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Description:
DNA mismatch repair protein Mlh1 (MutL protein homolog 1).
Molecular weight: 84601
View which proteins in this organism that is involved with DNA Repair;
classified after biological processes (using data from the GOA project):
DNA repair( GO:0006281 ) mismatch repair( GO:0006298 )
Important dates:
01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
01-FEB-1995, sequence version 1.
07-FEB-2006, entry version 61.
Phylogenetic order:
Eukaryota Metazoa Chordata Craniata Vertebrata Euteleostomi Mammalia Eutheria Euarchontoglires Primates Catarrhini Hominidae Homo.
To calculate the pI (Isoelectric point - the pH where a protein has a neutral charge),
go to this page and enter the protein ID (e.g 3MG_ECOLI): http://us.expasy.org/tools/pi_tool.html
Links to references in other databases for protein MLH1_HUMAN:
Keywords:
Anti-oncogene; Cell cycle; Disease mutation; DNA damage; DNA repair; Hereditary nonpolyposis colorectal cancer; Nuclear protein; Polymorphism.
References:
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX MEDLINE=94195398; PubMed=8145827; DOI=10.1038/368258a0;
RA Bronner C.E., Baker S.M., Morrison P.T., Warren G., Smith L.G.,
RA Lescoe M.K., Kane M.F., Earibino C., Lipford J., Lindblom A.,
RA Tannergaard P., Bollag R.J., Godwin A.R., Ward D.C., Nordenskjoeld M.,
RA Fishel R., Kolodner R.D., Liskay R.M.;
RT "Mutation in the DNA mismatch repair gene homologue hMLH1 is
RT associated with hereditary non-polyposis colon cancer.";
RL Nature 368:258-261(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Gall bladder;
RX MEDLINE=94174309; PubMed=8128251;
RA Papadopoulos N., Nicolaides N.C., Wei Y.-F., Ruben S.M., Carter K.C.,
RA Rosen C.A., Haseltine W.A., Fleischmann R.D., Fraser C.M., Adams M.D.,
RA Venter J.C., Hamilton S.R., Petersen G.M., Watson P., Lynch H.T.,
RA Peltomaeki P., Mecklin J.-P., de la Chapelle A., Kinzler K.W.,
RA Vogelstein B.;
RT "Mutation of a mutL homolog in hereditary colon cancer.";
RL Science 263:1625-1629(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX MEDLINE=95112274; PubMed=7812952;
RA Kolodner R.D., Hall N.R., Lipford J.R., Kane M.F., Morrison P.,
RA Finan P.J., Burn J., Chapman P., Earabino C., Merchant E.,
RA Bishop D.T.;
RT "Structure of the human MLH1 locus and analysis of a large hereditary
RT nonpolyposis colorectal carcinoma kindred for mlh1 mutations.";
RL Cancer Res. 55:242-248(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS HNPCC2 LEU-542;
RP PRO-574; VAL-582 AND THR-618.
RX MEDLINE=95276736; PubMed=7757073;
RA Han H.-J., Maruyama M., Baba S., Park J.-G., Nakamura Y.;
RT "Genomic structure of human mismatch repair gene, hMLH1, and its
RT mutation analysis in patients with hereditary non-polyposis colorectal
RT cancer (HNPCC).";
RL Hum. Mol. Genet. 4:237-242(1995).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT HNPCC2 MET-213, AND
RP VARIANTS VAL-32 AND VAL-219.
RA Rieder M.J., Livingston R.J., Daniels M.R., Montoya M.A., Chung M.-W.,
RA Miyamoto K.E., Nguyen C.P., Nguyen D.A., Poel C.L., Robertson P.D.,
RA Schackwitz W.S., Sherwood J.K., Witrak L.A., Nickerson D.A.;
RT "NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department
RT of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu).";
RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
RX MEDLINE=22388257; PubMed=12477932; DOI=10.1073/pnas.242603899;
RA Strausberg R.L., Feingold E.A., Grouse L.H., Derge J.G.,
RA Klausner R.D., Collins F.S., Wagner L., Shenmen C.M., Schuler G.D.,
RA Altschul S.F., Zeeberg B., Buetow K.H., Schaefer C.F., Bhat N.K.,
RA Hopkins R.F., Jordan H., Moore T., Max S.I., Wang J., Hsieh F.,
RA Diatchenko L., Marusina K., Farmer A.A., Rubin G.M., Hong L.,
RA Stapleton M., Soares M.B., Bonaldo M.F., Casavant T.L., Scheetz T.E.,
RA Brownstein M.J., Usdin T.B., Toshiyuki S., Carninci P., Prange C.,
RA Raha S.S., Loquellano N.A., Peters G.J., Abramson R.D., Mullahy S.J.,
RA Bosak S.A., McEwan P.J., McKernan K.J., Malek J.A., Gunaratne P.H.,
RA Richards S., Worley K.C., Hale S., Garcia A.M., Gay L.J., Hulyk S.W.,
RA Villalon D.K., Muzny D.M., Sodergren E.J., Lu X., Gibbs R.A.,
RA Fahey J., Helton E., Ketteman M., Madan A., Rodrigues S., Sanchez A.,
RA Whiting M., Madan A., Young A.C., Shevchenko Y., Bouffard G.G.,
RA Blakesley R.W., Touchman J.W., Green E.D., Dickson M.C.,
RA Rodriguez A.C., Grimwood J., Schmutz J., Myers R.M.,
RA Butterfield Y.S.N., Krzywinski M.I., Skalska U., Smailus D.E.,
RA Schnerch A., Schein J.E., Jones S.J.M., Marra M.A.;
RT "Generation and initial analysis of more than 15,000 full-length human
RT and mouse cDNA sequences.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:16899-16903(2002).
RN [7]
RP IDENTIFICATION OF MLH1 AS MEMBER OF BASC.
RX MEDLINE=20245492; PubMed=10783165; DOI=10.1101/gad.827000;
RA Wang Y., Cortez D., Yazdi P., Neff N., Elledge S.J., Qin J.;
RT "BASC, a super complex of BRCA1-associated proteins involved in the
RT recognition and repair of aberrant DNA structures.";
RL Genes Dev. 14:927-939(2000).
RN [8]
RP INTERACTION WITH MBD4.
