meissner,
T.; Mayatepek, E.; Kere, J.; Sipila, I.: Physical exercise-induced
hyperinsulinemic hypoglycemia is an autosomal-dominant trait characterized
by abnormal pyruvate-induced insulin release. Diabetes 52: 199-204,
2003.
12. Quintens, R.; Hendrickx, N.; Lemaire, K.; Schuit, F.: Why expression
of some genes is disallowed in beta-cells. Biochem. Soc. Trans. 36:
300-305, 2008.
13. Ritzhaupt, A.; Wood, I. S.; Ellis, A.; Hosie, K. B.; Shirazi-Beechey,
S. P.: Identification and characterization of a monocarboxylate transporter
(MCI1) in pig and human colon: its potential to transport L-lactate
as well as butyrate. J. Physiol. 513: 719-732, 1998.
*FIELD* CN
Ada Hamosh - updated: 04/11/2013
Ada Hamosh - updated: 9/18/2012
Marla J. F. O'Neill - updated: 11/6/2008
Patricia A. Hartz - updated: 5/5/2006
Cassandra L. Kniffin - updated: 5/1/2006
*FIELD* CD
Victor A. McKusick: 8/9/1995
*FIELD* ED
alopez: 04/11/2013
alopez: 9/19/2012
terry: 9/18/2012
carol: 7/22/2010
wwang: 11/13/2008
terry: 11/6/2008
mgross: 6/6/2006
terry: 5/5/2006
carol: 5/3/2006
ckniffin: 5/1/2006
mgross: 2/6/2003
alopez: 3/16/1999
mark: 8/18/1995
terry: 8/9/1995
*RECORD*
*FIELD* NO
600682
*FIELD* TI
*600682 SOLUTE CARRIER FAMILY 16 (MONOCARBOXYLIC ACID TRANSPORTER), MEMBER
1; SLC16A1
read more;;MONOCARBOXYLATE TRANSPORTER 1; MCT1
*FIELD* TX
DESCRIPTION
The SLC16A1 gene encodes a monocarboxylate transporter (MCT1) that
mediates the movement of lactate and pyruvate across cell membranes
Import and export of these substrates by tissues such as erythrocytes,
muscle, intestine, and kidney are ascribed largely to the action of a
proton-coupled MCT (Garcia et al., 1994).
CLONING
In a Chinese hamster ovary (CHO) cell line, Kim et al. (1992) identified
a mutant protein, designated Mev, that acted as a mevalonate
transporter. The corresponding cDNA was isolated by an expression
cloning strategy and found to encode a protein with 12 putative
membrane-spanning regions. The cloned mutant 'mevalonate transporter'
differed from its wildtype progenitor by 1 amino acid in the tenth
membrane-spanning region, which changed a phenylalanine (wildtype) to a
cysteine (mutant). The mutant cells were heterozygous for this dominant
gain-of-function mutation. The finding that the wildtype cDNA did not
elicit increased mevalonate transport in transfected cells suggested
that the wildtype protein is a transporter for a molecule other than
mevalonate (i.e., lactate). The mRNA transcribed from the wildtype gene
was expressed in highest levels in heart. Subsequent studies by Garcia
et al. (1994) showed that the wildtype protein, which they designated
MCT1, could transport lactate, pyruvate, and related monocarboxylates.
MCT1 exhibited properties resembling those of the erythrocyte MCT,
including proton symport, transacceleration, and sensitivity to
alpha-cyanocinnamates. The amino acid sequence of MCT1 did not resemble
that of any known protein, suggesting that MCT1 may represent a new
class of solute carriers (solute carrier family 16).
Garcia et al. (1994) isolated cDNA clones corresponding to human MCT1
from a heart cDNA library. The deduced 500-residue protein showed 86%
identity to the hamster protein.
Using primers derived from the human heart MCT1 cDNA isolated by Garcia
et al. (1994), Ritzhaupt et al. (1998) cloned MCT1 from human colon
mRNA. The heart and colon MCT1 cDNAs are identical. Northern blot
analysis detected a 3.3-kb transcript in ileal and colonic RNA. Western
blot analysis detected MCT1 at an apparent molecular mass of 40 kD in
colonic luminal membrane vesicles.
GENE STRUCTURE
Cuff and Shirazi-Beechey (2002) determined that the SLC16A1 gene
contains 5 exons and spans about 44 kb. The first exon is noncoding, and
the first intron is more than 26 kb long. The promoter region lacks a
TATA box, but it contains potential binding sites for several
transcription factors.
