FRS1L_HUMAN
ID FRS1L_HUMAN Reviewed; 293 AA.
AC Q9P0K9; Q5T4G4;
DT 21-MAR-2006, integrated into UniProtKB/Swiss-Prot.
DT 23-FEB-2022, sequence version 3.
DT 03-AUG-2022, entry version 130.
DE RecName: Full=DOMON domain-containing protein FRRS1L;
DE AltName: Full=Brain protein CG-6;
DE AltName: Full=Ferric-chelate reductase 1-like protein;
DE Flags: Precursor;
GN Name=FRRS1L; Synonyms=C9orf4;
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], AND TISSUE SPECIFICITY.
RX PubMed=10603000; DOI=10.1007/s003350010017;
RA Chadwick B.P., Leyne M., Gill S., Liebert C.B., Mull J., Mezey E.,
RA Robbins C.M., Pinkett H.W., Makalowska I., Maayan C., Blumenfeld A.,
RA Axelrod F.B., Brownstein M., Gusella J.F., Slaugenhaupt S.A.;
RT "Cloning, mapping, and expression of a novel brain-specific transcript in
RT the familial dysautonomia candidate region on chromosome 9q31.";
RL Mamm. Genome 11:81-83(2000).
RN [2]
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 [3]
RP FUNCTION, INVOLVEMENT IN DEE37, AND VARIANT DEE37 GLY-195 DEL.
RX PubMed=27236917; DOI=10.1016/j.ajhg.2016.04.008;
RA Madeo M., Stewart M., Sun Y., Sahir N., Wiethoff S., Chandrasekar I.,
RA Yarrow A., Rosenfeld J.A., Yang Y., Cordeiro D., McCormick E.M.,
RA Muraresku C.C., Jepperson T.N., McBeth L.J., Seidahmed M.Z.,
RA El Khashab H.Y., Hamad M., Azzedine H., Clark K., Corrochano S., Wells S.,
RA Elting M.W., Weiss M.M., Burn S., Myers A., Landsverk M., Crotwell P.L.,
RA Waisfisz Q., Wolf N.I., Nolan P.M., Padilla-Lopez S., Houlden H.,
RA Lifton R., Mane S., Singh B.B., Falk M.J., Mercimek-Mahmutoglu S.,
RA Bilguvar K., Salih M.A., Acevedo-Arozena A., Kruer M.C.;
RT "Loss-of-function mutations in FRRS1L lead to an epileptic-dyskinetic
RT encephalopathy.";
RL Am. J. Hum. Genet. 98:1249-1255(2016).
RN [4]
RP INVOLVEMENT IN DEE37.
RX PubMed=27239025; DOI=10.1111/cge.12796;
RA Shaheen R., Al Tala S., Ewida N., Abouelhoda M., Alkuraya F.S.;
RT "Epileptic encephalopathy with continuous spike-and-wave during sleep maps
RT to a homozygous truncating mutation in AMPA receptor component FRRS1L.";
RL Clin. Genet. 90:282-283(2016).
CC -!- FUNCTION: Important modulator of glutamate signaling pathway.
CC {ECO:0000269|PubMed:27236917}.
CC -!- SUBUNIT: Component of the outer core of AMPAR complex. AMPAR complex
CC consists of an inner core made of 4 pore-forming GluA/GRIA proteins
CC (GRIA1, GRIA2, GRIA3 and GRIA4) and 4 major auxiliary subunits arranged
CC in a twofold symmetry. One of the two pairs of distinct binding sites
CC is occupied either by CNIH2, CNIH3 or CACNG2, CACNG3. The other harbors
CC CACNG2, CACNG3, CACNG4, CACNG8 or GSG1L. This inner core of AMPAR
CC complex is complemented by outer core constituents binding directly to
CC the GluA/GRIA proteins at sites distinct from the interaction sites of
CC the inner core constituents. Outer core constituents include at least
CC PRRT1, PRRT2, CKAMP44/SHISA9, FRRS1L and NRN1. The proteins of the
CC inner and outer core serve as a platform for other, more peripherally
CC associated AMPAR constituents. Alone or in combination, these auxiliary
CC subunits control the gating and pharmacology of the AMPAR complex and
CC profoundly impact their biogenesis and protein processing (By
CC similarity). {ECO:0000250|UniProtKB:B1AXV0}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:B1AXV0}.
CC Synapse {ECO:0000250|UniProtKB:B1AXV0}.
CC -!- TISSUE SPECIFICITY: Expressed in adult and fetal brain. Very weak
CC expression in medulla, spinal cord and in adult ovary.
CC {ECO:0000269|PubMed:10603000}.
CC -!- DISEASE: Developmental and epileptic encephalopathy 37 (DEE37)
CC [MIM:616981]: A form of epileptic encephalopathy, a heterogeneous group
CC of severe early-onset epilepsies characterized by refractory seizures,
CC neurodevelopmental impairment, and poor prognosis. Development is
CC normal prior to seizure onset, after which cognitive and motor delays
CC become apparent. DEE37 is an autosomal recessive, severe form
CC manifesting in the first years of life. Affected individuals show
CC hyperkinetic movement disorder with choreoathetosis, spasticity,
CC rigidity, intellectual disability, absent speech, and impaired
CC volitional movements. {ECO:0000269|PubMed:27236917,
CC ECO:0000269|PubMed:27239025}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- CAUTION: Named FRRS1L by HGNC because it shares limited sequence
CC similarity with FRRS1. However, sequence similarities lie outside of
CC the reductase region, suggesting it has no oxidoreductase activity.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAF28159.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF155065; AAF28159.1; ALT_INIT; mRNA.