RX MEDLINE=99199294; PubMed=10097147; DOI=10.1073/pnas.96.7.3969;
RA Bellacosa A., Cicchillitti L., Schepis F., Riccio A., Yeung A.T.,
RA Matsumoto Y., Golemis E.A., Genuardi M., Neri G.;
RT "MED1, a novel human methyl-CpG-binding endonuclease, interacts with
RT DNA mismatch repair protein MLH1.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:3969-3974(1999).
RN [9]
RP INTERACTIONS WITH EXO1 AND PMS2, AND MUTAGENESIS OF LEU-574; LEU-616;
RP ARG-659 AND ALA-681.
RX PubMed=11427529; DOI=10.1074/jbc.M102670200;
RA Schmutte C., Sadoff M.M., Shim K.-S., Acharya S., Fishel R.;
RT "The interaction of DNA mismatch repair proteins with human
RT exonuclease I.";
RL J. Biol. Chem. 276:33011-33018(2001).
RN [10]
RP INTERACTION WITH EXO1, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF
RP VARIANT MET-117.
RX PubMed=11429708; DOI=10.1038/sj/onc/1204467;
RA Jaeger A.C., Rasmussen M., Bisgaard H.C., Singh K.K., Nielsen F.C.,
RA Rasmussen L.J.;
RT "HNPCC mutations in the human DNA mismatch repair gene hMLH1 influence
RT assembly of hMutLalpha and hMLH1-hEXO1 complexes.";
RL Oncogene 20:3590-3595(2001).
RN [11]
RP INTERACTION WITH EXO1.
RA Sun X., Zheng L., Shen B.;
RT "Functional alterations of human exonuclease 1 mutants identified in
RT atypical hereditary nonpolyposis colorectal cancer syndrome.";
RL Cancer Res. 62:6026-6030(2002).
RN [12]
RP INTERACTION WITH EXO1, AND SUBCELLULAR LOCATION.
RX PubMed=14676842; DOI=10.1038/sj.onc.1207265;
RA Nielsen F.C., Jaeger A.C., Luetzen A., Bundgaard J.R., Rasmussen L.J.;
RT "Characterization of human exonuclease 1 in complex with mismatch
RT repair proteins, subcellular localization and association with PCNA.";
RL Oncogene 23:1457-1468(2004).
RN [13]
RP DISEASE.
RX MEDLINE=96354569; PubMed=8751876;
RA Bapat B., Xia L., Madlensky L., Mitri A., Tonin P., Narod S.A.,
RA Gallinger S.;
RT "The genetic basis of Muir-Torre syndrome includes the hMLH1 locus.";
RL Am. J. Hum. Genet. 59:736-739(1996).
RN [14]
RP REVIEW ON VARIANTS.
RX MEDLINE=97403931; PubMed=9259192;
RX DOI=10.1002/(SICI)1098-1004(1997)10:2<89::AID-HUMU1>3.3.CO;2-K;
RA Papadopoulos N., Lindblom A.;
RT "Molecular basis of HNPCC: mutations of MMR genes.";
RL Hum. Mutat. 10:89-99(1997).
RN [15]
RP VARIANT TURCOT SYNDROME LYS-616 DEL.
RX MEDLINE=95174843; PubMed=7661930; DOI=10.1056/NEJM199503303321302;
RA Hamilton S.R., Liu B., Parsons R.E., Papadopoulos N., Jen J.,
RA Powell S.M., Krush A.J., Berk T., Cohen Z., Tetu B., Burger P.C.,
RA Wood P.A., Taqi F., Booker S.V., Petersen G.M., Offerhaus G.J.A.,
RA Tersmette A.C., Giardiello F.M., Vogelstein B., Kinzler K.W.;
RT "The molecular basis of Turcot's syndrome.";
RL N. Engl. J. Med. 332:839-847(1995).
RN [16]
RP VARIANT HNPCC2 LYS-616 DEL.
RX MEDLINE=96152126; PubMed=8571956;
RA Wijnen J., Khan P.M., Vasen H., Menko F., van der Klift H.,
RA van den Broek M., van Leeuwen-Cornelisse I., Nagengast F.,
RA Meijers-Heijboer E.J., Lindhout D., Griffioen G., Cats A.,
RA Kleibeuker J., Varesco L., Bertario L., Bisgaard M.-L., Mohr J.,
RA Kolodner R.D., Fodde R.;
RT "Majority of hMLH1 mutations responsible for hereditary nonpolyposis
RT colorectal cancer cluster at the exonic region 15-16.";
RL Am. J. Hum. Genet. 58:300-307(1996).
RN [17]
RP VARIANTS HNPCC2 MET-117 AND LEU-226.
RX MEDLINE=96163505; PubMed=8566964;
RA Maliaka Y.K., Chudina A.P., Belev N.F., Alday P., Bochkov N.P.,
RA Buerstedde J.-M.;
RT "CpG dinucleotides in the hMSH2 and hMLH1 genes are hotspots for HNPCC
RT mutations.";
RL Hum. Genet. 97:251-255(1996).
RN [18]
RP VARIANTS HNPCC2 LYS-616 DEL AND THR-618, AND VARIANT CRC THR-492.
RX MEDLINE=97026284; PubMed=8872463; DOI=10.1093/hmg/5.9.1245;
RA Moslein G., Tester D.J., Lindor N.M., Honchel R., Cunningham J.M.,
RA French A.J., Halling K.C., Schwab M., Goretzki P., Thibodeau S.N.;
RT "Microsatellite instability and mutation analysis of hMSH2 and hMLH1
RT in patients with sporadic, familial and hereditary colorectal
RT cancer.";
RL Hum. Mol. Genet. 5:1245-1252(1996).
RN [19]
RP VARIANTS HNPCC2 CYS-217; LEU-542; PRO-549 AND PRO-574.
RX MEDLINE=96390800; PubMed=8797773;
RA Han H.-J., Yuan Y., Ku J.-L., Oh J.-H., Won Y.-J., Kang K.J.,
RA Kim K.Y., Kim S., Kim C.Y., Kim J.-P., Oh N.-G., Lee K.H., Choe K.J.,
RA Nakamura Y., Park J.-G.;
RT "Germline mutations of hMLH1 and hMSH2 genes in Korean hereditary
RT nonpolyposis colorectal cancer.";
RL J. Natl. Cancer Inst. 88:1317-1319(1996).