MAPPING
Garcia et al. (1994) mapped the SLC16A1 gene to chromosome 1p13.2-p12 by
PCR analysis of panels of human/rodent cell hybrid lines and by
fluorescence in situ hybridization.
GENE FUNCTION
Using radiolabeled lactate, Ritzhaupt et al. (1998) examined the
properties of the L-lactate transporter in human and pig colonic luminal
membrane vesicles. L-lactate uptake was stimulated in the presence of an
outward-directed anion gradient at an extravesicular pH of 5.5.
Transport of L-lactate into anion-loaded colonic membrane vesicles
appeared to be via a proton-activated, anion exchange mechanism.
L-lactate uptake was competitively inhibited by pyruvate, butyrate,
propionate, and acetate, but not by Cl- or SO4(2-), and it was
pharmacologically inhibited by several mercurial compounds. Based on
these findings, Ritzhaupt et al. (1998) concluded that MCT1 is the
protein responsible for L-lactate transport into colonic luminal
membrane vesicles.
Lee et al. (2012) showed that the most abundant lactate transporter in
the central nervous system, MCT1 (also known as SLC16A1), is highly
enriched within oligodendroglia and that disruption of this transporter
produces axon damage and neuron loss in animal and cell culture models.
In addition, this same transporter is reduced in patients with, and in
mouse models of, amyotrophic lateral sclerosis (ALS; see 105400),
suggesting a role for oligodendroglial MCT1 in pathogenesis. Lee et al.
(2012) concluded that the role of oligodendroglia in axon function and
neuron survival has been elusive; this study defines a new fundamental
mechanism by which oligodendroglia support neurons and axons.
In a genomewide haploid genetics screen to identify resistance
mechanisms to 3-bromopyruvate (3-BrPA), a cancer drug candidate that
inhibits glycolysis, Birsoy et al. (2013) identified the SLC16A1 gene
product, MCT1, as the main determinant of 3-BrPA sensitivity. MCT1 is
necessary and sufficient for 3-BrPA uptake by cancer cells. Breast
cancer cell lines with high amounts of MCT1 protein were sensitive to
3-BrPA, whereas those with low or no MCT1 concentration were resistant
to even high concentrations of 3-BrPA. SLC16A1 mRNA levels were most
elevated in glycolytic cancer cells. Forced MCT1 expression in
3-BrPA-resistant cancer cells sensitized tumor xenografts to 3-BrPA
treatment in vivo.
MOLECULAR GENETICS
- Erythrocyte Lactate Transporter Defect
In a patient with erythrocyte lactate transporter defect (245340)
originally reported by Fishbein (1986), Merezhinskaya et al. (2000)
identified a heterozygous mutation in the SLC16A1 gene (600682.0001).
Two additional patients were found to be heterozygous for another
SLC16A1 mutation (600682.0002). All 3 patients had erythrocyte lactate
clearance rates that were 40 to 50% of normal control values. The
authors suggested that homozygous individuals would be more severely
compromised.
- Hyperinsulinemic Hypoglycemia 7
In affected members of 2 Finnish families, previously examined by
Otonkoski et al. (2003) and segregating autosomal dominant
exercise-induced hyperinsulinemic hypoglycemia (610021) mapping to
chromosome 1p, Otonkoski et al. (2007) identified a 163G-A transition
(600682.0003) in the noncoding exon 1 and a 25-bp duplication
(600682.0004), in the promoter region of the SLC16A1 gene, respectively.
In a German proband previously reported by Meissner et al. (2001), they
identified several sequence variants, including a 2-bp insertion. All 3
mutations were located within the binding sites of several transcription
factors; patient fibroblasts displayed abnormally high SLC16A1
transcript levels, although monocarboxylate transport activities were
not changed in those cells, reflecting additional posttranscriptional
control of MCT1 levels in extrapancreatic tissues. In contrast,
functional studies in beta cells demonstrated that these mutations
resulted in increased protein binding to the corresponding promoter
elements and a marked (3- to 10-fold) increase in transcription. Thus,
promoter-activating mutations in patients with hyperinsulinemic
hypoglycemia induce SLC16A1 expression in beta cells, where this gene is
not usually transcribed, permitting pyruvate uptake and
pyruvate-stimulated insulin release despite ensuing hypoglycemia.
