FBXL4_HUMAN
ID FBXL4_HUMAN Reviewed; 621 AA.
AC Q9UKA2; B2R7Q5; E1P530; O95919; Q5BJH0; Q9UJU0;
DT 27-MAY-2002, integrated into UniProtKB/Swiss-Prot.
DT 27-MAY-2002, sequence version 2.
DT 03-AUG-2022, entry version 178.
DE RecName: Full=F-box/LRR-repeat protein 4;
DE AltName: Full=F-box and leucine-rich repeat protein 4;
DE AltName: Full=F-box protein FBL4/FBL5;
GN Name=FBXL4; Synonyms=FBL4, FBL5;
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], TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=10531037; DOI=10.1016/s0960-9822(00)80021-4;
RA Winston J.T., Koepp D.M., Zhu C., Elledge S.J., Harper J.W.;
RT "A family of mammalian F-box proteins.";
RL Curr. Biol. 9:1180-1182(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=10531035; DOI=10.1016/s0960-9822(00)80020-2;
RA Cenciarelli C., Chiaur D.S., Guardavaccaro D., Parks W., Vidal M.,
RA Pagano M.;
RT "Identification of a family of human F-box proteins.";
RL Curr. Biol. 9:1177-1179(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=10945468; DOI=10.1006/geno.2000.6211;
RA Ilyin G.P., Rialland M., Pigeon C., Guguen-Guillouzo C.;
RT "cDNA cloning and expression analysis of new members of the mammalian F-box
RT protein family.";
RL Genomics 67:40-47(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Hippocampus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [6]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Eye, and PNS;
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 [8]
RP SUBCELLULAR LOCATION, AND INVOLVEMENT IN MTDPS13.
RX PubMed=23993193; DOI=10.1016/j.ajhg.2013.07.017;
RA Bonnen P.E., Yarham J.W., Besse A., Wu P., Faqeih E.A., Al-Asmari A.M.,
RA Saleh M.A., Eyaid W., Hadeel A., He L., Smith F., Yau S., Simcox E.M.,
RA Miwa S., Donti T., Abu-Amero K.K., Wong L.J., Craigen W.J., Graham B.H.,
RA Scott K.L., McFarland R., Taylor R.W.;
RT "Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of
RT mitochondrial DNA maintenance.";
RL Am. J. Hum. Genet. 93:471-481(2013).
RN [9]
RP SUBCELLULAR LOCATION, AND VARIANTS MTDPS13 THR-205; TRP-482; ASN-551;
RP GLY-565; ALA-568 AND PRO-597.
RX PubMed=23993194; DOI=10.1016/j.ajhg.2013.07.016;
RA Gai X., Ghezzi D., Johnson M.A., Biagosch C.A., Shamseldin H.E.,
RA Haack T.B., Reyes A., Tsukikawa M., Sheldon C.A., Srinivasan S., Gorza M.,
RA Kremer L.S., Wieland T., Strom T.M., Polyak E., Place E., Consugar M.,
RA Ostrovsky J., Vidoni S., Robinson A.J., Wong L.J., Sondheimer N.,
RA Salih M.A., Al-Jishi E., Raab C.P., Bean C., Furlan F., Parini R.,
RA Lamperti C., Mayr J.A., Konstantopoulou V., Huemer M., Pierce E.A.,
RA Meitinger T., Freisinger P., Sperl W., Prokisch H., Alkuraya F.S.,
RA Falk M.J., Zeviani M.;
RT "Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset
RT mitochondrial encephalomyopathy.";
RL Am. J. Hum. Genet. 93:482-495(2013).
RN [10]
RP VARIANT MTDPS13 PRO-481.
RX PubMed=27182039; DOI=10.1016/j.ejmg.2016.05.005;
RA Baroey T., Pedurupillay C.R., Bliksrud Y.T., Rasmussen M., Holmgren A.,
RA Vigeland M.D., Hughes T., Brink M., Rodenburg R., Nedregaard B.,
RA Stroemme P., Frengen E., Misceo D.;
RT "A novel mutation in FBXL4 in a Norwegian child with encephalomyopathic
RT mitochondrial DNA depletion syndrome 13.";
RL Eur. J. Med. Genet. 59:342-346(2016).