RN [20]
RP VARIANT ENDOMETRIAL CANCER LEU-ASN-HIS-37 INS, AND VARIANT ASP-384.
RX MEDLINE=96183273; PubMed=8609062;
RA Kobayashi K., Matsushima M., Koi S., Saito H., Sagae S., Kudo R.,
RA Nakamura Y.;
RT "Mutational analysis of mismatch repair genes, hMLH1 and hMSH2, in
RT sporadic endometrial carcinomas with microsatellite instability.";
RL Jpn. J. Cancer Res. 87:141-145(1996).
RN [21]
RP VARIANTS HNPCC2 LYS-62; SER-64; LYS-616 DEL; ALA-618 AND PRO-659.
RX MEDLINE=97456423; PubMed=9311737;
RA Wijnen J., Khan P.M., Vasen H., van der Klift H., Mulder A.,
RA van Leeuwen-Cornelisse I., Bakker B., Losekoot M., Moeller P.,
RA Fodde R.;
RT "Hereditary nonpolyposis colorectal cancer families not complying with
RT the Amsterdam criteria show extremely low frequency of mismatch-
RT repair-gene mutations.";
RL Am. J. Hum. Genet. 61:329-335(1997).
RN [22]
RP VARIANT HNPCC2 LYS-616 DEL, AND VARIANT HIS-265.
RX MEDLINE=97147120; PubMed=8993976;
RX DOI=10.1002/(SICI)1098-2264(199701)18:1<8::AID-GCC2>3.0.CO;2-7;
RA Viel A., Genuardi M., Capozzi E., Leonardi F., Bellacosa A.,
RA Paravatou-Petsotas M., Pomponi M.G., Fornasarig M., Percesepe A.,
RA Roncucci L., Tamassia M.G., Benatti P., Ponz de Leon M., Valenti A.,
RA Covino M., Anti M., Foletto M., Boiocchi M., Neri G.;
RT "Characterization of MSH2 and MLH1 mutations in Italian families with
RT hereditary nonpolyposis colorectal cancer.";
RL Genes Chromosomes Cancer 18:8-18(1997).
RN [23]
RP VARIANTS CRC GLU-54; VAL-244 AND GLN-325, AND VARIANTS VAL-219 AND
RP ASN-406.
RX MEDLINE=97242567; PubMed=9087566;
RX DOI=10.1002/(SICI)1098-2264(199704)18:4<269::AID-GCC4>3.3.CO;2-9;
RA Wu Y., Nystroem-Lahti M., Osinga J., Looman M.W.G., Peltomaeki P.,
RA Aaltonen L.A., de la Chapelle A., Hofstra R.M.W., Buys C.H.C.M.;
RT "MSH2 and MLH1 mutations in sporadic replication error-positive
RT colorectal carcinoma as assessed by two-dimensional DNA
RT electrophoresis.";
RL Genes Chromosomes Cancer 18:269-278(1997).
RN [24]
RP VARIANTS HNPCC2 PRO-128 AND ASP-244, AND VARIANT VAL-219.
RX MEDLINE=97362529; PubMed=9218993;
RX DOI=10.1002/(SICI)1098-2264(199707)19:3<135::AID-GCC1>3.3.CO;2-X;
RA Pensotti V., Radice P., Presciuttini S., Calistri D., Gazzoli I.,
RA Grimalt Perez A.P., Mondini P., Buonsanti G., Sala P., Rossetti C.,
RA Ranzani G.N., Bertario L., Pierotti M.A.;
RT "Mean age of tumor onset in hereditary nonpolyposis colorectal cancer
RT (HNPCC) families correlates with the presence of mutations in DNA
RT mismatch repair genes.";
RL Genes Chromosomes Cancer 19:135-142(1997).
RN [25]
RP VARIANT HNPCC2 ARG-67, AND VARIANT VAL-219.
RX MEDLINE=97220595; PubMed=9067757;
RX DOI=10.1002/(SICI)1098-1004(1997)9:2<164::AID-HUMU9>3.3.CO;2-6;
RA Sasaki S., Tokino T., Miyatsu T., Muto T., Nakamura Y.;
RT "Mutational analysis of the hMLH1 gene using an automated two-
RT dimensional DNA typing system.";
RL Hum. Mutat. 9:164-171(1997).
RN [26]
RP VARIANT HNPCC2 626-SER-THR-627.
RX MEDLINE=97201114; PubMed=9048925; DOI=10.1007/s004390050343;
RA Beck N.E., Tomlinson I.P.M., Homfray T., Frayling I., Hodgson S.V.,
RA Harocopos C.J., Bodmer W.F.;
RT "Use of SSCP analysis to identify germline mutations in HNPCC families
RT fulfilling the Amsterdam criteria.";
RL Hum. Genet. 99:219-224(1997).
RN [27]
RP VARIANT HNPCC2 PRO-329.
RX MEDLINE=97418119; PubMed=9272156; DOI=10.1007/s004390050517;
RA Wang Y., Friedl W., Lamberti C., Ruelfs C., Kruse R., Propping P.;
RT "Hereditary nonpolyposis colorectal cancer: causative role of a
RT germline missense mutation in the hMLH1 gene confirmed by the
RT independent occurrence of the same somatic mutation in tumour
RT tissue.";
RL Hum. Genet. 100:362-364(1997).
RN [28]
RP VARIANT HNPCC2 LEU-28.
RX MEDLINE=97442278; PubMed=9298827;
RX DOI=10.1002/(SICI)1098-1004(1997)10:3<241::AID-HUMU12>3.3.CO;2-3;
RA Wehner M., Buschhausen L., Lamberti C., Kruse R., Caspari R.,
RA Propping P., Friedl W.;
RT "Hereditary nonpolyposis colorectal cancer (HNPCC): eight novel
RT germline mutations in hMSH2 or hMLH1 genes.";
RL Hum. Mutat. 10:241-244(1997).
RN [29]
RP VARIANTS HNPCC2 GLY-182; THR-295 AND THR-551.