Otonkoski et al. (2007) stated that this represented a novel disease
mechanism based on the failure of cell-specific transcriptional
silencing of a gene that is highly expressed in other tissues.
Quintens et al. (2008) noted that repression of certain ubiquitously
expressed housekeeping genes is necessary in pancreatic beta cells, in
order to prevent the insulin toxicity that might result from exocytosis
under conditions when circulating insulin is unwanted, citing low-K(m)
hexokinases (see HK1, 142600) and monocarboxylic acid transporters
(MCTs) as examples. The absence of MCTs in beta cells explains the
so-called 'pyruvate paradox' whereby pyruvate, despite being an
excellent substrate for mitochondrial ATP production, does not stimulate
insulin release when added to beta cells. The importance of this
disallowance is exemplified by patients who have gain-of-function MCT1
promoter mutations and loss of the pyruvate paradox, with resultant
exercise-induced inappropriate insulin release.
*FIELD* AV
.0001
ERYTHROCYTE LACTATE TRANSPORTER DEFECT
SLC16A1, LYS204GLU
In a patient with erythrocyte lactate transporter defect (245340)
originally reported by Fishbein (1986), Merezhinskaya et al. (2000)
identified a heterozygous 610A-G transition in the SLC16A1 gene,
resulting in a lys204-to-glu (K204E) substitution in a highly conserved
residue. The substitution occurs in the early part of the large central
cytoplasmic loop between transmembrane segments 6 and 7. The
substitution was not identified in 90 healthy control individuals.
Erythrocyte lactate clearance was 40 to 50% that of normal control
values.
.0002
ERYTHROCYTE LACTATE TRANSPORTER DEFECT
SLC16A1, GLY472ARG
In 2 unrelated male patients with erythrocyte lactate transporter defect
(245340), Merezhinskaya et al. (2000) identified a heterozygous 1414G-A
transition in the SLC16A1 gene, resulting in a gly472-to-arg (G472R)
substitution halfway along the cytoplasmic C-terminal chain. The
substitution is not conserved, but was not identified in 90 healthy
control individuals. Erythrocyte lactate clearance was 40 to 50% that of
normal control values.
.0003
HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 7
SLC16A1, 163G-A, 5-PRIME UTR
In affected members of a Finnish family segregating autosomal dominant
exercise-induced hyperinsulinemic hypoglycemia (610021), including the
female patient originally reported by Meissner et al. (2001), Otonkoski
et al. (2007) identified heterozygosity for a 163G-A transition in exon
1 of the SLC16A1 gene, located within a binding site for nuclear matrix
protein-1 (RAD21; 606462) and predicted to disrupt the binding sites of
2 potential transcriptional repressors. The mutation was not found in 92
Finnish and German controls. Functional studies in beta cells
demonstrated increased protein binding to the corresponding promoter
elements, resulting in a 3-fold increase in transcription.
.0004
HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 7
SLC16A1, 25-BP INS, NT-24
In affected members of a Finnish family segregating autosomal dominant
exercise-induced hyperinsulinemic hypoglycemia (610021), Otonkoski et
al. (2007) identified heterozygosity for a 25-bp insertion at nucleotide
-24 of the SLC16A1 gene, introducing additional binding sites for the
ubiquitous transcription factors SP1 (189906), USF (see 191523), and
MXF1 (194550). The mutation was not found in 92 Finnish and German
controls. Functional studies in beta cells demonstrated increased
protein binding to the corresponding promoter elements, resulting in a
10-fold increase in transcription.
*FIELD* RF
1. Birsoy, K.; Wang, T.; Possemato, R.; Yilmaz, O. H.; Koch, C. E.;
Chen, W. W.; Hutchins, A. W.; Gultekin, Y.; Peterson, T. R.; Carette,
J. E.; Brummelkamp, T. R.; Clish, C. B.; Sabatini, D. M.: MCT1-mediated
transport of a toxic molecule is an effective strategy for targeting
glycolytic tumors. Nature Genet. 45: 104-108, 2013.
2. Cuff, M. A.; Shirazi-Beechey, S. P.: The human monocarboxylate
transporter, MCT1: genomic organization and promoter analysis. Biochem.
Biophys. Res. Commun. 292: 1048-1056, 2002.
3. Fishbein, W. N.: Lactate transporter defect: a new disease of
muscle. Science 234: 1254-1256, 1986.
