Full text data of ACSL4
ACSL4
(ACS4, FACL4, LACS4)
[Confidence: high (present in two of the MS resources)]
Long-chain-fatty-acid--CoA ligase 4; 6.2.1.3 (Long-chain acyl-CoA synthetase 4; LACS 4)
Long-chain-fatty-acid--CoA ligase 4; 6.2.1.3 (Long-chain acyl-CoA synthetase 4; LACS 4)
UniProt
O60488
ID ACSL4_HUMAN Reviewed; 711 AA.
AC O60488; D3DUY2; O60848; O60849;
DT 15-DEC-1998, integrated into UniProtKB/Swiss-Prot.
read moreDT 27-APR-2001, sequence version 2.
DT 22-JAN-2014, entry version 140.
DE RecName: Full=Long-chain-fatty-acid--CoA ligase 4;
DE EC=6.2.1.3;
DE AltName: Full=Long-chain acyl-CoA synthetase 4;
DE Short=LACS 4;
GN Name=ACSL4; Synonyms=ACS4, FACL4, LACS4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SHORT).
RX PubMed=9598324; DOI=10.1006/geno.1998.5268;
RA Cao Y., Traer E., Zimmerman G.A., McIntyre T.M., Prescott S.M.;
RT "Cloning, expression, and chromosomal localization of human long-chain
RT fatty acid-CoA ligase 4 (FACL4).";
RL Genomics 49:327-330(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS LONG AND SHORT).
RC TISSUE=Placenta, and Retina;
RX PubMed=9480748; DOI=10.1006/geno.1997.5104;
RA Piccini M., Vitelli F., Bruttini M., Pober B.R., Jonsson J.J.,
RA Villanova M., Zollo M., Borsani G., Ballabio A., Renieri A.;
RT "FACL4, a new gene encoding long-chain acyl-CoA synthetase 4, is
RT deleted in a family with Alport syndrome, elliptocytosis, and mental
RT retardation.";
RL Genomics 47:350-358(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM SHORT).
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [7]
RP VARIANT MRX63 SER-570.
RX PubMed=11889465; DOI=10.1038/ng857;
RA Meloni I., Muscettola M., Raynaud M., Longo I., Bruttini M.,
RA Moizard M.-P., Gomot M., Chelly J., des Portes V., Fryns J.-P.,
RA Ropers H.-H., Magi B., Bellan C., Volpi N., Yntema H.G., Lewis S.E.,
RA Schaffer J.E., Renieri A.;
RT "FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-
RT linked mental retardation.";
RL Nat. Genet. 30:436-440(2002).
RN [8]
RP VARIANT [LARGE SCALE ANALYSIS] CYS-133.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Activation of long-chain fatty acids for both synthesis
CC of cellular lipids, and degradation via beta-oxidation.
CC Preferentially uses arachidonate and eicosapentaenoate as
CC substrates.
CC -!- CATALYTIC ACTIVITY: ATP + a long-chain fatty acid + CoA = AMP +
CC diphosphate + an acyl-CoA.
CC -!- COFACTOR: Magnesium (By similarity).
CC -!- SUBCELLULAR LOCATION: Mitochondrion outer membrane; Single-pass
CC type III membrane protein (By similarity). Peroxisome membrane;
CC Single-pass type III membrane protein (By similarity). Microsome
CC membrane; Single-pass type III membrane protein (By similarity).
CC Endoplasmic reticulum membrane; Single-pass type III membrane
CC protein (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Long;
CC IsoId=O60488-1; Sequence=Displayed;
CC Name=Short;
CC IsoId=O60488-2; Sequence=VSP_000238;
CC -!- DISEASE: Mental retardation, X-linked 63 (MRX63) [MIM:300387]: A
CC disorder characterized by significantly below average general
CC intellectual functioning associated with impairments in adaptive
CC behavior and manifested during the developmental period.
CC Intellectual deficiency is the only primary symptom of non-
CC syndromic X-linked mental retardation, while syndromic mental
CC retardation presents with associated physical, neurological and/or
CC psychiatric manifestations. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Alport syndrome with mental retardation, midface
CC hypoplasia and elliptocytosis (ATS-MR) [MIM:300194]: A X-linked
CC contiguous gene deletion syndrome characterized by
CC glomerulonephritis, sensorineural hearing loss, mental
CC retardation, midface hypoplasia and elliptocytosis. Note=The gene
CC represented in this entry may be involved in disease pathogenesis.
CC -!- SIMILARITY: Belongs to the ATP-dependent AMP-binding enzyme
CC family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ACSL4";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF030555; AAC17493.1; -; mRNA.
DR EMBL; Y12777; CAA73314.1; -; mRNA.
DR EMBL; Y13058; CAA73501.1; -; mRNA.
DR EMBL; CH471120; EAX02671.1; -; Genomic_DNA.
DR EMBL; CH471120; EAX02673.1; -; Genomic_DNA.
DR EMBL; BC034959; AAH34959.1; -; mRNA.
DR RefSeq; NP_004449.1; NM_004458.2.
DR RefSeq; NP_075266.1; NM_022977.2.
DR RefSeq; XP_005262165.1; XM_005262108.1.
DR RefSeq; XP_005262166.1; XM_005262109.1.
DR RefSeq; XP_005262167.1; XM_005262110.1.
DR UniGene; Hs.268785; -.
DR ProteinModelPortal; O60488; -.
DR SMR; O60488; 122-598.
DR IntAct; O60488; 7.
DR MINT; MINT-3000036; -.
DR STRING; 9606.ENSP00000339787; -.
DR DrugBank; DB00159; Icosapent.
DR DrugBank; DB00197; Troglitazone.
DR PhosphoSite; O60488; -.
DR PaxDb; O60488; -.
DR PRIDE; O60488; -.
DR DNASU; 2182; -.
DR Ensembl; ENST00000340800; ENSP00000339787; ENSG00000068366.
DR Ensembl; ENST00000348502; ENSP00000262835; ENSG00000068366.
DR Ensembl; ENST00000469796; ENSP00000419171; ENSG00000068366.
DR Ensembl; ENST00000469857; ENSP00000423077; ENSG00000068366.
DR GeneID; 2182; -.
DR KEGG; hsa:2182; -.
DR UCSC; uc004eoi.2; human.
DR CTD; 2182; -.
DR GeneCards; GC0XM108872; -.
DR HGNC; HGNC:3571; ACSL4.
DR HPA; HPA005552; -.
DR MIM; 300157; gene.
DR MIM; 300194; phenotype.
DR MIM; 300387; phenotype.
DR neXtProt; NX_O60488; -.
DR Orphanet; 86818; Alport syndrome - intellectual deficit - midface hypoplasia - elliptocytosis.
DR Orphanet; 777; X-linked non-syndromic intellectual deficit.
DR PharmGKB; PA27968; -.
DR eggNOG; COG1022; -.
DR HOGENOM; HOG000159459; -.
DR HOVERGEN; HBG106947; -.
DR InParanoid; O60488; -.
DR KO; K01897; -.
DR OMA; NAMKLER; -.
DR OrthoDB; EOG7P2XRD; -.
DR PhylomeDB; O60488; -.
DR BioCyc; MetaCyc:HS00935-MONOMER; -.
DR BRENDA; 6.2.1.3; 2681.
DR Reactome; REACT_111217; Metabolism.
DR ChiTaRS; ACSL4; human.
DR GeneWiki; ACSL4; -.
DR GenomeRNAi; 2182; -.