RX MEDLINE=98060582; PubMed=9399661;
RX DOI=10.1002/(SICI)1097-0215(19971210)73:6<831::AID-IJC11>3.0.CO;2-7;
RA Wang Q., Desseigne F., Lasset C., Saurin J.-C., Navarro C., Yagci T.,
RA Keser I., Bagci H., Luleci G., Gelen T., Chayvialle J.-A.,
RA Puisieux A., Ozturk M.;
RT "Germline hMSH2 and hMLH1 gene mutations in incomplete HNPCC
RT families.";
RL Int. J. Cancer 73:831-836(1997).
RN [30]
RP VARIANT CRC TYR-77, AND VARIANT VAL-219.
RX MEDLINE=97184879; PubMed=9032648;
RA Tomlinson I.P.M., Beck N.E., Homfray T., Harocopos C.J., Bodmer W.F.;
RT "Germline HNPCC gene variants have little influence on the risk for
RT sporadic colorectal cancer.";
RL J. Med. Genet. 34:39-42(1997).
RN [31]
RP VARIANTS HNPCC2 PHE-44 AND THR-441.
RX MEDLINE=97467715; PubMed=9326924;
RA Hackman P., Tannergaerd P., Osei-Mensa S., Chen J., Kane M.F.,
RA Kolodner R.D., Lambert B., Hellgren D., Lindblom A.;
RT "A human compound heterozygote for two MLH1 missense mutations.";
RL Nat. Genet. 17:135-136(1997).
RN [32]
RP VARIANTS HNPCC2, AND VARIANTS.
RX MEDLINE=98386069; PubMed=9718327;
RA Farrington S.M., Lin-Goerke J., Ling J., Wang Y., Burczak J.D.,
RA Robbins D.J., Dunlop M.G.;
RT "Systematic analysis of hMSH2 and hMLH1 in young colon cancer patients
RT and controls.";
RL Am. J. Hum. Genet. 63:749-759(1998).
RN [33]
RP VARIANT CRC GLY-268.
RX MEDLINE=98272630; PubMed=9611074;
RA Liu T., Wahlberg S., Rubio C., Holmberg E., Groenberg H., Lindblom A.;
RT "DGGE screening of mutations in mismatch repair genes (hMSH2 and
RT hMLH1) in 34 Swedish families with colorectal cancer.";
RL Clin. Genet. 53:131-135(1998).
RN [34]
RP VARIANT HNPCC2 CYS-217.
RX MEDLINE=98218529; PubMed=9559627;
RA Yuan Y., Han H.-J., Zheng S., Park J.-G.;
RT "Germline mutations of hMLH1 and hMSH2 genes in patients with
RT suspected hereditary nonpolyposis colorectal cancer and sporadic
RT early-onset colorectal cancer.";
RL Dis. Colon Rectum 41:434-440(1998).
RN [35]
RP VARIANT HNPCC2 LYS-69.
RX MEDLINE=20089933; PubMed=10627141;
RX DOI=10.1002/(SICI)1098-1004(1998)12:1<73::AID-HUMU20>3.3.CO;2-6;
RA Herfarth K.K.-F., Ogunbiyi O.A., Moley J.F., Kodner I.J.,
RA Wells S.A. Jr., Goodfellow P.J.;
RT "Four new mutations in the DNA mismatch repair gene MLH1 in colorectal
RT cancers with microsatellite instability.";
RL Hum. Mutat. 12:73-73(1998).
RN [36]
RP VARIANTS HNPCC2 ARG-77 AND PRO-193.
RX MEDLINE=20123068; PubMed=10660333;
RA Panariello L., Scarano M.I., de Rosa M., Capasso L., Renda A.,
RA Riegler G., Rossi G.B., Salvatore F., Izzo P.;
RT "hMLH1 mutations in hereditary nonpolyposis colorectal cancer
RT kindreds.";
RL Hum. Mutat. 12:216-217(1998).
RN [37]
RP VARIANT HNPCC2 GLY-93.
RX MEDLINE=20133866; PubMed=10671064;
RX DOI=10.1002/(SICI)1098-1004(1998)12:6<433::AID-HUMU13>3.0.CO;2-J;
RA Quaresima B., Grandinetti C., Baudi F., Tassone P., Barbieri V.,
RA Conforti S., Avvedimento E.V., Costanzo F., Venuta S.;
RT "Hereditary nonpolyposis colorectal cancer: identification of novel
RT germline mutations in two kindreds not fulfilling the Amsterdam
RT criteria.";
RL Hum. Mutat. 12:433-433(1998).
RN [38]
RP VARIANTS HNPCC2 ARG-67; ILE-262 DEL; THR-551; PHE-565 AND MET-716, AND
RP VARIANT VAL-219.
RX MEDLINE=99049505; PubMed=9833759;
RX DOI=10.1002/(SICI)1097-0215(19981209)78:6<680::AID-IJC3>3.0.CO;2-U;
RA Hutter P., Couturier A., Membrez V., Joris F., Sappino A.-P.,
RA Chappuis P.O.;
RT "Excess of hMLH1 germline mutations in Swiss families with hereditary
RT non-polyposis colorectal cancer.";
RL Int. J. Cancer 78:680-684(1998).
RN [39]
RP VARIANT HNPCC2 TRP-67.
RA Wang Q., Lasset C., Desseigne F., Frappaz D., Bergeron C., Navarro C.,
RA Ruano E., Puisieux A.;
RT "Neurofibromatosis and early onset of cancers in hMLH1-deficient
RT children.";
RL Cancer Res. 59:294-297(1999).
RN [40]
RP VARIANTS HNPCC2 LEU-28; GLU-84 AND PRO-329.
RX MEDLINE=99257295; PubMed=10323887;
RA Lamberti C., Kruse R., Ruelfs C., Caspari R., Wang Y., Jungck M.,
RA Mathiak M., Malayeri H.R.H., Friedl W., Sauerbruch T., Propping P.;
RT "Microsatellite instability, a useful diagnostic tool to select
RT patients at high risk for hereditary non-polyposis colorectal cancer:
RT a study in different groups of patients with colorectal cancer.";
RL Gut 44:839-843(1999).
RN [41]
RP VARIANTS HNPCC2 TRP-67; MET-117; GLY-182 AND LYS-616 DEL, AND VARIANT
RP HNPCC TRP-755.