4. Garcia, C. K.; Goldstein, J. L.; Pathak, R. K.; Anderson, R. G.
W.; Brown, M. S.: Molecular characterization of a membrane transporter
for lactate, pyruvate, and other monocarboxylates: implications for
the Cori cycle. Cell 76: 865-873, 1994.
5. Garcia, C. K.; Li, X.; Luna, J.; Francke, U.: cDNA cloning of
the human monocarboxylate transporter 1 and chromosomal localization
of the SLC16A1 locus to 1p13.2-p12. Genomics 23: 500-503, 1994.
6. Kim, C. M.; Goldstein, J. L.; Brown, M. S.: cDNA cloning of mev,
a mutant protein that facilitates cellular uptake of mevalonate, and
identification of the point mutation responsible for its gain of function. J.
Biol. Chem. 267: 23113-23121, 1992.
7. Lee, Y.; Morrison, B. M.; Li, Y.; Lengacher, S.; Farah, M. H.;
Hoffman, P. N.; Liu, Y.; Tsingalia, A.; Jin, L.; Zhang, P.-W.; Pellerin,
L.; Magistretti, P. J.; Rothstein, J. D.: Oligodendroglia metabolically
support axons and contribute to neurodegeneration. Nature 487: 443-448,
2012.
8. Meissner, T.; Otonkoski, T.; Feneberg, R.; Beinbrech, B.; Apostolidou,
S.; Sipila, I.; Schaefer, F.; Mayatepek, E.: Exercise induced hypoglycaemic
hyperinsulinism. Arch. Dis. Child. 84: 254-257, 2001.
9. Merezhinskaya, N.; Fishbein, W. N.; Davis, J. I.; Foellmer, J.
W.: Mutations in MCT1 cDNA in patients with symptomatic deficiency
in lactate transport. Muscle Nerve 23: 90-97, 2000.
10. Otonkoski, T.; Jiao, H.; Kaminen-Ahola, N.; Tapia-Paez, I.; Ullah,
M. S.; Parton, L. E.; Schuit, F.; Quintens, R.; Sipila, I.; Mayatepek,
E.; Meissner, T.; Halestrap, A. P.; Rutter, G. A.; Kere, J.: Physical
exercise-induced hypoglycemia caused by failed silencing of monocarboxylate
transporter 1 in pancreatic beta cells. Am. J. Hum. Genet. 81: 467-474,
2007.
11. Otonkoski, T.; Kaminen, N.; Ustinov, J.; Lapatto, R.; Meissner,
T.; Mayatepek, E.; Kere, J.; Sipila, I.: Physical exercise-induced
hyperinsulinemic hypoglycemia is an autosomal-dominant trait characterized
by abnormal pyruvate-induced insulin release. Diabetes 52: 199-204,
2003.
12. Quintens, R.; Hendrickx, N.; Lemaire, K.; Schuit, F.: Why expression
of some genes is disallowed in beta-cells. Biochem. Soc. Trans. 36:
300-305, 2008.
13. Ritzhaupt, A.; Wood, I. S.; Ellis, A.; Hosie, K. B.; Shirazi-Beechey,
S. P.: Identification and characterization of a monocarboxylate transporter
(MCI1) in pig and human colon: its potential to transport L-lactate
as well as butyrate. J. Physiol. 513: 719-732, 1998.
*FIELD* CN
Ada Hamosh - updated: 04/11/2013
Ada Hamosh - updated: 9/18/2012
Marla J. F. O'Neill - updated: 11/6/2008
Patricia A. Hartz - updated: 5/5/2006
Cassandra L. Kniffin - updated: 5/1/2006
*FIELD* CD
Victor A. McKusick: 8/9/1995
*FIELD* ED
alopez: 04/11/2013
alopez: 9/19/2012
terry: 9/18/2012
carol: 7/22/2010
wwang: 11/13/2008
terry: 11/6/2008
mgross: 6/6/2006
terry: 5/5/2006
carol: 5/3/2006
ckniffin: 5/1/2006
mgross: 2/6/2003
alopez: 3/16/1999
mark: 8/18/1995
terry: 8/9/1995
MIM
610021
*RECORD*
*FIELD* NO
610021
*FIELD* TI
#610021 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 7; HHF7
;;HYPERINSULINEMIC HYPOGLYCEMIA, EXERCISE-INDUCED
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that this
form of hyperinsulinemic hypoglycemia is caused by mutation in the
SLC16A1 gene (600682).