DR NextBio; 8811; -.
DR PRO; PR:O60488; -.
DR ArrayExpress; O60488; -.
DR Bgee; O60488; -.
DR CleanEx; HS_ACSL4; -.
DR Genevestigator; O60488; -.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005811; C:lipid particle; IDA:UniProtKB.
DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0005778; C:peroxisomal membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0047676; F:arachidonate-CoA ligase activity; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004467; F:long-chain fatty acid-CoA ligase activity; IDA:MGI.
DR GO; GO:0031957; F:very long-chain fatty acid-CoA ligase activity; IMP:UniProtKB.
DR GO; GO:0060996; P:dendritic spine development; IEA:Ensembl.
DR GO; GO:0060136; P:embryonic process involved in female pregnancy; IEA:Ensembl.
DR GO; GO:0015908; P:fatty acid transport; IEA:Ensembl.
DR GO; GO:0008610; P:lipid biosynthetic process; IDA:UniProtKB.
DR GO; GO:0035338; P:long-chain fatty-acyl-CoA biosynthetic process; TAS:Reactome.
DR GO; GO:0032307; P:negative regulation of prostaglandin secretion; IDA:UniProtKB.
DR GO; GO:0030307; P:positive regulation of cell growth; IDA:UniProtKB.
DR GO; GO:0070672; P:response to interleukin-15; IEA:Ensembl.
DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl.
DR GO; GO:0019432; P:triglyceride biosynthetic process; TAS:Reactome.
DR InterPro; IPR020845; AMP-binding_CS.
DR InterPro; IPR000873; AMP-dep_Synth/Lig.
DR Pfam; PF00501; AMP-binding; 1.
DR PROSITE; PS00455; AMP_BINDING; 1.
PE 1: Evidence at protein level;
KW Alport syndrome; Alternative splicing; ATP-binding; Complete proteome;
KW Deafness; Disease mutation; Elliptocytosis; Endoplasmic reticulum;
KW Fatty acid metabolism; Hereditary hemolytic anemia; Ligase;
KW Lipid metabolism; Magnesium; Membrane; Mental retardation; Microsome;
KW Mitochondrion; Mitochondrion outer membrane; Nucleotide-binding;
KW Peroxisome; Polymorphism; Reference proteome; Signal-anchor;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1 711 Long-chain-fatty-acid--CoA ligase 4.
FT /FTId=PRO_0000193109.
FT TRANSMEM 8 28 Helical; Signal-anchor for type III
FT membrane protein; (Potential).
FT TOPO_DOM 29 711 Cytoplasmic (Potential).
FT VAR_SEQ 1 41 Missing (in isoform Short).
FT /FTId=VSP_000238.
FT VARIANT 133 133 R -> C (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036376.
FT VARIANT 570 570 R -> S (in MRX63).
FT /FTId=VAR_013180.
FT CONFLICT 181 181 Y -> C (in Ref. 2; CAA73314).
SQ SEQUENCE 711 AA; 79188 MW; 6483CD17FE78FE73 CRC64;
MKLKLNVLTI ILLPVHLLIT IYSALIFIPW YFLTNAKKKN AMAKRIKAKP TSDKPGSPYR
SVTHFDSLAV IDIPGADTLD KLFDHAVSKF GKKDSLGTRE ILSEENEMQP NGKVFKKLIL
GNYKWMNYLE VNRRVNNFGS GLTALGLKPK NTIAIFCETR AEWMIAAQTC FKYNFPLVTL
YATLGKEAVV HGLNESEASY LITSVELLES KLKTALLDIS CVKHIIYVDN KAINKAEYPE
GFEIHSMQSV EELGSNPENL GIPPSRPTPS DMAIVMYTSG STGRPKGVMM HHSNLIAGMT
GQCERIPGLG PKDTYIGYLP LAHVLELTAE ISCFTYGCRI GYSSPLTLSD QSSKIKKGSK
GDCTVLKPTL MAAVPEIMDR IYKNVMSKVQ EMNYIQKTLF KIGYDYKLEQ IKKGYDAPLC
NLLLFKKVKA LLGGNVRMML SGGAPLSPQT HRFMNVCFCC PIGQGYGLTE SCGAGTVTEV
TDYTTGRVGA PLICCEIKLK DWQEGGYTIN DKPNPRGEIV IGGQNISMGY FKNEEKTAED
YSVDENGQRW FCTGDIGEFH PDGCLQIIDR KKDLVKLQAG EYVSLGKVEA ALKNCPLIDN
ICAFAKSDQS YVISFVVPNQ KRLTLLAQQK GVEGTWVDIC NNPAMEAEIL KEIREAANAM
KLERFEIPIK VRLSPEPWTP ETGLVTDAFK LKRKELRNHY LKDIERMYGG K
//
ID ACSL4_HUMAN Reviewed; 711 AA.
AC O60488; D3DUY2; O60848; O60849;
DT 15-DEC-1998, integrated into UniProtKB/Swiss-Prot.
read moreDT 27-APR-2001, sequence version 2.
DT 22-JAN-2014, entry version 140.
DE RecName: Full=Long-chain-fatty-acid--CoA ligase 4;
DE EC=6.2.1.3;
DE AltName: Full=Long-chain acyl-CoA synthetase 4;
DE Short=LACS 4;
GN Name=ACSL4; Synonyms=ACS4, FACL4, LACS4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SHORT).
RX PubMed=9598324; DOI=10.1006/geno.1998.5268;
RA Cao Y., Traer E., Zimmerman G.A., McIntyre T.M., Prescott S.M.;
RT "Cloning, expression, and chromosomal localization of human long-chain
RT fatty acid-CoA ligase 4 (FACL4).";
RL Genomics 49:327-330(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS LONG AND SHORT).
RC TISSUE=Placenta, and Retina;
RX PubMed=9480748; DOI=10.1006/geno.1997.5104;
RA Piccini M., Vitelli F., Bruttini M., Pober B.R., Jonsson J.J.,
RA Villanova M., Zollo M., Borsani G., Ballabio A., Renieri A.;
RT "FACL4, a new gene encoding long-chain acyl-CoA synthetase 4, is
RT deleted in a family with Alport syndrome, elliptocytosis, and mental
RT retardation.";
RL Genomics 47:350-358(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM SHORT).
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [7]
RP VARIANT MRX63 SER-570.
RX PubMed=11889465; DOI=10.1038/ng857;
RA Meloni I., Muscettola M., Raynaud M., Longo I., Bruttini M.,
RA Moizard M.-P., Gomot M., Chelly J., des Portes V., Fryns J.-P.,
RA Ropers H.-H., Magi B., Bellan C., Volpi N., Yntema H.G., Lewis S.E.,
RA Schaffer J.E., Renieri A.;
RT "FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-
RT linked mental retardation.";
RL Nat. Genet. 30:436-440(2002).
RN [8]
RP VARIANT [LARGE SCALE ANALYSIS] CYS-133.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Activation of long-chain fatty acids for both synthesis
CC of cellular lipids, and degradation via beta-oxidation.
CC Preferentially uses arachidonate and eicosapentaenoate as
CC substrates.
CC -!- CATALYTIC ACTIVITY: ATP + a long-chain fatty acid + CoA = AMP +
CC diphosphate + an acyl-CoA.
CC -!- COFACTOR: Magnesium (By similarity).
CC -!- SUBCELLULAR LOCATION: Mitochondrion outer membrane; Single-pass
CC type III membrane protein (By similarity). Peroxisome membrane;
CC Single-pass type III membrane protein (By similarity). Microsome
CC membrane; Single-pass type III membrane protein (By similarity).