RX MEDLINE=99408236; PubMed=10480359; DOI=10.1007/s004390051067;
RA Wang Q., Lasset C., Desseigne F., Saurin J.-C., Maugard C.,
RA Navarro C., Ruano E., Descos L., Trillet-Lenoir V., Bosset J.-F.,
RA Puisieux A.;
RT "Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and
RT hMSH6 genes in 75 French kindreds with nonpolyposis colorectal
RT cancer.";
RL Hum. Genet. 105:79-85(1999).
RN [42]
RP VARIANT CRC GLY-578, AND VARIANT HNPCC2 ALA-618.
RX MEDLINE=20065868; PubMed=10598809; DOI=10.1007/s004390051127;
RA Liu T., Tannergaerd P., Hackman P., Rubio C., Kressner U.,
RA Lindmark G., Hellgren D., Lambert B., Lindblom A.;
RT "Missense mutations in hMLH1 associated with colorectal cancer.";
RL Hum. Genet. 105:437-441(1999).
RN [43]
RP VARIANTS HNPCC2 VAL-111 AND PRO-588, AND VARIANTS VAL-219 AND ASP-384.
RX MEDLINE=20241830; PubMed=10777691; DOI=10.1006/bbrc.2000.2547;
RA Nomura S., Sugano K., Kashiwabara H., Taniguchi T., Fukayama N.,
RA Fujita S., Akasu T., Moriya Y., Ohhigashi S., Kakizoe T., Sekiya T.;
RT "Enhanced detection of deleterious and other germline mutations of
RT hMSH2 and hMLH1 in Japanese hereditary nonpolyposis colorectal cancer
RT kindreds.";
RL Biochem. Biophys. Res. Commun. 271:120-129(2000).
RN [44]
RP VARIANTS HNPCC2 MET-213; HIS-607; ALA-618 AND LEU-659.
RX MEDLINE=20178226; PubMed=10713887; DOI=10.1038/sj.ejhg.5200393;
RA Fidalgo P., Almeida M.R., West S., Gaspar C., Maia L., Wijnen J.,
RA Albuquerque C., Curtis A., Cravo M., Fodde R., Leitao C.N., Burn J.;
RT "Detection of mutations in mismatch repair genes in Portuguese
RT families with hereditary non-polyposis colorectal cancer (HNPCC) by a
RT multi-method approach.";
RL Eur. J. Hum. Genet. 8:49-53(2000).
RN [45]
RP VARIANT LCIS HIS-607.
RX MEDLINE=21261646; PubMed=11369138; DOI=10.1016/S0304-3835(01)00448-7;
RA Stone J.G., Coleman G., Gusterson B., Marossy A., Lakhani S.R.,
RA Ward A., Nash A., McKinna A., A'Hern R., Stratton M.R., Houlston R.S.;
RT "Contribution of germline MLH1 and MSH2 mutations to lobular carcinoma
RT in situ of the breast.";
RL Cancer Lett. 167:171-174(2001).
RN [46]
RP INVOLVEMENT IN TUMORIGENESIS.
RA Vilkki S., Tsao J.-L., Loukola A., Poyhonen M., Vierimaa O., Herva R.,
RA Aaltonen L.A., Shibata D.;
RT "Extensive somatic microsatellite mutations in normal human tissue.";
RL Cancer Res. 61:4541-4544(2001).
RN [47]
RP VARIANTS HNPCC2 VAL-80; PRO-329; ARG-603; ALA-618; LEU-648; PRO-662
RP AND MET-716, AND VARIANT HNPCC ARG-689.
RX MEDLINE=21583375; PubMed=11726306;
RA Mueller-Koch Y., Kopp R., Lohse P., Baretton G., Stoetzer A., Aust D.,
RA Daum J., Kerker B., Gross M., Dietmeier W., Holinski-Feder E.;
RT "Sixteen rare sequence variants of the hMLH1 and hMSH2 genes found in
RT a cohort of 254 suspected HNPCC (hereditary non-polyposis colorectal
RT cancer) patients: mutations or polymorphisms?";
RL Eur. J. Med. Res. 6:473-482(2001).
RN [48]
RP CHARACTERIZATION OF VARIANTS.
RX MEDLINE=21439334; PubMed=11555625; DOI=10.1093/hmg/10.18.1889;
RA Ellison A.R., Lofing J., Bitter G.A.;
RT "Functional analysis of human MLH1 and MSH2 missense variants and
RT hybrid human-yeast MLH1 proteins in Saccharomyces cerevisiae.";
RL Hum. Mol. Genet. 10:1889-1900(2001).
RN [49]
RP VARIANT HNPCC2 ARG-751.
RX MEDLINE=20579875; PubMed=11139242;
RX DOI=10.1002/1098-1004(2001)17:1<52::AID-HUMU6>3.0.CO;2-E;
RA Jakubowska A., Gorski B., Kurzawski G., Debniak T., Hadaczek P.,
RA Cybulski C., Kladny J., Oszurek O., Scott R.J., Lubinski J.;
RT "Optimization of experimental conditions for RNA-based sequencing of
RT MLH1 and MSH2 genes.";
RL Hum. Mutat. 17:52-60(2001).
RN [50]
RP VARIANTS HNPCC2 HIS-622 AND TRP-687.
RX MEDLINE=21614892; PubMed=11748856; DOI=10.1002/humu.1240;
RA Godino J., de La Hoya M., Diaz-Rubio E., Benito M., Caldes T.;
RT "Eight novel germline MLH1 and MSH2 mutations in hereditary non-
RT polyposis colorectal cancer families from Spain.";
RL Hum. Mutat. 18:549-549(2001).
RN [51]
RP CHARACTERIZATION OF VARIANTS HNPCC2 MET-117; GLY-185; CYS-217; ASP-244
RP AND ALA-326, AND CHARACTERIZATION OF VARIANTS VAL-219 AND HIS-265.
RX MEDLINE=21640300; PubMed=11781295;
RA Trojan J., Zeuzem S., Randolph A., Hemmerle C., Brieger A., Raedle J.,
RA Plotz G., Jiricny J., Marra G.;
RT "Functional analysis of hMLH1 variants and HNPCC-related mutations
RT using a human expression system.";
RL Gastroenterology 122:211-219(2002).