DR EMBL; AL358815; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS35098.1; -.
DR RefSeq; NP_055149.2; NM_014334.3.
DR AlphaFoldDB; Q9P0K9; -.
DR BioGRID; 117238; 1.
DR IntAct; Q9P0K9; 1.
DR STRING; 9606.ENSP00000477141; -.
DR iPTMnet; Q9P0K9; -.
DR PhosphoSitePlus; Q9P0K9; -.
DR BioMuta; FRRS1L; -.
DR DMDM; 90111980; -.
DR MassIVE; Q9P0K9; -.
DR PaxDb; Q9P0K9; -.
DR PeptideAtlas; Q9P0K9; -.
DR PRIDE; Q9P0K9; -.
DR ProteomicsDB; 83566; -.
DR Antibodypedia; 71944; 74 antibodies from 17 providers.
DR DNASU; 23732; -.
DR Ensembl; ENST00000561981.5; ENSP00000477141.2; ENSG00000260230.5.
DR GeneID; 23732; -.
DR KEGG; hsa:23732; -.
DR MANE-Select; ENST00000561981.5; ENSP00000477141.2; NM_014334.4; NP_055149.3.
DR UCSC; uc004bdv.4; human.
DR CTD; 23732; -.
DR DisGeNET; 23732; -.
DR GeneCards; FRRS1L; -.
DR HGNC; HGNC:1362; FRRS1L.
DR HPA; ENSG00000260230; Tissue enhanced (brain, ovary).
DR MalaCards; FRRS1L; -.
DR MIM; 604574; gene.
DR MIM; 616981; phenotype.
DR neXtProt; NX_Q9P0K9; -.
DR OpenTargets; ENSG00000260230; -.
DR Orphanet; 88616; Autosomal recessive non-syndromic intellectual disability.
DR Orphanet; 725; Continuous spikes and waves during sleep.
DR PharmGKB; PA25979; -.
DR VEuPathDB; HostDB:ENSG00000260230; -.
DR eggNOG; KOG4293; Eukaryota.
DR GeneTree; ENSGT00940000159043; -.
DR HOGENOM; CLU_069383_0_0_1; -.
DR InParanoid; Q9P0K9; -.
DR OrthoDB; 1060739at2759; -.
DR PhylomeDB; Q9P0K9; -.
DR TreeFam; TF316169; -.
DR PathwayCommons; Q9P0K9; -.
DR SignaLink; Q9P0K9; -.
DR BioGRID-ORCS; 23732; 10 hits in 1057 CRISPR screens.
DR ChiTaRS; FRRS1L; human.
DR GenomeRNAi; 23732; -.
DR Pharos; Q9P0K9; Tbio.
DR PRO; PR:Q9P0K9; -.
DR Proteomes; UP000005640; Chromosome 9.
DR RNAct; Q9P0K9; protein.
DR Bgee; ENSG00000260230; Expressed in middle temporal gyrus and 138 other tissues.
DR ExpressionAtlas; Q9P0K9; baseline and differential.
DR Genevisible; Q9P0K9; HS.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0045202; C:synapse; IEA:UniProtKB-SubCell.
DR GO; GO:0045505; F:dynein intermediate chain binding; IEA:Ensembl.
DR GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl.
DR GO; GO:1904717; P:regulation of AMPA glutamate receptor clustering; IEA:Ensembl.
DR GO; GO:1900449; P:regulation of glutamate receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0099072; P:regulation of postsynaptic membrane neurotransmitter receptor levels; IBA:GO_Central.
DR GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; IEA:Ensembl.
DR InterPro; IPR005018; DOMON_domain.
DR InterPro; IPR042789; FRRS1L.
DR PANTHER; PTHR46902; PTHR46902; 1.
DR SMART; SM00664; DoH; 1.
DR PROSITE; PS50836; DOMON; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Disease variant; Epilepsy; Membrane; Reference proteome;
KW Signal; Synapse; Transmembrane; Transmembrane helix.
FT SIGNAL 1..28
FT /evidence="ECO:0000255"
FT CHAIN 29..293
FT /note="DOMON domain-containing protein FRRS1L"
FT /evidence="ECO:0000255"
FT /id="PRO_0000228720"
FT TRANSMEM 271..291
FT /note="Helical"
FT /evidence="ECO:0000255"
FT DOMAIN 119..234
FT /note="DOMON"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00246"
FT REGION 29..61
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VARIANT 195
FT /note="Missing (in DEE37)"
FT /evidence="ECO:0000269|PubMed:27236917"
FT /id="VAR_077052"
SQ SEQUENCE 293 AA; 32389 MW; D3E293757648EEDB CRC64;
MARPPRQHPG VWASLLLLLL TGPAACAASP ADDGAGPGGR GPRGRARGDT GADEAVPRHD
SSYGTFAGEF YDLRYLSEEG YPFPTAPPVD PFAKIKVDDC GKTKGCFRYG KPGCNAETCD
YFLSYRMIGA DVEFELSADT DGWVAVGFSS DKKMGGDDVM ACVHDDNGRV RIQHFYNVGQ
WAKEIQRNPA RDEEGVFENN RVTCRFKRPV NVPRDETIVD LHLSWYYLFA WGPAIQGSIT
RHDIDSPPAS ERVVSIYKYE DIFMPSAAYQ TFSSPFCLLL IVALTFYLLM GTP