CC Endoplasmic reticulum membrane; Single-pass type III membrane
CC protein (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Long;
CC IsoId=O60488-1; Sequence=Displayed;
CC Name=Short;
CC IsoId=O60488-2; Sequence=VSP_000238;
CC -!- DISEASE: Mental retardation, X-linked 63 (MRX63) [MIM:300387]: A
CC disorder characterized by significantly below average general
CC intellectual functioning associated with impairments in adaptive
CC behavior and manifested during the developmental period.
CC Intellectual deficiency is the only primary symptom of non-
CC syndromic X-linked mental retardation, while syndromic mental
CC retardation presents with associated physical, neurological and/or
CC psychiatric manifestations. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Alport syndrome with mental retardation, midface
CC hypoplasia and elliptocytosis (ATS-MR) [MIM:300194]: A X-linked
CC contiguous gene deletion syndrome characterized by
CC glomerulonephritis, sensorineural hearing loss, mental
CC retardation, midface hypoplasia and elliptocytosis. Note=The gene
CC represented in this entry may be involved in disease pathogenesis.
CC -!- SIMILARITY: Belongs to the ATP-dependent AMP-binding enzyme
CC family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ACSL4";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF030555; AAC17493.1; -; mRNA.
DR EMBL; Y12777; CAA73314.1; -; mRNA.
DR EMBL; Y13058; CAA73501.1; -; mRNA.
DR EMBL; CH471120; EAX02671.1; -; Genomic_DNA.
DR EMBL; CH471120; EAX02673.1; -; Genomic_DNA.
DR EMBL; BC034959; AAH34959.1; -; mRNA.
DR RefSeq; NP_004449.1; NM_004458.2.
DR RefSeq; NP_075266.1; NM_022977.2.
DR RefSeq; XP_005262165.1; XM_005262108.1.
DR RefSeq; XP_005262166.1; XM_005262109.1.
DR RefSeq; XP_005262167.1; XM_005262110.1.
DR UniGene; Hs.268785; -.
DR ProteinModelPortal; O60488; -.
DR SMR; O60488; 122-598.
DR IntAct; O60488; 7.
DR MINT; MINT-3000036; -.
DR STRING; 9606.ENSP00000339787; -.
DR DrugBank; DB00159; Icosapent.
DR DrugBank; DB00197; Troglitazone.
DR PhosphoSite; O60488; -.
DR PaxDb; O60488; -.
DR PRIDE; O60488; -.
DR DNASU; 2182; -.
DR Ensembl; ENST00000340800; ENSP00000339787; ENSG00000068366.
DR Ensembl; ENST00000348502; ENSP00000262835; ENSG00000068366.
DR Ensembl; ENST00000469796; ENSP00000419171; ENSG00000068366.
DR Ensembl; ENST00000469857; ENSP00000423077; ENSG00000068366.
DR GeneID; 2182; -.
DR KEGG; hsa:2182; -.
DR UCSC; uc004eoi.2; human.
DR CTD; 2182; -.
DR GeneCards; GC0XM108872; -.
DR HGNC; HGNC:3571; ACSL4.
DR HPA; HPA005552; -.
DR MIM; 300157; gene.
DR MIM; 300194; phenotype.
DR MIM; 300387; phenotype.
DR neXtProt; NX_O60488; -.
DR Orphanet; 86818; Alport syndrome - intellectual deficit - midface hypoplasia - elliptocytosis.
DR Orphanet; 777; X-linked non-syndromic intellectual deficit.
DR PharmGKB; PA27968; -.
DR eggNOG; COG1022; -.
DR HOGENOM; HOG000159459; -.
DR HOVERGEN; HBG106947; -.
DR InParanoid; O60488; -.
DR KO; K01897; -.
DR OMA; NAMKLER; -.
DR OrthoDB; EOG7P2XRD; -.
DR PhylomeDB; O60488; -.
DR BioCyc; MetaCyc:HS00935-MONOMER; -.
DR BRENDA; 6.2.1.3; 2681.
DR Reactome; REACT_111217; Metabolism.
DR ChiTaRS; ACSL4; human.
DR GeneWiki; ACSL4; -.
DR GenomeRNAi; 2182; -.
DR NextBio; 8811; -.
DR PRO; PR:O60488; -.
DR ArrayExpress; O60488; -.
DR Bgee; O60488; -.
DR CleanEx; HS_ACSL4; -.
DR Genevestigator; O60488; -.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005811; C:lipid particle; IDA:UniProtKB.
DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0005778; C:peroxisomal membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0047676; F:arachidonate-CoA ligase activity; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004467; F:long-chain fatty acid-CoA ligase activity; IDA:MGI.
DR GO; GO:0031957; F:very long-chain fatty acid-CoA ligase activity; IMP:UniProtKB.
DR GO; GO:0060996; P:dendritic spine development; IEA:Ensembl.
DR GO; GO:0060136; P:embryonic process involved in female pregnancy; IEA:Ensembl.
DR GO; GO:0015908; P:fatty acid transport; IEA:Ensembl.
DR GO; GO:0008610; P:lipid biosynthetic process; IDA:UniProtKB.
DR GO; GO:0035338; P:long-chain fatty-acyl-CoA biosynthetic process; TAS:Reactome.
DR GO; GO:0032307; P:negative regulation of prostaglandin secretion; IDA:UniProtKB.
DR GO; GO:0030307; P:positive regulation of cell growth; IDA:UniProtKB.
DR GO; GO:0070672; P:response to interleukin-15; IEA:Ensembl.
DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl.
DR GO; GO:0019432; P:triglyceride biosynthetic process; TAS:Reactome.
DR InterPro; IPR020845; AMP-binding_CS.
DR InterPro; IPR000873; AMP-dep_Synth/Lig.
DR Pfam; PF00501; AMP-binding; 1.
DR PROSITE; PS00455; AMP_BINDING; 1.
PE 1: Evidence at protein level;
KW Alport syndrome; Alternative splicing; ATP-binding; Complete proteome;
KW Deafness; Disease mutation; Elliptocytosis; Endoplasmic reticulum;
KW Fatty acid metabolism; Hereditary hemolytic anemia; Ligase;
KW Lipid metabolism; Magnesium; Membrane; Mental retardation; Microsome;
KW Mitochondrion; Mitochondrion outer membrane; Nucleotide-binding;
KW Peroxisome; Polymorphism; Reference proteome; Signal-anchor;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1 711 Long-chain-fatty-acid--CoA ligase 4.
FT /FTId=PRO_0000193109.
FT TRANSMEM 8 28 Helical; Signal-anchor for type III
FT membrane protein; (Potential).
FT TOPO_DOM 29 711 Cytoplasmic (Potential).
FT VAR_SEQ 1 41 Missing (in isoform Short).
FT /FTId=VSP_000238.
FT VARIANT 133 133 R -> C (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036376.
FT VARIANT 570 570 R -> S (in MRX63).
FT /FTId=VAR_013180.
FT CONFLICT 181 181 Y -> C (in Ref. 2; CAA73314).