RN [52]
RP CHARACTERIZATION OF VARIANTS HNPCC2 ARG-77; GLY-93; ARG-107 AND
RP PRO-659.
RX MEDLINE=21652714; PubMed=11793442; DOI=10.1002/gcc.1225.abs;
RA Nystroem-Lahti M., Perrera C., Raeschle M., Panyushkina-Seiler E.,
RA Marra G., Curci A., Quaresima B., Costanzo F., D'Urso M., Venuta S.,
RA Jiricny J.;
RT "Functional analysis of MLH1 mutations linked to hereditary
RT nonpolyposis colon cancer.";
RL Genes Chromosomes Cancer 33:160-167(2002).
RN [53]
RP VARIANT HNPCC2 PRO-662, AND VARIANT VAL-219.
RX MEDLINE=21623227; PubMed=11754112; DOI=10.1002/humu.9004;
RA Krueger S., Plaschke J., Pistorius S., Jeske B., Haas S., Kraemer H.,
RA Hinterseher I., Bier A., Kreuz F.R., Theissig F., Saeger H.D.,
RA Schackert H.K.;
RT "Seven novel MLH1 and MSH2 germline mutations in hereditary
RT nonpolyposis colorectal cancer.";
RL Hum. Mutat. 19:82-82(2002).
RN [54]
RP VARIANT HNPCC2 PRO-586.
RX MEDLINE=22541470; PubMed=12655562; DOI=10.1002/humu.9121;
RA Kruger S., Plaschke J., Jeske B., Gorgens H., Pistorius S.R., Bier A.,
RA Kreuz F.R., Theissig F., Aust D.E., Saeger H.D., Schackert H.K.;
RT "Identification of six novel MSH2 and MLH1 germline mutations in
RT HNPCC.";
RL Hum. Mutat. 21:445-446(2003).
RN [55]
RP VARIANTS HNPCC2 CYS-18; ASP-101; LYS-182; CYS-379; ARG-559 AND LYS-616
RP DEL.
RX PubMed=14635101; DOI=10.1002/humu.10291;
RA Taylor C.F., Charlton R.S., Burn J., Sheridan E., Taylor G.R.;
RT "Genomic deletions in MSH2 or MLH1 are a frequent cause of hereditary
RT non-polyposis colorectal cancer: identification of novel and recurrent
RT deletions by MLPA.";
RL Hum. Mutat. 22:428-433(2003).
RN [56]
RP VARIANT HNPCC2 SER-648.
RX PubMed=15139004; DOI=10.1002/gcc.20040;
RA Raevaara T.E., Gerdes A.-M., Loennqvist K.E., Tybjaerg-Hansen A.,
RA Abdel-Rahman W.M., Kariola R., Peltomaeki P., Nystroem-Lahti M.;
RT "HNPCC mutation MLH1 P648S makes the functional protein unstable, and
RT homozygosity predisposes to mild neurofibromatosis type 1.";
RL Genes Chromosomes Cancer 40:261-265(2004).
RN [57]
RP VARIANT CRC HIS-132.
RX PubMed=15184898; DOI=10.1038/ng1374;
RA Lipkin S.M., Rozek L.S., Rennert G., Yang W., Chen P.-C., Hacia J.,
RA Hunt N., Shin B., Fodor S., Kokoris M., Greenson J.K., Fearon E.,
RA Lynch H., Collins F., Gruber S.B.;
RT "The MLH1 D132H variant is associated with susceptibility to sporadic
RT colorectal cancer.";
RL Nat. Genet. 36:694-699(2004).
Feature:
CHAIN 1 756 DNA mismatch repair protein Mlh1.
/FTId=PRO_0000178000.
REGION 410 650 Interaction with EXO1.
VARIANT 18 18 R -> C (in HNPCC2).
/FTId=VAR_022663.
VARIANT 28 28 P -> L (in HNPCC2).
/FTId=VAR_004433.
VARIANT 32 32 I -> V (in dbSNP:2020872).
/FTId=VAR_014876.
VARIANT 35 35 M -> R (in HNPCC2).
/FTId=VAR_004434.
VARIANT 37 37 E -> ELNH (in endometrial cancer;
somatic).
/FTId=VAR_004435.
VARIANT 44 44 S -> F (in HNPCC2; the equivalent
substitution in yeast causes loss of
function in a mismatch repair assay).
/FTId=VAR_004436.
VARIANT 54 54 G -> E (in sporadic CRC; somatic
mutation).
/FTId=VAR_012902.
VARIANT 62 62 Q -> K (in HNPCC2; reduced repair
efficiency in a yeast mismatch repair
assay).
/FTId=VAR_004437.
VARIANT 64 64 N -> S (in HNPCC2).
/FTId=VAR_004438.
VARIANT 67 67 G -> R (in HNPCC2; the equivalent
substitution in yeast causes loss of
function in a mismatch repair assay).
/FTId=VAR_004439.
VARIANT 67 67 G -> W (in HNPCC2).
/FTId=VAR_012903.
VARIANT 68 68 I -> N (in HNPCC2; the equivalent
substitution in yeast causes loss of
function in a mismatch repair assay).
/FTId=VAR_004440.
VARIANT 69 69 R -> K (in HNPCC2; reduced repair
efficiency in a mismatch repair assay).
/FTId=VAR_004441.
VARIANT 77 77 C -> R (in HNPCC2 and sporadic CRC;
normal interaction with PMS2; loss of
function in a mismatch repair assay).
/FTId=VAR_004442.
VARIANT 77 77 C -> Y (in sporadic CRC; early onset).
/FTId=VAR_012904.
VARIANT 80 80 F -> V (in HNPCC2; suspected).
/FTId=VAR_012905.
VARIANT 84 84 K -> E (in HNPCC2; suspected).
/FTId=VAR_012906.
VARIANT 93 93 S -> G (in HNPCC2; could be a
polymorphism; normal interaction with
PMS2; no functional alteration detected
by an in vitro mismatch repair assay).
/FTId=VAR_004443.
VARIANT 101 101 G -> D (in HNPCC2).
/FTId=VAR_022664.
