FOXE1_HUMAN
ID FOXE1_HUMAN Reviewed; 373 AA.
AC O00358; O75765; Q5T109; Q99526;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 23-SEP-2008, sequence version 3.
DT 03-AUG-2022, entry version 189.
DE RecName: Full=Forkhead box protein E1;
DE AltName: Full=Forkhead box protein E2;
DE AltName: Full=Forkhead-related protein FKHL15;
DE AltName: Full=HFKH4;
DE AltName: Full=HNF-3/fork head-like protein 5;
DE Short=HFKL5;
DE AltName: Full=Thyroid transcription factor 2;
DE Short=TTF-2;
GN Name=FOXE1; Synonyms=FKHL15, FOXE2, TITF2, TTF2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP PRELIMINARY NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Fetal brain;
RX PubMed=9052737; DOI=10.1089/dna.1997.16.165;
RA Wiese S., Emmerich D., Schroeder B., Murphy D.B., Grzeschik K.H.,
RA Van Kessel A.G., Thies U.;
RT "The novel human HNF-3/fork head-like 5 gene: chromosomal localization and
RT expression pattern.";
RL DNA Cell Biol. 16:165-171(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND POLYMORPHISM OF POLY-ALA REGION.
RC TISSUE=Keratinocyte;
RX PubMed=9169137; DOI=10.1006/geno.1997.4692;
RA Chadwick B.P., Obermayr F., Frischauf A.-M.;
RT "FKHL15, a new human member of the forkhead gene family located on
RT chromosome 9q22.";
RL Genomics 41:390-396(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND POLYMORPHISM.
RX PubMed=10403172; DOI=10.1016/s0300-9084(99)80092-3;
RA Macchia P.E., Mattei M.-G., Lapi P., Fenzi G., Di Lauro R.;
RT "Cloning, chromosomal localization and identification of polymorphisms in
RT the human thyroid transcription factor 2 gene (TITF2).";
RL Biochimie 81:433-440(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L.,
RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S.,
RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K.,
RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C.,
RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E.,
RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M.,
RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J.,
RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P.,
RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S.,
RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J.,
RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E.,
RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V.,
RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S.,
RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K.,
RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J.,
RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M.,
RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L.,
RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J.,
RA Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP FUNCTION, INVOLVEMENT IN BLS, VARIANT BLS VAL-65, AND CHARACTERIZATION OF
RP VARIANT BLS VAL-65.
RX PubMed=9697705; DOI=10.1038/1294;
RA Clifton-Bligh R.J., Wentworth J.M., Heinz P., Crisp M.S., John R.,
RA Lazarus J.H., Ludgate M., Chatterjee V.K.;
RT "Mutation of the gene encoding human TTF-2 associated with thyroid
RT agenesis, cleft palate and choanal atresia.";
RL Nat. Genet. 19:399-401(1998).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANTS BLS ASN-57 AND
RP VAL-65, AND CHARACTERIZATION OF VARIANTS CONGENITAL HYPOTHYROIDISM CYS-102
RP AND SER-137.
RX PubMed=21177256; DOI=10.1093/hmg/ddq547;
RA Venza I., Visalli M., Parrillo L., De Felice M., Teti D., Venza M.;
RT "MSX1 and TGF-beta3 are novel target genes functionally regulated by
RT FOXE1.";
RL Hum. Mol. Genet. 20:1016-1025(2011).
RN [8]
RP FUNCTION, INVOLVEMENT IN NMTC4, VARIANT NMTC4 GLY-248, AND CHARACTERIZATION
RP OF VARIANT NMTC4 GLY-248.
RX PubMed=25381600; DOI=10.1007/s12020-014-0470-0;
RA Pereira J.S., da Silva J.G., Tomaz R.A., Pinto A.E., Bugalho M.J.,
RA Leite V., Cavaco B.M.;
RT "Identification of a novel germline FOXE1 variant in patients with familial
RT non-medullary thyroid carcinoma (FNMTC).";
RL Endocrine 49:204-214(2015).
RN [9]
RP VARIANT BLS ASN-57, CHARACTERIZATION OF VARIANT BLS ASN-57 AND VAL-65, AND
RP FUNCTION.
RX PubMed=12165566; DOI=10.1093/hmg/11.17.2051;
RA Castanet M., Park S.M., Smith A., Bost M., Leger J., Lyonnet S., Pelet A.,
RA Czernichow P., Chatterjee K., Polak M.;
RT "A novel loss-of-function mutation in TTF-2 is associated with congenital
RT hypothyroidism, thyroid agenesis and cleft palate.";
RL Hum. Mol. Genet. 11:2051-2059(2002).
RN [10]
RP VARIANT CONGENITAL HYPOTHYROIDISM CYS-102, CHARACTERIZATION OF VARIANT
RP CONGENITAL HYPOTHYROIDISM CYS-102, AND FUNCTION.
RX PubMed=16882747; DOI=10.1210/jc.2006-0405;
RA Baris I., Arisoy A.E., Smith A., Agostini M., Mitchell C.S., Park S.M.,
RA Halefoglu A.M., Zengin E., Chatterjee V.K., Battaloglu E.;
RT "A novel missense mutation in human TTF-2 (FKHL15) gene associated with
RT congenital hypothyroidism but not athyreosis.";
RL J. Clin. Endocrinol. Metab. 91:4183-4187(2006).
RN [11]
RP VARIANT CONGENITAL HYPOTHYROIDISM ASP-132, CHARACTERIZATION OF VARIANT
RP CONGENITAL HYPOTHYROIDISM ASP-132, AND FUNCTION.
RX PubMed=20094846; DOI=10.1007/s10528-009-9306-7;
RA Kang I.N., Musa M., Harun F., Junit S.M.;
RT "Characterization of mutations in the FOXE1 gene in a cohort of unrelated
RT Malaysian patients with congenital hypothyroidism and thyroid dysgenesis.";
RL Biochem. Genet. 48:141-151(2010).
RN [12]
RP VARIANT CONGENITAL HYPOTHYROIDISM SER-137, CHARACTERIZATION OF VARIANT
RP CONGENITAL HYPOTHYROIDISM SER-137, AND FUNCTION.
RX PubMed=20484477; DOI=10.1210/jc.2010-0275;
RA Castanet M., Mallya U., Agostini M., Schoenmakers E., Mitchell C.,
RA Demuth S., Raymond F.L., Schwabe J., Gurnell M., Chatterjee V.K.;
RT "Maternal isodisomy for chromosome 9 causing homozygosity for a novel FOXE1
RT mutation in syndromic congenital hypothyroidism.";
RL J. Clin. Endocrinol. Metab. 95:4031-4036(2010).
RN [13]
RP VARIANT BLS SER-73, CHARACTERIZATION OF VARIANT BLS SER-73, AND FUNCTION.
RX PubMed=24219130; DOI=10.1089/thy.2013.0417;
RA Carre A., Hamza R.T., Kariyawasam D., Guillot L., Teissier R., Tron E.,
RA Castanet M., Dupuy C., El Kholy M., Polak M.;
RT "A novel FOXE1 mutation (R73S) in Bamforth-Lazarus syndrome causing
RT increased thyroidal gene expression.";
RL Thyroid 24:649-654(2014).
CC -!- FUNCTION: Transcription factor that binds consensus sites on a variety
CC of gene promoters and activate their transcription. Involved in proper
CC palate formation, most probably through the expression of MSX1 and
CC TGFB3 genes which are direct targets of this transcription factor. Also
CC implicated in thyroid gland morphogenesis. May indirectly play a role
CC in cell growth and migration through the regulation of WNT5A
CC expression. {ECO:0000269|PubMed:12165566, ECO:0000269|PubMed:16882747,
CC ECO:0000269|PubMed:20094846, ECO:0000269|PubMed:20484477,
CC ECO:0000269|PubMed:21177256, ECO:0000269|PubMed:24219130,
CC ECO:0000269|PubMed:25381600, ECO:0000269|PubMed:9697705}.
CC -!- INTERACTION:
CC O00358; P19419: ELK1; NbExp=8; IntAct=EBI-11317834, EBI-726632;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:21177256}.
CC -!- TISSUE SPECIFICITY: Detected in adult brain, placenta, lung, liver,
CC skeletal muscle, kidney, pancreas, heart, colon, small intestine testis
CC and thymus. Expression was strongest in heart and pancreas.
CC -!- PTM: Phosphorylated. {ECO:0000250}.
CC -!- POLYMORPHISM: An alanine stretch that varies from 12 to 19 residues is
CC present. This polymorphisms can be used as a marker to study the role
CC of FOXE1 in other cases of thyroid dysgenesis, especially in familial
CC cases.
CC -!- DISEASE: Bamforth-Lazarus syndrome (BLS) [MIM:241850]: A disease
CC characterized by thyroid agenesis, cleft palate and choanal atresia.
CC {ECO:0000269|PubMed:12165566, ECO:0000269|PubMed:21177256,
CC ECO:0000269|PubMed:24219130, ECO:0000269|PubMed:9697705}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Thyroid cancer, non-medullary, 4 (NMTC4) [MIM:616534]: A form
CC of non-medullary thyroid cancer (NMTC), a cancer characterized by
CC tumors originating from the thyroid follicular cells. NMTCs represent
CC approximately 95% of all cases of thyroid cancer and are classified
CC into papillary, follicular, Hurthle cell, and anaplastic neoplasms.