SQ SEQUENCE 711 AA; 79188 MW; 6483CD17FE78FE73 CRC64;
MKLKLNVLTI ILLPVHLLIT IYSALIFIPW YFLTNAKKKN AMAKRIKAKP TSDKPGSPYR
SVTHFDSLAV IDIPGADTLD KLFDHAVSKF GKKDSLGTRE ILSEENEMQP NGKVFKKLIL
GNYKWMNYLE VNRRVNNFGS GLTALGLKPK NTIAIFCETR AEWMIAAQTC FKYNFPLVTL
YATLGKEAVV HGLNESEASY LITSVELLES KLKTALLDIS CVKHIIYVDN KAINKAEYPE
GFEIHSMQSV EELGSNPENL GIPPSRPTPS DMAIVMYTSG STGRPKGVMM HHSNLIAGMT
GQCERIPGLG PKDTYIGYLP LAHVLELTAE ISCFTYGCRI GYSSPLTLSD QSSKIKKGSK
GDCTVLKPTL MAAVPEIMDR IYKNVMSKVQ EMNYIQKTLF KIGYDYKLEQ IKKGYDAPLC
NLLLFKKVKA LLGGNVRMML SGGAPLSPQT HRFMNVCFCC PIGQGYGLTE SCGAGTVTEV
TDYTTGRVGA PLICCEIKLK DWQEGGYTIN DKPNPRGEIV IGGQNISMGY FKNEEKTAED
YSVDENGQRW FCTGDIGEFH PDGCLQIIDR KKDLVKLQAG EYVSLGKVEA ALKNCPLIDN
ICAFAKSDQS YVISFVVPNQ KRLTLLAQQK GVEGTWVDIC NNPAMEAEIL KEIREAANAM
KLERFEIPIK VRLSPEPWTP ETGLVTDAFK LKRKELRNHY LKDIERMYGG K
//
MIM
300157
*RECORD*
*FIELD* NO
300157
*FIELD* TI
*300157 ACYL-CoA SYNTHETASE LONG CHAIN FAMILY, MEMBER 4; ACSL4
;;FATTY ACID CoA LIGASE, LONG CHAIN 4; FACL4;;
read moreACYL-CoA SYNTHETASE 4; ACS4
*FIELD* TX
DESCRIPTION
Long chain acyl-CoA synthetase (LACS), or long chain fatty acid-CoA
ligase (FACL; EC 6.2.1.3), converts free long chain fatty acids into
fatty acyl-CoA esters, which are key intermediates in the synthesis of
complex lipids. The ACSL4 gene encodes a form of LACS and is expressed
in several tissues, including brain (Cao et al., 1998; Piccini et al.,
1998).
CLONING
Kang et al. (1997) identified rat Acsl4, which they called Acs4. By
searching databases with rat Acs4 as query, Cao et al. (1998) identified
ESTs encoding human ACSL4, which they called FACL4. They used the ESTs
to identify a brain cDNA containing the remainder of the FACL4 coding
region. The predicted 670-amino acid human protein is 97% identical to
rat Acs4.
Independently, Piccini et al. (1998) cloned FACL4 cDNAs. Northern blot
analysis revealed that FACL4 was expressed as a 5-kb mRNA in a variety
of tissues. The transcript in brain appeared to be slightly larger.
Sequence analysis of FACL4 cDNAs showed that the larger mRNAs result
from alternative splicing and encode a predicted protein with 41
additional N-terminal amino acids. The authors stated that the 41-amino
acid peptide is hydrophobic and suggested that it may change the
intracellular localization of FACL4 or its fatty acid specificity.
Meloni et al. (2002) found that FACL4 was highly expressed in adult
human brain, especially in cerebellum and hippocampus, and showed a
distribution similar to that obtained in mouse. A strong cytoplasmic
staining was found in Purkinje and granular cells of cerebellum and in
the pyramidal layer of hippocampus, indicating that FACL4 is
specifically expressed in neurons and not in glial cells. Within the
neuron, FACL4 was found primarily in neuronal soma and proximal
dendrites.
Vitelli et al. (2000) cloned the mouse Facl4 gene.
GENE STRUCTURE
Minekura et al. (2001) determined that the ACSL4 gene contains 16 exons
and spans approximately 90 kb. The 5-prime flanking region does not have
a typical TATA box, but it has a CCAAT box and transcription
factor-binding sites for AP2 (see 107580), AP4 (600743), and CREB
(123810). Minekura et al. (2001) identified several other potential
binding sites.
Watkins et al. (2007) determined that the ACSL4 gene contains at least
17 exons.
MAPPING
By somatic cell hybrid analysis and FISH, Cao et al. (1998) mapped the
ACSL4 gene to chromosome Xq23. Piccini et al. (1998) further refined the
map position to chromosome Xq22.3 by showing that the ACSL4 gene was
contained within a YAC contig from that region. Watkins et al. (2007)
mapped the ACSL4 gene to the minus strand of chromosome Xq22.3-q23 by
genomic sequence analysis.
Vitelli et al. (2000) mapped the mouse Acsl4 gene to chromosome XF1-F3
by FISH.
GENE FUNCTION
Kang et al. (1997) showed that rat Acs4 preferentially used arachidonate
and eicosapentaenoate as substrates.
Cao et al. (1998) showed that human FACL4 exhibited FACL activity with a
preference for arachidonic acid as substrate when expressed in mammalian
cells.
MOLECULAR GENETICS
Piccini et al. (1998) reported that the 2 patients with Alport syndrome,
elliptocytosis, and mental retardation described by Jonsson et al.
(1998) (300194) carried a large deletion of the COL4A5 (303630) region
that included the contiguous FACL4. Piccini et al. (1998) suggested that
the absence of FACL4 might play a role in the development of mental
retardation or other signs associated with Alport syndrome in these
patients.
Meloni et al. (2002) reported the identification of 2 point mutations, 1
missense and 1 splice site change, in the FACL4 gene in 2 families with
nonspecific mental retardation (MRX63; 300387). Analysis of enzymatic
activity in lymphoblastoid cell lines of affected individuals of both
families revealed low levels compared with normal cells, indicating that
both mutations are null mutations. All carrier females with either point
mutations or genomic deletions in FACL4 showed a completely skewed X
inactivation, suggesting that the gene influences survival advantage.
ANIMAL MODEL
Cho et al. (2001) found that female mice heterozygous for Facl4
deficiency became pregnant less frequently and produced small litters,
with 40% of embryos surviving gestation. The transmission rate for the
disrupted allele was low. Heterozygous females had extremely enlarged
uteri and lumina filled with numerous proliferative cysts, and showed
marked uterine accumulation of prostaglandins. Hemizygous males (-/Y)
appeared normal and were fertile when crossed with wildtype females.
Zhang et al. (2009) demonstrated that the Drosophila ACSL-like protein,
Acsl, and ACSL4 are highly conserved, allowing ACSL4 to substitute for
Acsl in organismal viability, lipid storage, and the neural wiring in
the visual center. In neurodevelopment, production of decapentaplegic
(Dpp), a BMP-like protein in Drosophila, diminished specifically in the
larval brain of Drosophila Acsl mutants. Consistent with the Dpp
reduction, the number of glial cells and neurons dramatically decreased
and the retinal axons mistargeted in the visual cortex. All of these
defects in Drosophila brain were rescued by the wildtype ACSL4 but not
by the mutant products found in nonsyndromic X-linked mental retardation
patients. Expression of an MRX63-associated ACSL4 mutant form in a
wildtype background led to lesions in the visual center, suggesting a
dominant-negative effect. Zhang et al. (2009) proposed a connection
between ACSL4 and the BMP pathway in neurodevelopment.