VARIANT 107 107 I -> R (in HNPCC2; normal interaction
with PMS2; loss of function in a mismatch
repair assay).
/FTId=VAR_004444.
VARIANT 111 111 A -> V (in HNPCC2).
/FTId=VAR_012907.
VARIANT 117 117 T -> M (in HNPCC2; fails to interact with
PMS2 and EXO1; loss of function in a
mismatch repair assay).
/FTId=VAR_004445.
VARIANT 117 117 T -> R (in HNPCC2; equivalent
substitution in yeast causes loss of
function in mismatch repair assay).
/FTId=VAR_004446.
VARIANT 128 128 A -> P (in HNPCC2).
/FTId=VAR_012908.
VARIANT 132 132 D -> H (in sporadic CRC; susceptibility
to; ATPase function attenuated but not
eliminated).
/FTId=VAR_022665.
VARIANT 182 182 R -> G (in HNPCC2; incomplete).
/FTId=VAR_012909.
VARIANT 182 182 R -> K (in HNPCC2).
/FTId=VAR_022666.
VARIANT 185 185 V -> G (in HNPCC2; defective in a
mismatch repair assay).
/FTId=VAR_004447.
VARIANT 193 193 S -> P (in HNPCC2).
/FTId=VAR_004448.
VARIANT 213 213 V -> M (in HNPCC2; dbSNP:2308317).
/FTId=VAR_012910.
VARIANT 217 217 R -> C (in HNPCC2; proficient in a
mismatch repair assay; dbSNP:4986782).
/FTId=VAR_004449.
VARIANT 217 217 R -> G (in dbSNP:4986782).
/FTId=VAR_020469.
VARIANT 219 219 I -> V (common polymorphism; found in 37%
of alleles; dbSNP:1799977).
/FTId=VAR_004450.
VARIANT 226 295 Missing (in HNPCC2).
/FTId=VAR_004452.
VARIANT 226 226 R -> L (in HNPCC2).
/FTId=VAR_004451.
VARIANT 244 244 G -> D (in HNPCC2; defective in a
mismatch repair assay).
/FTId=VAR_012911.
VARIANT 244 244 G -> V (in sporadic CRC; somatic
mutation; could be a polymorphism).
/FTId=VAR_012912.
VARIANT 262 262 Missing (in HNPCC2).
/FTId=VAR_012913.
VARIANT 265 265 R -> H (rare polymorphism; slightly lower
mismatch repair efficiency).
/FTId=VAR_012914.
VARIANT 268 268 E -> G (in CRC).
/FTId=VAR_012915.
VARIANT 295 295 S -> T (in HNPCC2).
/FTId=VAR_012916.
VARIANT 325 325 R -> Q (in sporadic CRC; somatic
mutation; could be a polymorphism).
/FTId=VAR_012917.
VARIANT 326 326 V -> A (in HNPCC2; proficient in a
mismatch repair assay).
/FTId=VAR_004453.
VARIANT 329 329 H -> P (in HNPCC2).
/FTId=VAR_012918.
VARIANT 379 379 Y -> C (in HNPCC2).
/FTId=VAR_022667.
VARIANT 384 384 V -> D.
/FTId=VAR_004454.
VARIANT 406 406 S -> N.
/FTId=VAR_012919.
VARIANT 441 441 A -> T (in HNPCC2).
/FTId=VAR_012920.
VARIANT 492 492 A -> T (in HNPCC2 and sporadic CRC).
/FTId=VAR_004455.
VARIANT 506 506 V -> A (in HNPCC2).
/FTId=VAR_004456.
VARIANT 542 542 Q -> L (in HNPCC2; type II; equivalent
substitution in yeast causes loss of
function in a mismatch repair assay).
/FTId=VAR_004457.
VARIANT 549 549 L -> P (in HNPCC2).
/FTId=VAR_012921.
VARIANT 551 551 N -> T (in HNPCC2).
/FTId=VAR_012922.
VARIANT 559 559 L -> R (in HNPCC2).
/FTId=VAR_022668.
VARIANT 565 565 I -> F (in HNPCC2).
/FTId=VAR_012923.
VARIANT 574 574 L -> P (in HNPCC2; type I).
/FTId=VAR_004458.
VARIANT 578 578 E -> G (in HNPCC2 and CRC).
/FTId=VAR_004459.
VARIANT 582 582 L -> V (in HNPCC2; type II).
/FTId=VAR_004460.
VARIANT 586 586 A -> P (in HNPCC2).
/FTId=VAR_015689.
VARIANT 588 588 L -> P (in HNPCC2).
/FTId=VAR_012924.
VARIANT 603 603 P -> R (in HNPCC2; suspected; could be a
polymorphism).
/FTId=VAR_012925.
VARIANT 607 607 L -> H (in LCIS and HNPCC2).
/FTId=VAR_012926.
VARIANT 616 616 Missing (in HNPCC2 and Turcot syndrome).
/FTId=VAR_004461.
VARIANT 618 618 K -> A (in HNPCC2; requires 2 nucleotide
substitutions).
/FTId=VAR_004462.
VARIANT 618 618 K -> T (in HNPCC2; type II).
/FTId=VAR_004463.
VARIANT 622 622 L -> H (in HNPCC2).
/FTId=VAR_012927.
VARIANT 626 627 FS -> ST (in HNPCC2).
/FTId=VAR_004464.
VARIANT 648 648 P -> L (in suspected HNPCC2).
/FTId=VAR_012928.
VARIANT 648 648 P -> S (in HNPCC2; protein unstable but
still functional in mismatch repair).
/FTId=VAR_022669.
VARIANT 659 659 R -> L (in HNPCC2).
/FTId=VAR_012929.
VARIANT 659 659 R -> P (in HNPCC2; interacts only very
weakly with PMS2; equivalent substitution
in yeast causes almost complete loss of
function in a mismatch repair assay).
/FTId=VAR_004465.
VARIANT 662 662 T -> P (in HNPCC2; could be a rare
polymorphism).
/FTId=VAR_012930.
VARIANT 681 681 A -> T (in HNPCC2; equivalent
substitution in yeast does not affect
mismatch repair).
/FTId=VAR_004466.
VARIANT 687 687 R -> W (in HNPCC2).