For a phenotypic description and a discussion of genetic heterogeneity
of familial hyperinsulinemic hypoglycemia, see HHF1 (256450).
CLINICAL FEATURES
Burman et al. (1992) described a brother and sister who had recurrent
syncope due to severe hyperinsulinemic hypoglycemia. The brother
presented at age 42 with a 15-year history of syncopal episodes after
vigorous exercise; his 34-year-old sister reported a 20-year history of
syncope and near-syncope, particularly when dieting. Using treadmill
exercise as a provocative test, both patients were found to have severe
postexercise hypoglycemia with marked hyperinsulinism. The male patient
underwent an 80% distal pancreatectomy; histology revealed diffuse islet
cell hyperplasia, and he was subsequently successfully treated with
diazoxide. When evaluated 6 years after presentation, the patient had
adopted a sedentary lifestyle, stopped taking diazoxide, and was
asymptomatic. His sister, who initially refused treatment, continued to
have hypoglycemic episodes over the next 5 years and eventually began
taking diazoxide with no further symptoms. Neither sib had any evidence
of multiple endocrine neoplasia type I (131100), and there was no
history of endocrine disorders in other family members (3 other sibs and
4 children of the patients).
Meissner et al. (2001) reported 2 unrelated teenagers with
exercise-induced hyperinsulinemic hypoglycemia. A 16-year-old boy had a
2-year history of syncope, primarily after vigorous exercise, and was
noted to have severe hypoglycemia during a syncopal episode. Physical
examination, including psychomotor development, was normal. He developed
symptomatic hypoglycemia after a 12-hour fast; serum ammonia levels were
repeatedly normal. Diagnostic laparotomy revealed no pancreatic
abnormalities and several pancreatic biopsies showed normal pancreatic
histology. He was treated with diazoxide and his blood glucose remained
stable as long as he avoided exercise. The second patient was a
15-year-old girl with hypoglycemia-like symptoms with prolonged
exercise, particularly swimming. She had a history of hypoglycemic
seizures and syncope in infancy and had a normal liver biopsy and MRI of
the pancreas at age 5. Exercise tests in both patients revealed
hyperinsulinemic hypoglycemia 20 to 50 minutes after exercise, caused by
a massive burst of insulin secretion within a few minutes of the start
of exercise.
Otonkoski et al. (2003) examined family members of the 15-year-old girl
studied by Meissner et al. (2001) and of another patient who presented
with exercise-induced hyperinsulinemic hypoglycemia and identified 10
additional affected individuals over multiple generations in the 2
Finnish families, with an autosomal dominant mode of inheritance.
Affected members were diagnosed with exercise-induced hyperinsulinism
based on hypoglycemia and a greater than 3-fold increase in plasma
insulin induced by a 10-minute bicycle exercise test. An intravenous
bolus of pyruvate caused a 5.6-fold increase in plasma insulin in
patients compared to a 0.9-fold increase in controls (p less than
0.001). Pyruvate transport into cultured fibroblasts from the proband of
the second Finnish family originally reported by Meissner et al. (2001)
was normal. The severity of the condition was variable, with some
affected individuals suffering recurrent severe hypoglycemia whereas
others had minimal symptoms.
MAPPING
Otonkoski et al. (2007) performed linkage analysis in 10 affected and 9
unaffected individuals from 2 Finnish families segregating autosomal
dominant exercise-induced hyperglycemic hypoglycemia, previously
examined by Otonkoski et al. (2003), and obtained a maximum lod score of
3.6 on chromosome 1p. A haplotype formed by markers D1S250, D1S534,
D1S498, and D1S1595 was present in all affected but no unaffected
members of the larger family; it was not present in the smaller family,
suggesting that the families have independent mutations.
MOLECULAR GENETICS
In the unrelated boy and girl with exercise-induced hyperinsulinism and
pyruvate-stimulated insulin secretion originally reported by Meissner et
al. (2001), Otonkoski et al. (2003) sequenced the genes encoding CD147
and the 8 known monocarboxylate transporter proteins; no mutations were
identified.