CC -!- SUBUNIT: Part of a SCF (SKP1-cullin-F-box) protein ligase complex.
CC {ECO:0000250}.
CC -!- INTERACTION:
CC Q9UKA2; P50570-2: DNM2; NbExp=3; IntAct=EBI-2869903, EBI-10968534;
CC Q9UKA2; O14773: TPP1; NbExp=3; IntAct=EBI-2869903, EBI-2800203;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Mitochondrion.
CC -!- TISSUE SPECIFICITY: Expressed in heart, kidney, liver, lung, pancreas,
CC and placenta, but not in skeletal muscle.
CC {ECO:0000269|PubMed:10531037}.
CC -!- DISEASE: Mitochondrial DNA depletion syndrome 13 (MTDPS13)
CC [MIM:615471]: An autosomal recessive disorder characterized by early
CC infantile onset of encephalopathy, hypotonia, lactic acidosis, and
CC severe global developmental delay. Cells derived from patient tissues
CC show defects in mitochondrial oxidative phosphorylation and decreased
CC mtDNA content. {ECO:0000269|PubMed:23993193,
CC ECO:0000269|PubMed:23993194, ECO:0000269|PubMed:27182039}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
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DR EMBL; AF176699; AAF03699.1; -; mRNA.
DR EMBL; AF174590; AAF04511.1; -; mRNA.
DR EMBL; AF199355; AAF09247.1; -; mRNA.
DR EMBL; AK313076; BAG35902.1; -; mRNA.
DR EMBL; AL022395; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471051; EAW48489.1; -; Genomic_DNA.
DR EMBL; CH471051; EAW48490.1; -; Genomic_DNA.
DR EMBL; BC055010; AAH55010.1; -; mRNA.
DR EMBL; BC091484; AAH91484.1; -; mRNA.
DR CCDS; CCDS5041.1; -.
DR RefSeq; NP_001265645.1; NM_001278716.1.
DR RefSeq; NP_036292.2; NM_012160.4.
DR RefSeq; XP_016866215.1; XM_017010726.1.
DR AlphaFoldDB; Q9UKA2; -.
DR SMR; Q9UKA2; -.
DR BioGRID; 117626; 64.
DR IntAct; Q9UKA2; 40.
DR STRING; 9606.ENSP00000358247; -.
DR iPTMnet; Q9UKA2; -.
DR PhosphoSitePlus; Q9UKA2; -.
DR SwissPalm; Q9UKA2; -.
DR BioMuta; FBXL4; -.
DR DMDM; 21263631; -.
DR EPD; Q9UKA2; -.
DR jPOST; Q9UKA2; -.
DR MassIVE; Q9UKA2; -.
DR MaxQB; Q9UKA2; -.
DR PaxDb; Q9UKA2; -.
DR PeptideAtlas; Q9UKA2; -.
DR PRIDE; Q9UKA2; -.
DR ProteomicsDB; 84750; -.
DR Antibodypedia; 18894; 108 antibodies from 19 providers.
DR DNASU; 26235; -.
DR Ensembl; ENST00000229971.2; ENSP00000229971.1; ENSG00000112234.9.
DR Ensembl; ENST00000369244.7; ENSP00000358247.1; ENSG00000112234.9.
DR GeneID; 26235; -.
DR KEGG; hsa:26235; -.
DR MANE-Select; ENST00000369244.7; ENSP00000358247.1; NM_001278716.2; NP_001265645.1.
DR UCSC; uc003ppf.2; human.
DR CTD; 26235; -.
DR DisGeNET; 26235; -.
DR GeneCards; FBXL4; -.
DR GeneReviews; FBXL4; -.
DR HGNC; HGNC:13601; FBXL4.
DR HPA; ENSG00000112234; Low tissue specificity.
DR MalaCards; FBXL4; -.
DR MIM; 605654; gene.
DR MIM; 615471; phenotype.
DR neXtProt; NX_Q9UKA2; -.
DR OpenTargets; ENSG00000112234; -.
DR Orphanet; 369897; Mitochondrial DNA depletion syndrome, encephalomyopathic form with variable craniofacial anomalies.
DR PharmGKB; PA28024; -.
DR VEuPathDB; HostDB:ENSG00000112234; -.
DR eggNOG; KOG1947; Eukaryota.
DR GeneTree; ENSGT00940000155184; -.
DR HOGENOM; CLU_024764_2_0_1; -.
DR InParanoid; Q9UKA2; -.
DR OMA; GWCMREA; -.
DR OrthoDB; 672780at2759; -.
DR PhylomeDB; Q9UKA2; -.
DR TreeFam; TF323721; -.
DR PathwayCommons; Q9UKA2; -.
DR Reactome; R-HSA-8951664; Neddylation.
DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR SignaLink; Q9UKA2; -.
DR BioGRID-ORCS; 26235; 5 hits in 1117 CRISPR screens.
DR ChiTaRS; FBXL4; human.
DR GenomeRNAi; 26235; -.
DR Pharos; Q9UKA2; Tbio.
DR PRO; PR:Q9UKA2; -.
DR Proteomes; UP000005640; Chromosome 6.
DR RNAct; Q9UKA2; protein.
DR Bgee; ENSG00000112234; Expressed in adrenal tissue and 179 other tissues.
DR Genevisible; Q9UKA2; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005758; C:mitochondrial intermembrane space; IDA:UniProtKB.
DR GO; GO:0016607; C:nuclear speck; IDA:HPA.
DR GO; GO:0019005; C:SCF ubiquitin ligase complex; IBA:GO_Central.
DR GO; GO:0000151; C:ubiquitin ligase complex; TAS:ProtInc.
DR GO; GO:0000422; P:autophagy of mitochondrion; IMP:MGI.
DR GO; GO:0031146; P:SCF-dependent proteasomal ubiquitin-dependent protein catabolic process; IBA:GO_Central.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; TAS:ProtInc.
DR Gene3D; 3.80.10.10; -; 2.
DR InterPro; IPR036047; F-box-like_dom_sf.
DR InterPro; IPR001810; F-box_dom.
DR InterPro; IPR006553; Leu-rich_rpt_Cys-con_subtyp.
DR InterPro; IPR032675; LRR_dom_sf.
DR Pfam; PF00646; F-box; 1.
DR SMART; SM00367; LRR_CC; 7.
DR SUPFAM; SSF81383; SSF81383; 1.
DR PROSITE; PS50181; FBOX; 1.
PE 1: Evidence at protein level;
KW Cytoplasm; Disease variant; Leucine-rich repeat; Methylation;
KW Mitochondrion; Nucleus; Primary mitochondrial disease; Reference proteome;
KW Repeat; Ubl conjugation pathway.
FT CHAIN 1..621
FT /note="F-box/LRR-repeat protein 4"
FT /id="PRO_0000119844"
FT DOMAIN 277..332
FT /note="F-box"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00080"
FT REPEAT 376..397
FT /note="LRR 1"
FT REPEAT 402..421
FT /note="LRR 2"
FT REPEAT 427..448
FT /note="LRR 3"
FT REPEAT 452..474
FT /note="LRR 4"
FT REPEAT 480..501
FT /note="LRR 5"
FT REPEAT 504..524
FT /note="LRR 6"
FT REPEAT 532..558
FT /note="LRR 7"
FT REPEAT 559..583
FT /note="LRR 8"
FT REPEAT 584..609
FT /note="LRR 9"
FT MOD_RES 28
FT /note="Asymmetric dimethylarginine"
FT /evidence="ECO:0000250|UniProtKB:Q8BH70"
FT VARIANT 205
FT /note="I -> T (in MTDPS13; dbSNP:rs1350566881)"
FT /evidence="ECO:0000269|PubMed:23993194"
FT /id="VAR_070858"
FT VARIANT 481
FT /note="L -> P (in MTDPS13; dbSNP:rs772037717)"
FT /evidence="ECO:0000269|PubMed:27182039"
FT /id="VAR_076547"
FT VARIANT 482
FT /note="R -> W (in MTDPS13; dbSNP:rs398123061)"
FT /evidence="ECO:0000269|PubMed:23993194"
FT /id="VAR_070859"
FT VARIANT 551
FT /note="I -> N (in MTDPS13; dbSNP:rs1554215979)"
FT /evidence="ECO:0000269|PubMed:23993194"
FT /id="VAR_070860"
FT VARIANT 565
FT /note="D -> G (in MTDPS13; dbSNP:rs398123062)"
FT /evidence="ECO:0000269|PubMed:23993194"
FT /id="VAR_070861"
FT VARIANT 568
FT /note="G -> A (in MTDPS13; dbSNP:rs398123060)"
FT /evidence="ECO:0000269|PubMed:23993194"
FT /id="VAR_070862"
FT VARIANT 597
FT /note="Q -> P (in MTDPS13; dbSNP:rs201989042)"
FT /evidence="ECO:0000269|PubMed:23993194"
FT /id="VAR_070863"
FT CONFLICT 5
FT /note="F -> Y (in Ref. 1; AAF03699)"
FT /evidence="ECO:0000305"
FT CONFLICT 42
FT /note="S -> G (in Ref. 3; AAF09247)"
FT /evidence="ECO:0000305"
FT CONFLICT 122
FT /note="Q -> K (in Ref. 1; AAF03699)"
FT /evidence="ECO:0000305"
FT CONFLICT 126
FT /note="Y -> I (in Ref. 1; AAF03699)"
FT /evidence="ECO:0000305"
FT CONFLICT 219
FT /note="E -> G (in Ref. 1; AAF03699)"
FT /evidence="ECO:0000305"
FT CONFLICT 232
FT /note="P -> A (in Ref. 1; AAF03699)"
FT /evidence="ECO:0000305"
FT CONFLICT 533
FT /note="P -> L (in Ref. 4; BAG35902)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 621 AA; 70097 MW; D8FD51A5C4F922D3 CRC64;
MSPVFPMLTV LTMFYYICLR RRARTATRGE MMNTHRAIES NSQTSPLNAE VVQYAKEVVD
FSSHYGSENS MSYTMWNLAG VPNVFPSSGD FTQTAVFRTY GTWWDQCPSA SLPFKRTPPN
FQSQDYVELT FEQQVYPTAV HVLETYHPGA VIRILACSAN PYSPNPPAEV RWEILWSERP
TKVNASQARQ FKPCIKQINF PTNLIRLEVN SSLLEYYTEL DAVVLHGVKD KPVLSLKTSL
IDMNDIEDDA YAEKDGCGMD SLNKKFSSAV LGEGPNNGYF DKLPYELIQL ILNHLTLPDL
CRLAQTCKLL SQHCCDPLQY IHLNLQPYWA KLDDTSLEFL QSRCTLVQWL NLSWTGNRGF
ISVAGFSRFL KVCGSELVRL ELSCSHFLNE TCLEVISEMC PNLQALNLSS CDKLPPQAFN
HIAKLCSLKR LVLYRTKVEQ TALLSILNFC SELQHLSLGS CVMIEDYDVI ASMIGAKCKK
LRTLDLWRCK NITENGIAEL ASGCPLLEEL DLGWCPTLQS STGCFTRLAH QLPNLQKLFL
TANRSVCDTD IDELACNCTR LQQLDILGTR MVSPASLRKL LESCKDLSLL DVSFCSQIDN
RAVLELNASF PKVFIKKSFT Q