CC {ECO:0000269|PubMed:25381600}. Note=Disease susceptibility is
CC associated with variants affecting the gene represented in this entry.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA64246.1; Type=Miscellaneous discrepancy; Note=Several conflicts.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/FOXE1ID47197ch9q22.html";
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DR EMBL; X94553; CAA64246.1; ALT_SEQ; mRNA.
DR EMBL; U89995; AAC51294.1; -; mRNA.
DR EMBL; Y13386; CAA73816.1; -; Genomic_DNA.
DR EMBL; AL499604; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471105; EAW58856.1; -; Genomic_DNA.
DR CCDS; CCDS35078.1; -.
DR RefSeq; NP_004464.2; NM_004473.3.
DR AlphaFoldDB; O00358; -.
DR SMR; O00358; -.
DR BioGRID; 108593; 105.
DR IntAct; O00358; 76.
DR MINT; O00358; -.
DR STRING; 9606.ENSP00000364265; -.
DR iPTMnet; O00358; -.
DR PhosphoSitePlus; O00358; -.
DR BioMuta; FOXE1; -.
DR jPOST; O00358; -.
DR MassIVE; O00358; -.
DR PaxDb; O00358; -.
DR PeptideAtlas; O00358; -.
DR PRIDE; O00358; -.
DR ProteomicsDB; 47861; -.
DR Antibodypedia; 28896; 273 antibodies from 34 providers.
DR DNASU; 2304; -.
DR Ensembl; ENST00000375123.5; ENSP00000364265.3; ENSG00000178919.9.
DR GeneID; 2304; -.
DR KEGG; hsa:2304; -.
DR MANE-Select; ENST00000375123.5; ENSP00000364265.3; NM_004473.4; NP_004464.2.
DR UCSC; uc004axu.4; human.
DR CTD; 2304; -.
DR DisGeNET; 2304; -.
DR GeneCards; FOXE1; -.
DR HGNC; HGNC:3806; FOXE1.
DR HPA; ENSG00000178919; Tissue enriched (thyroid).
DR MalaCards; FOXE1; -.
DR MIM; 241850; phenotype.
DR MIM; 602617; gene.
DR MIM; 616534; phenotype.
DR neXtProt; NX_O00358; -.
DR OpenTargets; ENSG00000178919; -.
DR Orphanet; 95713; Athyreosis.
DR Orphanet; 1226; Bamforth-Lazarus syndrome.
DR Orphanet; 146; Differentiated thyroid carcinoma.
DR Orphanet; 319487; Familial papillary or follicular thyroid carcinoma.
DR PharmGKB; PA28223; -.
DR VEuPathDB; HostDB:ENSG00000178919; -.
DR eggNOG; KOG2294; Eukaryota.
DR GeneTree; ENSGT00940000162270; -.
DR HOGENOM; CLU_023357_0_1_1; -.
DR InParanoid; O00358; -.
DR OMA; QPAGCTG; -.
DR OrthoDB; 1270467at2759; -.
DR PhylomeDB; O00358; -.
DR TreeFam; TF316127; -.
DR PathwayCommons; O00358; -.
DR SignaLink; O00358; -.
DR SIGNOR; O00358; -.
DR BioGRID-ORCS; 2304; 16 hits in 1087 CRISPR screens.
DR ChiTaRS; FOXE1; human.
DR GeneWiki; FOXE1; -.
DR GenomeRNAi; 2304; -.
DR Pharos; O00358; Tbio.
DR PRO; PR:O00358; -.
DR Proteomes; UP000005640; Chromosome 9.
DR RNAct; O00358; protein.
DR Bgee; ENSG00000178919; Expressed in right lobe of thyroid gland and 74 other tissues.
DR Genevisible; O00358; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:UniProtKB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:UniProtKB.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0009653; P:anatomical structure morphogenesis; IBA:GO_Central.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0016477; P:cell migration; ISS:UniProtKB.
DR GO; GO:1904888; P:cranial skeletal system development; IEA:Ensembl.
DR GO; GO:0048562; P:embryonic organ morphogenesis; ISS:UniProtKB.
DR GO; GO:0031069; P:hair follicle morphogenesis; ISS:UniProtKB.
DR GO; GO:0060022; P:hard palate development; IMP:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0060465; P:pharynx development; IEP:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0060023; P:soft palate development; IMP:UniProtKB.
DR GO; GO:0048538; P:thymus development; IEP:UniProtKB.
DR GO; GO:0030878; P:thyroid gland development; IMP:UniProtKB.
DR GO; GO:0006590; P:thyroid hormone generation; ISS:UniProtKB.
DR CDD; cd00059; FH; 1.
DR Gene3D; 1.10.10.10; -; 1.
DR InterPro; IPR001766; Fork_head_dom.
DR InterPro; IPR018122; TF_fork_head_CS_1.
DR InterPro; IPR030456; TF_fork_head_CS_2.
DR InterPro; IPR036388; WH-like_DNA-bd_sf.
DR InterPro; IPR036390; WH_DNA-bd_sf.
DR Pfam; PF00250; Forkhead; 1.
DR PRINTS; PR00053; FORKHEAD.
DR SMART; SM00339; FH; 1.
DR SUPFAM; SSF46785; SSF46785; 1.
DR PROSITE; PS00657; FORK_HEAD_1; 1.
DR PROSITE; PS00658; FORK_HEAD_2; 1.
DR PROSITE; PS50039; FORK_HEAD_3; 1.
PE 1: Evidence at protein level;
KW Congenital hypothyroidism; Disease variant; DNA-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Transcription;
KW Transcription regulation.
FT CHAIN 1..373
FT /note="Forkhead box protein E1"
FT /id="PRO_0000091826"
FT DNA_BIND 53..147
FT /note="Fork-head"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00089"
FT REGION 19..51
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VARIANT 57
FT /note="S -> N (in BLS; without choanal atresia; no effect
FT on protein abundance; no effect on localization to the
FT nucleus; decreased sequence-specific DNA binding; decreased
FT transcriptional activity; dbSNP:rs28937575)"
FT /evidence="ECO:0000269|PubMed:12165566,
FT ECO:0000269|PubMed:21177256"
FT /id="VAR_016882"
FT VARIANT 65
FT /note="A -> V (in BLS; loss of sequence-specific DNA
FT binding; loss of transcriptional activity;
FT dbSNP:rs104894110)"
FT /evidence="ECO:0000269|PubMed:12165566,
FT ECO:0000269|PubMed:21177256, ECO:0000269|PubMed:9697705"
FT /id="VAR_008857"
FT VARIANT 73
FT /note="R -> S (in BLS; no effect on protein abundance; no
FT effect on sequence-specific DNA binding; enhances
FT transcriptional activity toward TG and TPO genes)"
FT /evidence="ECO:0000269|PubMed:24219130"
FT /id="VAR_075978"
FT VARIANT 102
FT /note="R -> C (in congenital hypothyroidism; with absence
FT of thyroid agenesis; loss of sequence-specific DNA binding;
FT loss of transcriptional activity; dbSNP:rs104894111)"
FT /evidence="ECO:0000269|PubMed:16882747,
FT ECO:0000269|PubMed:21177256"
FT /id="VAR_027508"
FT VARIANT 132
FT /note="N -> D (in congenital hypothyroidism; slightly
FT decreased sequence-specific DNA binding to the TPO
FT promoter; 0.5 fold decreased transcriptional activity;
FT dbSNP:rs762041111)"
FT /evidence="ECO:0000269|PubMed:20094846"
FT /id="VAR_075979"
FT VARIANT 137
FT /note="F -> S (in congenital hypothyroidism; loss of
FT sequence-specific DNA binding; loss of transcriptional
FT activity)"
FT /evidence="ECO:0000269|PubMed:20484477,
FT ECO:0000269|PubMed:21177256"
FT /id="VAR_075980"
FT VARIANT 179
FT /note="A -> AAA"
FT /id="VAR_037643"
FT VARIANT 248
FT /note="A -> G (in NMTC4; increased cell growth; increased
FT cell migration; associated with increased expression of the
FT WNT5A gene; dbSNP:rs538912281)"
FT /evidence="ECO:0000269|PubMed:25381600"
FT /id="VAR_075981"
SQ SEQUENCE 373 AA; 38076 MW; D201EAF05572FCF0 CRC64;
MTAESGPPPP QPEVLATVKE ERGETAAGAG VPGEATGRGA GGRRRKRPLQ RGKPPYSYIA
LIAMAIAHAP ERRLTLGGIY KFITERFPFY RDNPKKWQNS IRHNLTLNDC FLKIPREAGR
PGKGNYWALD PNAEDMFESG SFLRRRKRFK RSDLSTYPAY MHDAAAAAAA AAAAAAAAAI
FPGAVPAARP PYPGAVYAGY APPSLAAPPP VYYPAASPGP CRVFGLVPER PLSPELGPAP
SGPGGSCAFA SAGAPATTTG YQPAGCTGAR PANPSAYAAA YAGPDGAYPQ GAGSAIFAAA
GRLAGPASPP AGGSSGGVET TVDFYGRTSP GQFGALGACY NPGGQLGGAS AGAYHARHAA
AYPGGIDRFV SAM