In affected members of 2 Finnish families, previously examined by
Otonkoski et al. (2003) and segregating autosomal dominant
exercise-induced hyperglycemic hypoglycemia mapping to chromosome 1p,
Otonkoski et al. (2007) identified a 163G-A transition (600682.0003) and
a 25-bp duplication (600682.0004), respectively, in the 5-prime UTR of
the SLC16A1 gene. In a German proband previously reported by Meissner et
al. (2001), they identified several sequence variants, including a 2-bp
insertion. All 3 mutations were located within the binding sites of
several transcription factors; functional studies demonstrated induction
of SLC16A1 expression in beta cells, where SLC16A1 is not usually
transcribed, permitting pyruvate uptake and pyruvate-stimulated insulin
release despite ensuing hypoglycemia. Otonkoski et al. (2007) stated
that this represents a novel disease mechanism based on the failure of
cell-specific transcriptional silencing of a gene that is highly
expressed in other tissues.
Quintens et al. (2008) noted that repression of certain ubiquitously
expressed housekeeping proteins is necessary in pancreatic beta cells,
in order to prevent the insulin toxicity that might result from
exocytosis under conditions when circulating insulin is unwanted, citing
low-K(m) hexokinases (see HK1, 142600) and monocarboxylic acid
transporters (MCTs) as examples. The absence of MCTs in beta cells
explains the so-called 'pyruvate paradox' whereby pyruvate, despite
being an excellent substrate for mitochondrial ATP production, does not
stimulate insulin release when added to beta cells. The importance of
this disallowance is exemplified by patients who have gain-of-function
MCT1 promoter mutations and loss of the pyruvate paradox, with resultant
exercise-induced inappropriate insulin release.
*FIELD* RF
1. Burman, W. J.; McDermott, M. T.; Bornemann, M.: Familial hyperinsulinism
presenting in adults. Arch. Intern. Med. 152: 2125-2127, 1992.
2. Meissner, T.; Otonkoski, T.; Feneberg, R.; Beinbrech, B.; Apostolidou,
S.; Sipila, I.; Schaefer, F.; Mayatepek, E.: Exercise induced hypoglycaemic
hyperinsulinism. Arch. Dis. Child. 84: 254-257, 2001.
3. Otonkoski, T.; Jiao, H.; Kaminen-Ahola, N.; Tapia-Paez, I.; Ullah,
M. S.; Parton, L. E.; Schuit, F.; Quintens, R.; Sipila, I.; Mayatepek,
E.; Meissner, T.; Halestrap, A. P.; Rutter, G. A.; Kere, J.: Physical
exercise-induced hypoglycemia caused by failed silencing of monocarboxylate
transporter 1 in pancreatic beta cells. Am. J. Hum. Genet. 81: 467-474,
2007.
4. Otonkoski, T.; Kaminen, N.; Ustinov, J.; Lapatto, R.; Meissner,
T.; Mayatepek, E.; Kere, J.; Sipila, I.: Physical exercise-induced
hyperinsulinemic hypoglycemia is an autosomal-dominant trait characterized
by abnormal pyruvate-induced insulin release. Diabetes 52: 199-204,
2003.
5. Quintens, R.; Hendrickx, N.; Lemaire, K.; Schuit, F.: Why expression
of some genes is disallowed in beta-cells. Biochem. Soc. Trans. 36:
300-305, 2008.
*FIELD* CS
INHERITANCE:
Autosomal dominant
ABDOMEN:
[Pancreas];
Islet cell hyperplasia, diffuse
NEUROLOGIC:
[Central nervous system];
Loss on consciousness due to hypoglycemia;
Seizures, hypoglycemic
ENDOCRINE FEATURES:
Hyperinsulinemic hypoglycemia
LABORATORY ABNORMALITIES:
Hypoglycemia;
Hyperinsulinemia;
Exercise-induced hyperinsulinism;
Pyruvate-induced insulin secretion
MISCELLANEOUS:
Genetic heterogeneity (see HHF1 256450)
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 16, member 1 gene
(SLC16A1, 600682.0003)
*FIELD* CN
Marla J. F. O'Neill - updated: 03/02/2010
*FIELD* CD
Marla J. F. O'Neill: 4/24/2006
*FIELD* ED
joanna: 03/02/2010
joanna: 4/24/2006
*FIELD* CN
Marla J. F. O'Neill - updated: 11/6/2008
*FIELD* CD
Marla J. F. O'Neill: 3/30/2006
*FIELD* ED
joanna: 03/02/2010
wwang: 11/13/2008
terry: 11/6/2008
ckniffin: 3/31/2006
carol: 3/30/2006
*RECORD*
*FIELD* NO
610021
*FIELD* TI
#610021 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 7; HHF7
;;HYPERINSULINEMIC HYPOGLYCEMIA, EXERCISE-INDUCED
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that this
form of hyperinsulinemic hypoglycemia is caused by mutation in the
SLC16A1 gene (600682).
For a phenotypic description and a discussion of genetic heterogeneity
of familial hyperinsulinemic hypoglycemia, see HHF1 (256450).
CLINICAL FEATURES
Burman et al. (1992) described a brother and sister who had recurrent
syncope due to severe hyperinsulinemic hypoglycemia. The brother
presented at age 42 with a 15-year history of syncopal episodes after
vigorous exercise; his 34-year-old sister reported a 20-year history of
syncope and near-syncope, particularly when dieting. Using treadmill
exercise as a provocative test, both patients were found to have severe
postexercise hypoglycemia with marked hyperinsulinism. The male patient
underwent an 80% distal pancreatectomy; histology revealed diffuse islet
cell hyperplasia, and he was subsequently successfully treated with
diazoxide. When evaluated 6 years after presentation, the patient had
adopted a sedentary lifestyle, stopped taking diazoxide, and was
asymptomatic. His sister, who initially refused treatment, continued to
have hypoglycemic episodes over the next 5 years and eventually began
taking diazoxide with no further symptoms. Neither sib had any evidence
of multiple endocrine neoplasia type I (131100), and there was no
history of endocrine disorders in other family members (3 other sibs and
4 children of the patients).
Meissner et al. (2001) reported 2 unrelated teenagers with
exercise-induced hyperinsulinemic hypoglycemia. A 16-year-old boy had a
2-year history of syncope, primarily after vigorous exercise, and was
noted to have severe hypoglycemia during a syncopal episode. Physical
examination, including psychomotor development, was normal. He developed
symptomatic hypoglycemia after a 12-hour fast; serum ammonia levels were
repeatedly normal. Diagnostic laparotomy revealed no pancreatic
abnormalities and several pancreatic biopsies showed normal pancreatic
histology. He was treated with diazoxide and his blood glucose remained
stable as long as he avoided exercise. The second patient was a
15-year-old girl with hypoglycemia-like symptoms with prolonged
exercise, particularly swimming. She had a history of hypoglycemic
seizures and syncope in infancy and had a normal liver biopsy and MRI of
the pancreas at age 5. Exercise tests in both patients revealed
hyperinsulinemic hypoglycemia 20 to 50 minutes after exercise, caused by
a massive burst of insulin secretion within a few minutes of the start
of exercise.
Otonkoski et al. (2003) examined family members of the 15-year-old girl
studied by Meissner et al. (2001) and of another patient who presented
with exercise-induced hyperinsulinemic hypoglycemia and identified 10
additional affected individuals over multiple generations in the 2
Finnish families, with an autosomal dominant mode of inheritance.
Affected members were diagnosed with exercise-induced hyperinsulinism
based on hypoglycemia and a greater than 3-fold increase in plasma
insulin induced by a 10-minute bicycle exercise test. An intravenous
bolus of pyruvate caused a 5.6-fold increase in plasma insulin in
patients compared to a 0.9-fold increase in controls (p less than
0.001). Pyruvate transport into cultured fibroblasts from the proband of
the second Finnish family originally reported by Meissner et al. (2001)
was normal. The severity of the condition was variable, with some
affected individuals suffering recurrent severe hypoglycemia whereas
others had minimal symptoms.
MAPPING
Otonkoski et al. (2007) performed linkage analysis in 10 affected and 9
unaffected individuals from 2 Finnish families segregating autosomal
dominant exercise-induced hyperglycemic hypoglycemia, previously
examined by Otonkoski et al. (2003), and obtained a maximum lod score of
3.6 on chromosome 1p. A haplotype formed by markers D1S250, D1S534,
D1S498, and D1S1595 was present in all affected but no unaffected
members of the larger family; it was not present in the smaller family,
suggesting that the families have independent mutations.
MOLECULAR GENETICS
In the unrelated boy and girl with exercise-induced hyperinsulinism and
pyruvate-stimulated insulin secretion originally reported by Meissner et
al. (2001), Otonkoski et al. (2003) sequenced the genes encoding CD147
and the 8 known monocarboxylate transporter proteins; no mutations were
identified.
In affected members of 2 Finnish families, previously examined by
Otonkoski et al. (2003) and segregating autosomal dominant
exercise-induced hyperglycemic hypoglycemia mapping to chromosome 1p,
Otonkoski et al. (2007) identified a 163G-A transition (600682.0003) and
a 25-bp duplication (600682.0004), respectively, in the 5-prime UTR of
the SLC16A1 gene. In a German proband previously reported by Meissner et
al. (2001), they identified several sequence variants, including a 2-bp
insertion. All 3 mutations were located within the binding sites of
several transcription factors; functional studies demonstrated induction
of SLC16A1 expression in beta cells, where SLC16A1 is not usually
transcribed, permitting pyruvate uptake and pyruvate-stimulated insulin
release despite ensuing hypoglycemia. Otonkoski et al. (2007) stated
that this represents a novel disease mechanism based on the failure of
cell-specific transcriptional silencing of a gene that is highly
expressed in other tissues.
Quintens et al. (2008) noted that repression of certain ubiquitously
expressed housekeeping proteins is necessary in pancreatic beta cells,
in order to prevent the insulin toxicity that might result from
exocytosis under conditions when circulating insulin is unwanted, citing
low-K(m) hexokinases (see HK1, 142600) and monocarboxylic acid
transporters (MCTs) as examples. The absence of MCTs in beta cells
explains the so-called 'pyruvate paradox' whereby pyruvate, despite
being an excellent substrate for mitochondrial ATP production, does not
stimulate insulin release when added to beta cells. The importance of
this disallowance is exemplified by patients who have gain-of-function
MCT1 promoter mutations and loss of the pyruvate paradox, with resultant
exercise-induced inappropriate insulin release.
*FIELD* RF
1. Burman, W. J.; McDermott, M. T.; Bornemann, M.: Familial hyperinsulinism
presenting in adults. Arch. Intern. Med. 152: 2125-2127, 1992.
2. Meissner, T.; Otonkoski, T.; Feneberg, R.; Beinbrech, B.; Apostolidou,
S.; Sipila, I.; Schaefer, F.; Mayatepek, E.: Exercise induced hypoglycaemic
hyperinsulinism. Arch. Dis. Child. 84: 254-257, 2001.
3. Otonkoski, T.; Jiao, H.; Kaminen-Ahola, N.; Tapia-Paez, I.; Ullah,
M. S.; Parton, L. E.; Schuit, F.; Quintens, R.; Sipila, I.; Mayatepek,
E.; Meissner, T.; Halestrap, A. P.; Rutter, G. A.; Kere, J.: Physical
exercise-induced hypoglycemia caused by failed silencing of monocarboxylate
transporter 1 in pancreatic beta cells. Am. J. Hum. Genet. 81: 467-474,
2007.
4. Otonkoski, T.; Kaminen, N.; Ustinov, J.; Lapatto, R.; Meissner,
T.; Mayatepek, E.; Kere, J.; Sipila, I.: Physical exercise-induced
hyperinsulinemic hypoglycemia is an autosomal-dominant trait characterized
by abnormal pyruvate-induced insulin release. Diabetes 52: 199-204,
2003.
5. Quintens, R.; Hendrickx, N.; Lemaire, K.; Schuit, F.: Why expression
of some genes is disallowed in beta-cells. Biochem. Soc. Trans. 36:
300-305, 2008.
*FIELD* CS
INHERITANCE:
Autosomal dominant
ABDOMEN:
[Pancreas];
Islet cell hyperplasia, diffuse
NEUROLOGIC:
[Central nervous system];
Loss on consciousness due to hypoglycemia;
Seizures, hypoglycemic
ENDOCRINE FEATURES:
Hyperinsulinemic hypoglycemia
LABORATORY ABNORMALITIES:
Hypoglycemia;
Hyperinsulinemia;
Exercise-induced hyperinsulinism;
Pyruvate-induced insulin secretion
MISCELLANEOUS:
Genetic heterogeneity (see HHF1 256450)
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 16, member 1 gene
(SLC16A1, 600682.0003)
*FIELD* CN
Marla J. F. O'Neill - updated: 03/02/2010
*FIELD* CD
Marla J. F. O'Neill: 4/24/2006
*FIELD* ED
joanna: 03/02/2010
joanna: 4/24/2006
*FIELD* CN
Marla J. F. O'Neill - updated: 11/6/2008
*FIELD* CD
Marla J. F. O'Neill: 3/30/2006
*FIELD* ED
joanna: 03/02/2010
wwang: 11/13/2008
terry: 11/6/2008
ckniffin: 3/31/2006
carol: 3/30/2006