*FIELD* AV
.0001
MENTAL RETARDATION, X-LINKED 63
ACSL4, ARG529SER
In a family segregating nonsyndromic X-linked mental retardation (MRX63;
300387), Meloni et al. (2002) identified a C-to-A transversion at
nucleotide 1585 in exon 15 of the FACL4 gene, leading to an arg-to-ser
substitution in amino acid 529 (R529S), corresponding to amino acid 570
of the brain isoform (R570S). All females carrying this mutation had
completely skewed X inactivation in leukocytes.
.0002
MENTAL RETARDATION, X-LINKED 63
ACSL4, IVS10, A-G, -2
In a patient with severe nonspecific X-linked mental retardation (MRX63;
300387), Meloni et al. (2002) identified an A-to-G transition at the -2
position of the splice site of intron 10 of the FACL4 gene (1003-2A-G),
resulting in activation of a cryptic splice site within the intron and
inducing an additional 28 nucleotides with an in-frame stop codon. This
mutation was not identified in 600 normal control chromosomes. The
carrier mother of the affected male had completely skewed X inactivation
in leukocytes.
.0003
MENTAL RETARDATION, X-LINKED 68
ACSL4, PRO375LEU
In affected members of a family with nonspecific X-linked mental
retardation (MRX68; 300387), Longo et al. (2003) identified a 1001C-T
change in the FACL4 gene, resulting in a pro375-to-leu (P375L)
substitution. Carrier females had 100% skewed X inactivation. Functional
studies of the mutant protein showed a marked reduction in enzyme
activity. The authors suggested that reduction of FACL4 activity may
lead to deranged fatty acid metabolism in neurons, causing defects of
neuron outgrowth, synaptogenesis, and other developmental functions
important for normal brain development.
*FIELD* RF
1. Cao, Y.; Traer, E.; Zimmerman, G. A.; McIntyre, T. M.; Prescott,
S. M.: Cloning, expression, and chromosomal localization of human
long-chain fatty acid-CoA ligase 4 (FACL4). Genomics 49: 327-330,
1998.
2. Cho, Y.-Y.; Kang, M.-J.; Sone, H.; Suzuki, T.; Abe, M.; Igarashi,
M.; Tokunaga, T.; Ogawa, S.; Takei, Y. A.; Miyazawa, T.; Sasano, H.;
Fujino, T.; Yamamoto, T. T.: Abnormal uterus with polycysts, accumulation
of uterine prostaglandins, and reduced fertility in mice heterozygous
for acyl-CoA synthetase 4 deficiency. Biochem. Biophys. Res. Commun. 284:
993-997, 2001.
3. Jonsson, J. J.; Renieri, A.; Gallagher, P. G.; Kashtan, C. E.;
Cherniske, E. M.; Bruttini, M.; Piccini, M.; Vitelli, F.; Ballabio,
A.; Pober, B. R.: Alport syndrome, mental retardation, midface hypoplasia,
and elliptocytosis: a new X linked contiguous gene deletion syndrome? J.
Med. Genet. 35: 273-278, 1998.
4. Kang, M. J.; Fujino, T.; Sasano, H.; Minekura, H.; Yabuki, N.;
Nagura, H.; Iijima, H.; Yamamoto, T. T.: A novel arachidonate-preferring
acyl-CoA synthetase is present in steroidogenic cells of the rat adrenal,
ovary, and testis. Proc. Nat. Acad. Sci. 94: 2880-2884, 1997.
5. Longo, I.; Frints, S. G. M.; Fryns, J.-P.; Meloni, I.; Pescucci,
C.; Ariani, F.; Borghgraef, M.; Raynaud, M.; Marynen, P.; Schwartz,
C.; Renieri, A.; Froyen, G.: A third MRX family (MRX68) is the result
of mutation in the long chain fatty acid-CoA ligase 4 (FACL4) gene:
proposal of a rapid enzymatic assay for screening mentally retarded
patients. J. Med. Genet. 40: 11-17, 2003.
6. Meloni, I.; Muscettola, M.; Raynaud, M.; Longo, I.; Bruttini, M.;
Moizard, M.-P.; Gomot, M.; Chelly, J.; des Portes, V.; Fryns, J.-P.;
Ropers, H.-H.; Magi, B.; Bellan, C.; Volpi, N.; Yntema, H. G.; Lewis,
S. E.; Schaffer, J. E.; Renieri, A.: FACL4, encoding fatty acid-CoA
ligase 4, is mutated in nonspecific X-linked mental retardation. Nature
Genet. 30: 436-440, 2002.
7. Minekura, H.; Kang, M.-J.; Inagaki, Y.; Cho, Y.-Y.; Suzuki, H.;
Fujino, T.; Yamamoto, T. T.: Exon/intron organization and transcription
units of the human acyl-CoA synthetase 4 gene. Biochem. Biophys.
Res. Commun. 286: 80-86, 2001.
8. Piccini, M.; Vitelli, F.; Bruttini, M.; Pober, B. R.; Jonsson,
J. J.; Villanova, M.; Zollo, M.; Borsani, G.; Ballabio, A.; Renieri,
A.: FACL4, a new gene encoding long-chain acyl-CoA synthetase 4,
is deleted in a family with Alport syndrome, elliptocytosis, and mental
retardation. Genomics 47: 350-358, 1998.
9. Vitelli, F.; Meloni, I.; Fineschi, S.; Favara, F.; Tiziana Storlazzi,
C.; Rocchi, M.; Renieri, A.: Identification and characterization
of mouse orthologs of the AMMECR1 and FACL4 genes deleted in AMME
syndrome: orthology of Xq22.3 and MmuXF1-F3. Cytogenet. Cell Genet. 88:
259-263, 2000.
10. Watkins, P. A.; Maiguel, D.; Jia, Z.; Pevsner, J.: Evidence for
26 distinct acyl-coenzyme A synthetase genes in the human genome. J.
Lipid Res. 48: 2736-2750, 2007.
11. Zhang, Y.; Chen, D.; Wang, Z.: Analyses of mental dysfunction-related
ACSl4 (sic) in Drosophila reveal its requirement for Dpp/BMP production
and visual wiring in the brain. Hum. Molec. Genet. 18: 3894-3905,
2009.
*FIELD* CN
Patricia A. Hartz - updated: 10/4/2011
George E. Tiller - updated: 8/10/2010
Cassandra L. Kniffin - updated: 12/8/2003
Patricia A. Hartz - updated: 6/13/2002
Ada Hamosh - updated: 3/29/2002
Carol A. Bocchini - updated: 2/15/2001
*FIELD* CD
Rebekah S. Rasooly: 11/5/1998
*FIELD* ED
mgross: 12/02/2011
mgross: 11/30/2011
terry: 10/4/2011
wwang: 8/10/2010
terry: 9/19/2008
mgross: 1/6/2004
carol: 12/12/2003
ckniffin: 12/8/2003
carol: 4/18/2003
carol: 6/19/2002
terry: 6/13/2002
alopez: 4/2/2002
terry: 3/29/2002
mgross: 2/22/2001
mcapotos: 2/16/2001
carol: 2/15/2001
terry: 4/25/2000
carol: 6/1/1999
alopez: 11/5/1998
*RECORD*
*FIELD* NO
300157
*FIELD* TI
*300157 ACYL-CoA SYNTHETASE LONG CHAIN FAMILY, MEMBER 4; ACSL4
;;FATTY ACID CoA LIGASE, LONG CHAIN 4; FACL4;;
read moreACYL-CoA SYNTHETASE 4; ACS4
*FIELD* TX
DESCRIPTION
Long chain acyl-CoA synthetase (LACS), or long chain fatty acid-CoA
ligase (FACL; EC 6.2.1.3), converts free long chain fatty acids into
fatty acyl-CoA esters, which are key intermediates in the synthesis of
complex lipids. The ACSL4 gene encodes a form of LACS and is expressed
in several tissues, including brain (Cao et al., 1998; Piccini et al.,
1998).
CLONING
Kang et al. (1997) identified rat Acsl4, which they called Acs4. By
searching databases with rat Acs4 as query, Cao et al. (1998) identified
ESTs encoding human ACSL4, which they called FACL4. They used the ESTs
to identify a brain cDNA containing the remainder of the FACL4 coding
region. The predicted 670-amino acid human protein is 97% identical to
rat Acs4.
Independently, Piccini et al. (1998) cloned FACL4 cDNAs. Northern blot
analysis revealed that FACL4 was expressed as a 5-kb mRNA in a variety
of tissues. The transcript in brain appeared to be slightly larger.
Sequence analysis of FACL4 cDNAs showed that the larger mRNAs result
from alternative splicing and encode a predicted protein with 41
additional N-terminal amino acids. The authors stated that the 41-amino
acid peptide is hydrophobic and suggested that it may change the
intracellular localization of FACL4 or its fatty acid specificity.
Meloni et al. (2002) found that FACL4 was highly expressed in adult
human brain, especially in cerebellum and hippocampus, and showed a
distribution similar to that obtained in mouse. A strong cytoplasmic
staining was found in Purkinje and granular cells of cerebellum and in
the pyramidal layer of hippocampus, indicating that FACL4 is
specifically expressed in neurons and not in glial cells. Within the
neuron, FACL4 was found primarily in neuronal soma and proximal
dendrites.
Vitelli et al. (2000) cloned the mouse Facl4 gene.
GENE STRUCTURE
Minekura et al. (2001) determined that the ACSL4 gene contains 16 exons
and spans approximately 90 kb. The 5-prime flanking region does not have
a typical TATA box, but it has a CCAAT box and transcription
factor-binding sites for AP2 (see 107580), AP4 (600743), and CREB
(123810). Minekura et al. (2001) identified several other potential
binding sites.
Watkins et al. (2007) determined that the ACSL4 gene contains at least
17 exons.
MAPPING
By somatic cell hybrid analysis and FISH, Cao et al. (1998) mapped the
ACSL4 gene to chromosome Xq23. Piccini et al. (1998) further refined the
map position to chromosome Xq22.3 by showing that the ACSL4 gene was
contained within a YAC contig from that region. Watkins et al. (2007)
mapped the ACSL4 gene to the minus strand of chromosome Xq22.3-q23 by
genomic sequence analysis.
Vitelli et al. (2000) mapped the mouse Acsl4 gene to chromosome XF1-F3
by FISH.
GENE FUNCTION
Kang et al. (1997) showed that rat Acs4 preferentially used arachidonate
and eicosapentaenoate as substrates.
Cao et al. (1998) showed that human FACL4 exhibited FACL activity with a
preference for arachidonic acid as substrate when expressed in mammalian
cells.
MOLECULAR GENETICS
Piccini et al. (1998) reported that the 2 patients with Alport syndrome,
elliptocytosis, and mental retardation described by Jonsson et al.
(1998) (300194) carried a large deletion of the COL4A5 (303630) region
that included the contiguous FACL4. Piccini et al. (1998) suggested that
the absence of FACL4 might play a role in the development of mental
retardation or other signs associated with Alport syndrome in these
patients.
Meloni et al. (2002) reported the identification of 2 point mutations, 1
missense and 1 splice site change, in the FACL4 gene in 2 families with
nonspecific mental retardation (MRX63; 300387). Analysis of enzymatic
activity in lymphoblastoid cell lines of affected individuals of both
families revealed low levels compared with normal cells, indicating that
both mutations are null mutations. All carrier females with either point
mutations or genomic deletions in FACL4 showed a completely skewed X
inactivation, suggesting that the gene influences survival advantage.
ANIMAL MODEL
Cho et al. (2001) found that female mice heterozygous for Facl4
deficiency became pregnant less frequently and produced small litters,
with 40% of embryos surviving gestation. The transmission rate for the
disrupted allele was low. Heterozygous females had extremely enlarged
uteri and lumina filled with numerous proliferative cysts, and showed
marked uterine accumulation of prostaglandins. Hemizygous males (-/Y)
appeared normal and were fertile when crossed with wildtype females.
Zhang et al. (2009) demonstrated that the Drosophila ACSL-like protein,
Acsl, and ACSL4 are highly conserved, allowing ACSL4 to substitute for
Acsl in organismal viability, lipid storage, and the neural wiring in
the visual center. In neurodevelopment, production of decapentaplegic
(Dpp), a BMP-like protein in Drosophila, diminished specifically in the
larval brain of Drosophila Acsl mutants. Consistent with the Dpp
reduction, the number of glial cells and neurons dramatically decreased
and the retinal axons mistargeted in the visual cortex. All of these
defects in Drosophila brain were rescued by the wildtype ACSL4 but not
by the mutant products found in nonsyndromic X-linked mental retardation
patients. Expression of an MRX63-associated ACSL4 mutant form in a
wildtype background led to lesions in the visual center, suggesting a
dominant-negative effect. Zhang et al. (2009) proposed a connection
between ACSL4 and the BMP pathway in neurodevelopment.
*FIELD* AV
.0001
MENTAL RETARDATION, X-LINKED 63
ACSL4, ARG529SER
In a family segregating nonsyndromic X-linked mental retardation (MRX63;
300387), Meloni et al. (2002) identified a C-to-A transversion at
nucleotide 1585 in exon 15 of the FACL4 gene, leading to an arg-to-ser
substitution in amino acid 529 (R529S), corresponding to amino acid 570
of the brain isoform (R570S). All females carrying this mutation had
completely skewed X inactivation in leukocytes.
.0002
MENTAL RETARDATION, X-LINKED 63
ACSL4, IVS10, A-G, -2
In a patient with severe nonspecific X-linked mental retardation (MRX63;
300387), Meloni et al. (2002) identified an A-to-G transition at the -2
position of the splice site of intron 10 of the FACL4 gene (1003-2A-G),
resulting in activation of a cryptic splice site within the intron and
inducing an additional 28 nucleotides with an in-frame stop codon. This
mutation was not identified in 600 normal control chromosomes. The
carrier mother of the affected male had completely skewed X inactivation
in leukocytes.
.0003
MENTAL RETARDATION, X-LINKED 68
ACSL4, PRO375LEU
In affected members of a family with nonspecific X-linked mental
retardation (MRX68; 300387), Longo et al. (2003) identified a 1001C-T
change in the FACL4 gene, resulting in a pro375-to-leu (P375L)
substitution. Carrier females had 100% skewed X inactivation. Functional
studies of the mutant protein showed a marked reduction in enzyme
activity. The authors suggested that reduction of FACL4 activity may
lead to deranged fatty acid metabolism in neurons, causing defects of
neuron outgrowth, synaptogenesis, and other developmental functions
important for normal brain development.
*FIELD* RF
1. Cao, Y.; Traer, E.; Zimmerman, G. A.; McIntyre, T. M.; Prescott,
S. M.: Cloning, expression, and chromosomal localization of human
long-chain fatty acid-CoA ligase 4 (FACL4). Genomics 49: 327-330,
1998.
2. Cho, Y.-Y.; Kang, M.-J.; Sone, H.; Suzuki, T.; Abe, M.; Igarashi,
M.; Tokunaga, T.; Ogawa, S.; Takei, Y. A.; Miyazawa, T.; Sasano, H.;
Fujino, T.; Yamamoto, T. T.: Abnormal uterus with polycysts, accumulation
of uterine prostaglandins, and reduced fertility in mice heterozygous
for acyl-CoA synthetase 4 deficiency. Biochem. Biophys. Res. Commun. 284:
993-997, 2001.
3. Jonsson, J. J.; Renieri, A.; Gallagher, P. G.; Kashtan, C. E.;
Cherniske, E. M.; Bruttini, M.; Piccini, M.; Vitelli, F.; Ballabio,
A.; Pober, B. R.: Alport syndrome, mental retardation, midface hypoplasia,
and elliptocytosis: a new X linked contiguous gene deletion syndrome? J.
Med. Genet. 35: 273-278, 1998.
4. Kang, M. J.; Fujino, T.; Sasano, H.; Minekura, H.; Yabuki, N.;
Nagura, H.; Iijima, H.; Yamamoto, T. T.: A novel arachidonate-preferring
acyl-CoA synthetase is present in steroidogenic cells of the rat adrenal,
ovary, and testis. Proc. Nat. Acad. Sci. 94: 2880-2884, 1997.
5. Longo, I.; Frints, S. G. M.; Fryns, J.-P.; Meloni, I.; Pescucci,
C.; Ariani, F.; Borghgraef, M.; Raynaud, M.; Marynen, P.; Schwartz,
C.; Renieri, A.; Froyen, G.: A third MRX family (MRX68) is the result
of mutation in the long chain fatty acid-CoA ligase 4 (FACL4) gene:
proposal of a rapid enzymatic assay for screening mentally retarded
patients. J. Med. Genet. 40: 11-17, 2003.
6. Meloni, I.; Muscettola, M.; Raynaud, M.; Longo, I.; Bruttini, M.;
Moizard, M.-P.; Gomot, M.; Chelly, J.; des Portes, V.; Fryns, J.-P.;
Ropers, H.-H.; Magi, B.; Bellan, C.; Volpi, N.; Yntema, H. G.; Lewis,
S. E.; Schaffer, J. E.; Renieri, A.: FACL4, encoding fatty acid-CoA
ligase 4, is mutated in nonspecific X-linked mental retardation. Nature
Genet. 30: 436-440, 2002.
7. Minekura, H.; Kang, M.-J.; Inagaki, Y.; Cho, Y.-Y.; Suzuki, H.;
Fujino, T.; Yamamoto, T. T.: Exon/intron organization and transcription
units of the human acyl-CoA synthetase 4 gene. Biochem. Biophys.
Res. Commun. 286: 80-86, 2001.
8. Piccini, M.; Vitelli, F.; Bruttini, M.; Pober, B. R.; Jonsson,
J. J.; Villanova, M.; Zollo, M.; Borsani, G.; Ballabio, A.; Renieri,
A.: FACL4, a new gene encoding long-chain acyl-CoA synthetase 4,
is deleted in a family with Alport syndrome, elliptocytosis, and mental
retardation. Genomics 47: 350-358, 1998.
9. Vitelli, F.; Meloni, I.; Fineschi, S.; Favara, F.; Tiziana Storlazzi,
C.; Rocchi, M.; Renieri, A.: Identification and characterization
of mouse orthologs of the AMMECR1 and FACL4 genes deleted in AMME
syndrome: orthology of Xq22.3 and MmuXF1-F3. Cytogenet. Cell Genet. 88:
259-263, 2000.
10. Watkins, P. A.; Maiguel, D.; Jia, Z.; Pevsner, J.: Evidence for
26 distinct acyl-coenzyme A synthetase genes in the human genome. J.
Lipid Res. 48: 2736-2750, 2007.
11. Zhang, Y.; Chen, D.; Wang, Z.: Analyses of mental dysfunction-related
ACSl4 (sic) in Drosophila reveal its requirement for Dpp/BMP production
and visual wiring in the brain. Hum. Molec. Genet. 18: 3894-3905,
2009.
*FIELD* CN
Patricia A. Hartz - updated: 10/4/2011
George E. Tiller - updated: 8/10/2010
Cassandra L. Kniffin - updated: 12/8/2003
Patricia A. Hartz - updated: 6/13/2002
Ada Hamosh - updated: 3/29/2002
Carol A. Bocchini - updated: 2/15/2001
*FIELD* CD
Rebekah S. Rasooly: 11/5/1998
*FIELD* ED
mgross: 12/02/2011
mgross: 11/30/2011
terry: 10/4/2011
wwang: 8/10/2010
terry: 9/19/2008
mgross: 1/6/2004
carol: 12/12/2003
ckniffin: 12/8/2003
carol: 4/18/2003
carol: 6/19/2002
terry: 6/13/2002
alopez: 4/2/2002
terry: 3/29/2002
mgross: 2/22/2001
mcapotos: 2/16/2001
carol: 2/15/2001
terry: 4/25/2000
carol: 6/1/1999
alopez: 11/5/1998
MIM
300194
*RECORD*
*FIELD* NO
300194
*FIELD* TI
#300194 AMME COMPLEX
;;ALPORT SYNDROME, MENTAL RETARDATION, MIDFACE HYPOPLASIA, AND ELLIPTOCYTOSIS;;
read moreATS-MR;;
CHROMOSOME Xq22.3 TELOMERIC DELETION SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
AMME complex is a contiguous gene deletion syndrome.
CLINICAL FEATURES
Robson et al. (1994) described a family in which 2 brothers and a
maternal uncle had mental retardation and macrocephaly in addition to
nephritis and sensorineural hearing loss. In one of the brothers,
microscopic hematuria and red blood cell casts were first noted at the
age of 2.5 years and persisted in subsequent urinalysis. He was treated
with peritoneal dialysis from the age of 13 years and died unexpectedly
at age 16. The second brother had a craniopharyngioma, which was removed
surgically at the age of 17.5 years. The uncle, who had severe mental
retardation, died of chronic renal failure at the age of 22 years. The
mother of the 2 brothers had persistent microscopic hematuria, as did
their maternal grandmother.
Jonsson et al. (1998) described a family with 4 members, a mother, 2
sons, and a daughter, with features of X-linked Alport syndrome. In
addition, the 2 males had mental retardation, dysmorphic facies with
midface hypoplasia, and elliptocytosis.
MOLECULAR GENETICS
Molecular characterization by Jonsson et al. (1998) of their family
suggested a submicroscopic deletion of the X chromosome including the
COL4A5 gene (303630). Jonsson et al. (1998) proposed that the additional
features in the affected males might be due to disruption of genes
adjacent to COL4A5 and that the phenotype might represent a contiguous
gene deletion syndrome. Piccini et al. (1998) presented evidence that
this was a true contiguous gene syndrome involving both the COL4A5 and
FACL4 (300157) genes. FACL4 encodes a long-chain acyl-CoA synthetase
(Piccini et al., 1998). Vitelli et al. (1999) showed that another gene
deleted in this syndrome is AMMECR1 (300195).
Meloni et al. (2002) identified a second family with Alport syndrome and
mental retardation, confirmed the existence of a contiguous gene
syndrome in Xq22.3, which they called ATS-MR, and characterized the
deletion in the 2 ATS-MR families. They compared the extent of deletion
between individuals with ATS-MR and individuals with ATS alone to define
a critical region for mental retardation of approximately 380 kb,
containing 4 candidate genes: FACL, NXT2 (300320), KCNE5 (KCNE1L;
300128), and GUCY2F (300041). Meloni et al. (2002) reported the
identification of 2 point mutations, 1 missense and 1 splice site
change, in the FACL4 gene in 2 families with nonspecific mental
retardation.
Meloni et al. (2002) further characterized the new contiguous syndrome
on Xq22.3 as well as the previously known contiguous gene syndrome in
this region, ATS-DL (Alport syndrome and diffuse leiomyomatosis;
308940). Both syndromes involve deletion of COL4A5, but whereas ATS-DL
extends centromerically, ATS-MR extends telomerically with respect to
the collagen gene. One of the families they studied had been described
by Robson et al. (1994).
*FIELD* RF
1. Jonsson, J. J.; Renieri, A.; Gallagher, P. G.; Kashtan, C. E.;
Cherniske, E. M.; Bruttini, M.; Piccini, M.; Vitelli, F.; Ballabio,
A.; Pober, B. R.: Alport syndrome, mental retardation, midface hypoplasia,
and elliptocytosis: a new X linked contiguous gene deletion syndrome? J.
Med. Genet. 35: 273-278, 1998.
2. Meloni, I.; Muscettola, M.; Raynaud, M.; Longo, I.; Bruttini, M.;
Moizard, M.-P.; Gomot, M.; Chelly, J.; des Portes, V.; Fryns, J.-P.;
Ropers, H.-H.; Magi, B.; Bellan, C.; Volpi, N.; Yntema, H. G.; Lewis,
S. E.; Schaffer, J. E.; Renieri, A.: FACL4, encoding fatty acid-CoA
ligase 4, is mutated in nonspecific X-linked mental retardation. Nature
Genet. 30: 436-440, 2002.
3. Meloni, I.; Vitelli, F.; Pucci, L.; Lowry, R. B.; Tonlorenzi, R.;
Rossi, E.; Ventura, M.; Rizzoni, G.; Kashtan, C. E.; Pober, B.; Renieri,
A.: Alport syndrome and mental retardation: clinical and genetic
dissection of the contiguous gene deletion syndrome in Xq22.3 (ATS-MR). J.
Med. Genet. 39: 359-365, 2002.
4. Piccini, M.; Vitelli, F.; Bruttini, M.; Pober, B. R.; Jonsson,
J. J.; Villanova, M.; Zollo, M.; Borsani, G.; Ballabio, A.; Renieri,
A.: FACL4, a new gene encoding long-chain acyl-CoA synthetase 4,
is deleted in a family with Alport syndrome, elliptocytosis, and mental
retardation. Genomics 47: 350-358, 1998.
5. Robson, W. L. M.; Lowry, R. B.; Leung, A. K. C.: X-linked recessive
nephritis with mental retardation, sensorineural hearing loss, and
macrocephaly. Clin. Genet. 45: 314-317, 1994.
6. Vitelli, F.; Piccini, M.; Caroli, F.; Franco, B.; Malandrini, A.;
Pober, B.; Jonsson, J.; Sorrentino, V.; Renieri, A.: Identification
and characterization of a highly conserved protein absent in the Alport
syndrome (A), mental retardation (M), midface hypoplasia (M), and
elliptocytosis (E) contiguous gene deletion syndrome (AMME). Genomics 55:
335-340, 1999.
*FIELD* CN
Victor A. McKusick - updated: 12/29/2003
Ada Hamosh - updated: 3/29/2002
*FIELD* CD
Victor A. McKusick: 6/1/1999
*FIELD* ED
carol: 05/26/2010
ckniffin: 5/26/2010
carol: 7/13/2004
cwells: 12/31/2003
terry: 12/29/2003
alopez: 4/2/2002
terry: 3/29/2002
carol: 6/3/1999
carol: 6/1/1999
*RECORD*
*FIELD* NO
300194
*FIELD* TI
#300194 AMME COMPLEX
;;ALPORT SYNDROME, MENTAL RETARDATION, MIDFACE HYPOPLASIA, AND ELLIPTOCYTOSIS;;
read moreATS-MR;;
CHROMOSOME Xq22.3 TELOMERIC DELETION SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
AMME complex is a contiguous gene deletion syndrome.
CLINICAL FEATURES
Robson et al. (1994) described a family in which 2 brothers and a
maternal uncle had mental retardation and macrocephaly in addition to
nephritis and sensorineural hearing loss. In one of the brothers,
microscopic hematuria and red blood cell casts were first noted at the
age of 2.5 years and persisted in subsequent urinalysis. He was treated
with peritoneal dialysis from the age of 13 years and died unexpectedly
at age 16. The second brother had a craniopharyngioma, which was removed
surgically at the age of 17.5 years. The uncle, who had severe mental
retardation, died of chronic renal failure at the age of 22 years. The
mother of the 2 brothers had persistent microscopic hematuria, as did
their maternal grandmother.
Jonsson et al. (1998) described a family with 4 members, a mother, 2
sons, and a daughter, with features of X-linked Alport syndrome. In
addition, the 2 males had mental retardation, dysmorphic facies with
midface hypoplasia, and elliptocytosis.
MOLECULAR GENETICS
Molecular characterization by Jonsson et al. (1998) of their family
suggested a submicroscopic deletion of the X chromosome including the
COL4A5 gene (303630). Jonsson et al. (1998) proposed that the additional
features in the affected males might be due to disruption of genes
adjacent to COL4A5 and that the phenotype might represent a contiguous
gene deletion syndrome. Piccini et al. (1998) presented evidence that
this was a true contiguous gene syndrome involving both the COL4A5 and
FACL4 (300157) genes. FACL4 encodes a long-chain acyl-CoA synthetase
(Piccini et al., 1998). Vitelli et al. (1999) showed that another gene
deleted in this syndrome is AMMECR1 (300195).
Meloni et al. (2002) identified a second family with Alport syndrome and
mental retardation, confirmed the existence of a contiguous gene
syndrome in Xq22.3, which they called ATS-MR, and characterized the
deletion in the 2 ATS-MR families. They compared the extent of deletion
between individuals with ATS-MR and individuals with ATS alone to define
a critical region for mental retardation of approximately 380 kb,
containing 4 candidate genes: FACL, NXT2 (300320), KCNE5 (KCNE1L;
300128), and GUCY2F (300041). Meloni et al. (2002) reported the
identification of 2 point mutations, 1 missense and 1 splice site
change, in the FACL4 gene in 2 families with nonspecific mental
retardation.
Meloni et al. (2002) further characterized the new contiguous syndrome
on Xq22.3 as well as the previously known contiguous gene syndrome in
this region, ATS-DL (Alport syndrome and diffuse leiomyomatosis;
308940). Both syndromes involve deletion of COL4A5, but whereas ATS-DL
extends centromerically, ATS-MR extends telomerically with respect to
the collagen gene. One of the families they studied had been described
by Robson et al. (1994).
*FIELD* RF
1. Jonsson, J. J.; Renieri, A.; Gallagher, P. G.; Kashtan, C. E.;
Cherniske, E. M.; Bruttini, M.; Piccini, M.; Vitelli, F.; Ballabio,
A.; Pober, B. R.: Alport syndrome, mental retardation, midface hypoplasia,
and elliptocytosis: a new X linked contiguous gene deletion syndrome? J.
Med. Genet. 35: 273-278, 1998.
2. Meloni, I.; Muscettola, M.; Raynaud, M.; