GDF6_HUMAN
ID GDF6_HUMAN Reviewed; 455 AA.
AC Q6KF10; Q6PI58;
DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 140.
DE RecName: Full=Growth/differentiation factor 6;
DE Short=GDF-6;
DE AltName: Full=Bone morphogenetic protein 13;
DE Short=BMP-13;
DE AltName: Full=Growth/differentiation factor 16;
DE Flags: Precursor;
GN Name=GDF6; Synonyms=BMP13, GDF16;
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 NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Hindbrain;
RA Guo J.H.;
RT "Cloning of human GDF16 and functional associated analysis.";
RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 255-455.
RC TISSUE=Testis;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP CHROMOSOMAL REARRANGEMENT, AND VARIANTS KFS1 GLU-249 AND PRO-289.
RX PubMed=18425797; DOI=10.1002/humu.20741;
RA Tassabehji M., Fang Z.M., Hilton E.N., McGaughran J., Zhao Z.,
RA de Bock C.E., Howard E., Malass M., Donnai D., Diwan A., Manson F.D.C.,
RA Murrell D., Clarke R.A.;
RT "Mutations in GDF6 are associated with vertebral segmentation defects in
RT Klippel-Feil syndrome.";
RL Hum. Mutat. 29:1017-1027(2008).
RN [4]
RP FUNCTION, SUBCELLULAR LOCATION, VARIANTS LCA17 HIS-57; THR-199; GLU-249 AND
RP ASP-292, AND CHARACTERIZATION OF VARIANTS LCA17 HIS-57; THR-199; GLU-249
RP AND ASP-292.
RX PubMed=23307924; DOI=10.1093/hmg/dds560;
RA Asai-Coakwell M., March L., Dai X.H., Duval M., Lopez I., French C.R.,
RA Famulski J., De Baere E., Francis P.J., Sundaresan P., Sauve Y.,
RA Koenekoop R.K., Berry F.B., Allison W.T., Waskiewicz A.J., Lehmann O.J.;
RT "Contribution of growth differentiation factor 6-dependent cell survival to
RT early-onset retinal dystrophies.";
RL Hum. Mol. Genet. 22:1432-1442(2013).
RN [5]
RP INVOLVEMENT IN DFNB118.
RX PubMed=32369452; DOI=10.1172/jci136951;
RA Bademci G., Abad C., Cengiz F.B., Seyhan S., Incesulu A., Guo S., Fitoz S.,
RA Atli E.I., Gosstola N.C., Demir S., Colbert B.M., Seyhan G.C., Sineni C.J.,
RA Duman D., Gurkan H., Morton C.C., Dykxhoorn D.M., Walz K., Tekin M.;
RT "Long-range cis-regulatory elements controlling GDF6 expression are
RT essential for ear development.";
RL J. Clin. Invest. 130:4213-4217(2020).
RN [6]
RP VARIANTS MCOP4 ARG-119; GLY-216; GLU-249; LEU-253 AND HIS-327, AND VARIANTS
RP KFS1 VAL-42 AND ARG-424.
RX PubMed=19129173; DOI=10.1093/hmg/ddp008;
RA Asai-Coakwell M., French C.R., Ye M., Garcha K., Bigot K., Perera A.G.,
RA Staehling-Hampton K., Mema S.C., Chanda B., Mushegian A., Bamforth S.,
RA Doschak M.R., Li G., Dobbs M.B., Giampietro P.F., Brooks B.P.,
RA Vijayalakshmi P., Sauve Y., Abitbol M., Sundaresan P., van Heyningen V.,
RA Pourquie O., Underhill T.M., Waskiewicz A.J., Lehmann O.J.;
RT "Incomplete penetrance and phenotypic variability characterize Gdf6-
RT attributable oculo-skeletal phenotypes.";
RL Hum. Mol. Genet. 18:1110-1121(2009).
RN [7]
RP VARIANT THR-199.
RX PubMed=19864492; DOI=10.1093/hmg/ddp496;
RA Ye M., Berry-Wynne K.M., Asai-Coakwell M., Sundaresan P., Footz T.,
RA French C.R., Abitbol M., Fleisch V.C., Corbett N., Allison W.T.,
RA Drummond G., Walter M.A., Underhill T.M., Waskiewicz A.J., Lehmann O.J.;
RT "Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal
RT anomalies.";
RL Hum. Mol. Genet. 19:287-298(2010).
RN [8]
RP VARIANT MCOP4 HIS-327.
RX PubMed=24033328; DOI=10.1111/cge.12275;
RA Chassaing N., Causse A., Vigouroux A., Delahaye A., Alessandri J.L.,
RA Boespflug-Tanguy O., Boute-Benejean O., Dollfus H., Duban-Bedu B.,
RA Gilbert-Dussardier B., Giuliano F., Gonzales M., Holder-Espinasse M.,
RA Isidor B., Jacquemont M.L., Lacombe D., Martin-Coignard D.,
RA Mathieu-Dramard M., Odent S., Picone O., Pinson L., Quelin C., Sigaudy S.,
RA Toutain A., Thauvin-Robinet C., Kaplan J., Calvas P.;
RT "Molecular findings and clinical data in a cohort of 150 patients with
RT anophthalmia/microphthalmia.";
RL Clin. Genet. 86:326-334(2014).
RN [9]
RP INVOLVEMENT IN SYNS4, VARIANT SYNS4 ASN-444, CHARACTERIZATION OF VARIANT
RP SYNS4 ASN-444, AND FUNCTION.
RX PubMed=26643732; DOI=10.1002/jbmr.2761;
RA Wang J., Yu T., Wang Z., Ohte S., Yao R.E., Zheng Z., Geng J., Cai H.,
RA Ge Y., Li Y., Xu Y., Zhang Q., Gusella J.F., Fu Q., Pregizer S., Rosen V.,
RA Shen Y.;
RT "A New Subtype of Multiple-Synostoses Syndrome is Caused by a Mutation in
RT GDF6 that Decreases its Sensitivity to Noggin and Enhances its Potency as a
RT BMP Signal.";
RL J. Bone Miner. Res. 31:882-889(2016).
RN [10]
RP VARIANT SYNS4 ARG-429, AND INVOLVEMENT IN SYNS4.
RX PubMed=29130651; DOI=10.1002/ajmg.a.38503;
RA Terhal P.A., Verbeek N.E., Knoers N., Nievelstein R.J.A.J.,
RA van den Ouweland A., Sakkers R.J., Speleman L., van Haaften G.;
RT "Further delineation of the GDF6 related multiple synostoses syndrome.";
RL Am. J. Med. Genet. A 176:225-229(2018).
CC -!- FUNCTION: Growth factor that controls proliferation and cellular
CC differentiation in the retina and bone formation. Plays a key role in
CC regulating apoptosis during retinal development. Establishes dorsal-
CC ventral positional information in the retina and controls the formation
CC of the retinotectal map (PubMed:23307924). Required for normal
CC formation of bones and joints in the limbs, skull, digits and axial
CC skeleton. Plays a key role in establishing boundaries between skeletal
CC elements during development. Regulation of GDF6 expression seems to be
CC a mechanism for evolving species-specific changes in skeletal
CC structures. Seems to positively regulate differentiation of
CC chondrogenic tissue through the growth factor receptors subunits
CC BMPR1A, BMPR1B, BMPR2 and ACVR2A, leading to the activation of SMAD1-
CC SMAD5-SMAD8 complex. The regulation of chondrogenic differentiation is
CC inhibited by NOG (PubMed:26643732). Also involved in the induction of
CC adipogenesis from mesenchymal stem cells. This mechanism acts through
CC the growth factor receptors subunits BMPR1A, BMPR2 and ACVR2A and the
CC activation of SMAD1-SMAD5-SMAD8 complex and MAPK14/p38 (By similarity).
CC {ECO:0000250|UniProtKB:P43028, ECO:0000269|PubMed:23307924,
CC ECO:0000269|PubMed:26643732}.
CC -!- SUBUNIT: Homodimer; disulfide-linked. {ECO:0000250|UniProtKB:P39905}.
CC -!- INTERACTION:
CC PRO_0000042253; P98066: TNFAIP6; NbExp=3; IntAct=EBI-11710019, EBI-11700693;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:23307924}.
CC -!- DISEASE: Klippel-Feil syndrome 1, autosomal dominant (KFS1)
CC [MIM:118100]: A skeletal disorder characterized by congenital fusion of
CC cervical vertebrae. It is due to a failure in the normal segmentation
CC of vertebrae during the early weeks of fetal development. The clinical
CC triad consists of short neck, low posterior hairline, and limited neck
CC movement. Deafness is a feature in some cases and may be of
CC sensorineural, conductive, or mixed type. {ECO:0000269|PubMed:18425797,
CC ECO:0000269|PubMed:19129173}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Note=A chromosomal aberration involving GDF6 has been found in
CC a patient with Klippel-Feil syndrome (KFS). Paracentric
CC inv(8)(q22;2q23.3). {ECO:0000269|PubMed:18425797}.
CC -!- DISEASE: Microphthalmia, isolated, 4 (MCOP4) [MIM:613094]: A disorder
CC of eye formation, ranging from small size of a single eye to complete
CC bilateral absence of ocular tissues. Ocular abnormalities like
CC opacities of the cornea and lens, scaring of the retina and choroid,
CC and other abnormalities may also be present.
CC {ECO:0000269|PubMed:19129173, ECO:0000269|PubMed:24033328}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Leber congenital amaurosis 17 (LCA17) [MIM:615360]: A severe
CC dystrophy of the retina, typically becoming evident in the first years
CC of life. Visual function is usually poor and often accompanied by
CC nystagmus, sluggish or almost absent pupillary responses, photophobia,
CC high hyperopia and keratoconus. {ECO:0000269|PubMed:23307924}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Multiple synostoses syndrome 4 (SYNS4) [MIM:617898]: A bone
CC disease characterized by multiple progressive joint fusions that
CC commonly involve proximal interphalangeal, tarsal-carpal, humeroradial
CC and cervical spine joints. Additional features can include progressive
CC conductive deafness and facial dysmorphism. SYNS4 inheritance is
CC autosomal dominant. {ECO:0000269|PubMed:26643732,
CC ECO:0000269|PubMed:29130651}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Deafness, autosomal recessive, 118, with cochlear aplasia
CC (DFNB118) [MIM:619553]: A form of non-syndromic deafness characterized
CC by congenital profound sensorineural hearing loss and cochlear aplasia.
CC Sensorineural hearing loss results from damage to the neural receptors
CC of the inner ear, the nerve pathways to the brain, or the area of the
CC brain that receives sound information. {ECO:0000269|PubMed:32369452}.
CC Note=The gene represented in this entry is involved in disease
CC pathogenesis. Homozygous deletions on chromosome 8 removing putative
CC enhancers of GDF6, segregate with the disease in families with
CC congenital deafness and cochlear aplasia.
CC {ECO:0000269|PubMed:32369452}.
CC -!- SIMILARITY: Belongs to the TGF-beta family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AJ537424; CAD60934.1; -; mRNA.
DR EMBL; BC043222; AAH43222.1; -; mRNA.
DR CCDS; CCDS34926.1; -.
DR RefSeq; NP_001001557.1; NM_001001557.3.
DR AlphaFoldDB; Q6KF10; -.
DR SMR; Q6KF10; -.
DR BioGRID; 134147; 4.
DR IntAct; Q6KF10; 1.
DR STRING; 9606.ENSP00000287020; -.
DR GlyGen; Q6KF10; 1 site.
DR iPTMnet; Q6KF10; -.
DR PhosphoSitePlus; Q6KF10; -.
DR BioMuta; GDF6; -.
DR DMDM; 74748876; -.
DR MassIVE; Q6KF10; -.
DR PaxDb; Q6KF10; -.
DR PeptideAtlas; Q6KF10; -.
DR PRIDE; Q6KF10; -.
DR ProteomicsDB; 66547; -.
DR Antibodypedia; 25942; 166 antibodies from 29 providers.
DR DNASU; 392255; -.
DR Ensembl; ENST00000287020.7; ENSP00000287020.4; ENSG00000156466.11.
DR GeneID; 392255; -.
DR KEGG; hsa:392255; -.
DR MANE-Select; ENST00000287020.7; ENSP00000287020.4; NM_001001557.4; NP_001001557.1.
DR UCSC; uc003yhp.3; human.
DR CTD; 392255; -.
DR DisGeNET; 392255; -.
DR GeneCards; GDF6; -.
DR HGNC; HGNC:4221; GDF6.
DR HPA; ENSG00000156466; Tissue enriched (placenta).
DR MalaCards; GDF6; -.
DR MIM; 118100; phenotype.
DR MIM; 601147; gene.
DR MIM; 613094; phenotype.
DR MIM; 615360; phenotype.
DR MIM; 617898; phenotype.
DR MIM; 619553; phenotype.
DR neXtProt; NX_Q6KF10; -.
DR OpenTargets; ENSG00000156466; -.
DR Orphanet; 98938; Colobomatous microphthalmia.
DR Orphanet; 2345; Isolated Klippel-Feil syndrome.
DR Orphanet; 65; Leber congenital amaurosis.
DR PharmGKB; PA28636; -.
DR VEuPathDB; HostDB:ENSG00000156466; -.
DR eggNOG; KOG3900; Eukaryota.
DR GeneTree; ENSGT00940000162274; -.
DR HOGENOM; CLU_020515_0_0_1; -.
DR InParanoid; Q6KF10; -.
DR OMA; KKSKYRC; -.
DR OrthoDB; 749511at2759; -.
DR PhylomeDB; Q6KF10; -.
DR TreeFam; TF316134; -.
DR PathwayCommons; Q6KF10; -.
DR SignaLink; Q6KF10; -.
DR SIGNOR; Q6KF10; -.
DR BioGRID-ORCS; 392255; 14 hits in 1065 CRISPR screens.
DR GeneWiki; GDF6; -.
DR GenomeRNAi; 392255; -.
DR Pharos; Q6KF10; Tbio.
DR PRO; PR:Q6KF10; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q6KF10; protein.
DR Bgee; ENSG00000156466; Expressed in placenta and 79 other tissues.
DR ExpressionAtlas; Q6KF10; baseline and differential.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0005125; F:cytokine activity; IBA:GO_Central.
DR GO; GO:0008083; F:growth factor activity; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl.
DR GO; GO:0032924; P:activin receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0006915; P:apoptotic process; ISS:UniProtKB.
DR GO; GO:0030509; P:BMP signaling pathway; IDA:BHF-UCL.
DR GO; GO:0035788; P:cell migration involved in metanephros development; IEA:Ensembl.
DR GO; GO:0045444; P:fat cell differentiation; ISS:UniProtKB.
DR GO; GO:0001656; P:metanephros development; IDA:MGI.
DR GO; GO:0060389; P:pathway-restricted SMAD protein phosphorylation; IDA:BHF-UCL.
DR GO; GO:0032332; P:positive regulation of chondrocyte differentiation; IMP:UniProtKB.
DR GO; GO:0045666; P:positive regulation of neuron differentiation; IEA:Ensembl.
DR GO; GO:1900745; P:positive regulation of p38MAPK cascade; ISS:UniProtKB.
DR GO; GO:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; IDA:BHF-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:BHF-UCL.
DR GO; GO:1990009; P:retinal cell apoptotic process; ISS:UniProtKB.
DR GO; GO:0060395; P:SMAD protein signal transduction; IMP:UniProtKB.
DR Gene3D; 2.10.90.10; -; 1.
DR InterPro; IPR029034; Cystine-knot_cytokine.
DR InterPro; IPR001839; TGF-b_C.
DR InterPro; IPR001111; TGF-b_propeptide.
DR InterPro; IPR015615; TGF-beta-rel.
DR InterPro; IPR017948; TGFb_CS.
DR PANTHER; PTHR11848; PTHR11848; 1.
DR Pfam; PF00019; TGF_beta; 1.
DR Pfam; PF00688; TGFb_propeptide; 1.
DR SMART; SM00204; TGFB; 1.
DR SUPFAM; SSF57501; SSF57501; 1.
DR PROSITE; PS00250; TGF_BETA_1; 1.
DR PROSITE; PS51362; TGF_BETA_2; 1.
PE 1: Evidence at protein level;
KW Apoptosis; Chromosomal rearrangement; Cleavage on pair of basic residues;
KW Cytokine; Deafness; Developmental protein; Disease variant; Disulfide bond;
KW Dwarfism; Glycoprotein; Growth factor; Leber congenital amaurosis;
KW Microphthalmia; Non-syndromic deafness; Reference proteome; Secreted;
KW Signal.
FT SIGNAL 1..22
FT /evidence="ECO:0000255"
FT PROPEP 23..335
FT /evidence="ECO:0000255"
FT /id="PRO_0000342206"
FT CHAIN 336..455
FT /note="Growth/differentiation factor 6"
FT /id="PRO_0000042253"
FT REGION 29..93
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 244..267
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 300..351
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 41..70
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 334..351
FT /note="Basic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 114
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 354..420
FT /evidence="ECO:0000250|UniProtKB:P39905"
FT DISULFID 383..452
FT /evidence="ECO:0000250|UniProtKB:P39905"
FT DISULFID 387..454
FT /evidence="ECO:0000250|UniProtKB:P39905"
FT DISULFID 419
FT /note="Interchain"
FT /evidence="ECO:0000250|UniProtKB:P39905"
FT VARIANT 42
FT /note="G -> V (in KFS1; dbSNP:rs121909354)"
FT /evidence="ECO:0000269|PubMed:19129173,
FT ECO:0000269|PubMed:24033328"
FT /id="VAR_063024"
FT VARIANT 57
FT /note="D -> H (in LCA17; reduced protein expression
FT associated with decrease in growth factor activity;
FT dbSNP:rs397514725)"
FT /evidence="ECO:0000269|PubMed:23307924"
FT /id="VAR_070254"
FT VARIANT 110
FT /note="K -> E (in dbSNP:rs2245091)"
FT /id="VAR_023599"
FT VARIANT 119
FT /note="Q -> R (in MCOP4; dbSNP:rs140579014)"
FT /evidence="ECO:0000269|PubMed:19129173"
FT /id="VAR_063025"
FT VARIANT 199
FT /note="A -> T (in LCA17; found also in a patient with
FT microphthalmia isolated with coloboma type 6 carrying a
FT mutation in GDF3; reduced protein expression associated
FT with decrease in growth factor activity;
FT dbSNP:rs387906794)"
FT /evidence="ECO:0000269|PubMed:19864492,
FT ECO:0000269|PubMed:23307924"
FT /id="VAR_065151"
FT VARIANT 216
FT /note="D -> G (in MCOP4)"
FT /evidence="ECO:0000269|PubMed:19129173"
FT /id="VAR_063026"
FT VARIANT 249
FT /note="A -> E (in KFS1, MCOP4 and LCA17; reduced protein
FT expression associated with decrease in growth factor
FT activity; dbSNP:rs121909352)"
FT /evidence="ECO:0000269|PubMed:18425797,
FT ECO:0000269|PubMed:19129173, ECO:0000269|PubMed:23307924"
FT /id="VAR_046903"
FT VARIANT 253
FT /note="Q -> L (in MCOP4; dbSNP:rs121909355)"
FT /evidence="ECO:0000269|PubMed:19129173"
FT /id="VAR_063027"
FT VARIANT 289
FT /note="L -> P (in KFS1; dbSNP:rs63751220)"
FT /evidence="ECO:0000269|PubMed:18425797"
FT /id="VAR_046904"
FT VARIANT 292
FT /note="E -> D (in LCA17; increased protein expression
FT associated with decrease in growth factor activity;
FT dbSNP:rs1401531865)"
FT /evidence="ECO:0000269|PubMed:23307924"
FT /id="VAR_070255"
FT VARIANT 327
FT /note="P -> H (in MCOP4; dbSNP:rs121909356)"
FT /evidence="ECO:0000269|PubMed:19129173"
FT /id="VAR_063028"
FT VARIANT 424
FT /note="K -> R (in KFS1; dbSNP:rs121909353)"
FT /evidence="ECO:0000269|PubMed:19129173"
FT /id="VAR_063029"
FT VARIANT 429
FT /note="S -> R (in SYNS4; unknown pathological significance;
FT dbSNP:rs1554571225)"
FT /evidence="ECO:0000269|PubMed:29130651"
FT /id="VAR_080489"
FT VARIANT 444
FT /note="Y -> N (in SYNS4; increases chondrogenic activity;
FT increases SMAD1/5/8 signaling pathway activation; not
FT inhibited by NOG; dbSNP:rs1554571213)"
FT /evidence="ECO:0000269|PubMed:26643732"
FT /id="VAR_075366"
FT CONFLICT 255
FT /note="P -> L (in Ref. 2; AAH43222)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 455 AA; 50662 MW; F9F365B99E8C659C CRC64;
MDTPRVLLSA VFLISFLWDL PGFQQASISS SSSSAELGST KGMRSRKEGK MQRAPRDSDA
GREGQEPQPR PQDEPRAQQP RAQEPPGRGP RVVPHEYMLS IYRTYSIAEK LGINASFFQS
SKSANTITSF VDRGLDDLSH TPLRRQKYLF DVSMLSDKEE LVGAELRLFR QAPSAPWGPP
AGPLHVQLFP CLSPLLLDAR TLDPQGAPPA GWEVFDVWQG LRHQPWKQLC LELRAAWGEL
DAGEAEARAR GPQQPPPPDL RSLGFGRRVR PPQERALLVV FTRSQRKNLF AEMREQLGSA
EAAGPGAGAE GSWPPPSGAP DARPWLPSPG RRRRRTAFAS RHGKRHGKKS RLRCSKKPLH
VNFKELGWDD WIIAPLEYEA YHCEGVCDFP LRSHLEPTNH AIIQTLMNSM DPGSTPPSCC
VPTKLTPISI LYIDAGNNVV YKQYEDMVVE SCGCR