/FTId=VAR_012931.
VARIANT 689 689 Q -> R (in HNPCC; suspected; could be a
polymorphism).
/FTId=VAR_012932.
VARIANT 716 716 V -> M (in HNPCC2; could be a
polymorphism).
/FTId=VAR_012933.
VARIANT 718 718 H -> Y (in dbSNP:2020873).
/FTId=VAR_004467.
VARIANT 729 729 L -> V (in dbSNP:1800149).
/FTId=VAR_004468.
VARIANT 751 751 K -> R (in HNPCC2).
/FTId=VAR_012934.
VARIANT 755 755 R -> W (in HNPCC; incomplete).
/FTId=VAR_012935.
MUTAGEN 574 574 L->P: Abrogates interaction with EXO1.
MUTAGEN 616 616 Missing: Abrogates interaction with EXO1.
MUTAGEN 659 659 R->P: Abrogates interaction with EXO1.
MUTAGEN 681 681 A->T: Abrogates interaction with EXO1.
CONFLICT 708 711 Missing (in Ref. 4).
Comments:
-!- FUNCTION: Involved in the repair of mismatches in DNA.
-!- SUBUNIT: Heterodimer of MLH1 and PMS2 or MLH1 and MLH3. Part of
the BRCA1-associated genome surveillance complex (BASC), which
contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-
MRE11-NBS1 protein complex. This association could be a dynamic
process changing throughout the cell cycle and within subnuclear
domains. Interacts with MBD4. Interacts with EXO1.
-!- SUBCELLULAR LOCATION: Nucleus.
-!- TISSUE SPECIFICITY: Colon, lymphocytes, breast, lung, spleen,
testis, prostate, thyroid, gall bladder and heart.
-!- DISEASE: Defects in MLH1 are the cause of hereditary non-polyposis
colorectal cancer type 2 (HNPCC2) [MIM:609310]. Mutations in more
than one gene locus can be involved alone or in combination in the
production of the HNPCC phenotype (also called Lynch syndrome).
Most families with clinically recognized HNPCC have mutations in
either MLH1 or MSH2 genes. HNPCC is an autosomal, dominantly
inherited disease associated with marked increase in cancer
susceptibility. It is characterized by a familial predisposition
to early onset colorectal carcinoma (CRC) and extra-colonic
cancers of the gastrointestinal, urological and female
reproductive tracts. HNPCC is reported to be the most common form
of inherited colorectal cancer in the Western world, and accounts
for 15% of all colon cancers. Cancers in HNPCC originate within
benign neoplastic polyps termed adenomas. Clinically, HNPCC is
often divided into two subgroups. Type I: hereditary
predisposition to colorectal cancer, a young age of onset, and
carcinoma observed in the proximal colon. Type II: patients have
an increased risk for cancers in certain tissues such as the
uterus, ovary, breast, stomach, small intestine, skin, and larynx
in addition to the colon. Diagnosis of classical HNPCC is based on
the Amsterdam criteria: 3 or more relatives affected by colorectal
cancer, one a first degree relative of the other two; 2 or more
generation affected; 1 or more colorectal cancers presenting
before 50 years of age; exclusion of hereditary polyposis
syndromes. The term "suspected HNPCC" or "incomplete HNPCC" can be
used to describe families who do not or only partially fulfill the
Amsterdam criteria, but in whom a genetic basis for colon cancer
is strongly suspected.
-!- DISEASE: Defects in MLH1 are a cause of Turcot syndrome
[MIM:276300]. Turcot syndrome is an autosomal dominant disorder
characterized by malignant tumors of the brain associated with
multiple colorectal adenomas. Skin features include sebaceous
cysts, hyperpigmented and cafe au lait spots.
-!- DISEASE: Defects in MLH1 are a cause of Muir-Torre syndrome (MTS)
[MIM:158320]. MTS is a rare autosomal dominant disorder
characterized by sebaceous neoplasms and visceral malignancy.
-!- DISEASE: Defects in MLH1 may contribute to lobular carcinoma in
situ (LCIS), a non-invasive neoplastic disease of the breast.
-!- DISEASE: Defects in MLH1 are a cause of susceptibility to
endometrial cancer [MIM:608089].
-!- SIMILARITY: Belongs to the DNA mismatch repair mutL/hexB family.
-!- DATABASE: NAME=Hereditary non-polyposis colorectal cancer db;
WWW="http://www.nfdht.nl/".
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Sequence length: 756
MSFVAGVIRR LDETVVNRIA AGEVIQRPAN AIKEMIENCL DAKSTSIQVI VKEGGLKLIQ
IQDNGTGIRK EDLDIVCERF TTSKLQSFED LASISTYGFR GEALASISHV AHVTITTKTA
DGKCAYRASY SDGKLKAPPK PCAGNQGTQI TVEDLFYNIA TRRKALKNPS EEYGKILEVV
GRYSVHNAGI SFSVKKQGET VADVRTLPNA STVDNIRSIF GNAVSRELIE IGCEDKTLAF
KMNGYISNAN YSVKKCIFLL FINHRLVEST SLRKAIETVY AAYLPKNTHP FLYLSLEISP
QNVDVNVHPT KHEVHFLHEE SILERVQQHI ESKLLGSNSS RMYFTQTLLP GLAGPSGEMV
KSTTSLTSSS TSGSSDKVYA HQMVRTDSRE QKLDAFLQPL SKPLSSQPQA IVTEDKTDIS
SGRARQQDEE MLELPAPAEV AAKNQSLEGD TTKGTSEMSE KRGPTSSNPR KRHREDSDVE
MVEDDSRKEM TAACTPRRRI INLTSVLSLQ EEINEQGHEV LREMLHNHSF VGCVNPQWAL
AQHQTKLYLL NTTKLSEELF YQILIYDFAN FGVLRLSEPA PLFDLAMLAL DSPESGWTEE
DGPKEGLAEY IVEFLKKKAE MLADYFSLEI DEEGNLIGLP LLIDNYVPPL EGLPIFILRL
ATEVNWDEEK ECFESLSKEC AMFYSIRKQY ISEESTLSGQ QSEVPGSIPN SWKWTVEHIV
YKALRSHILP PKHFTEDGNI LQLANLPDLY KVFERC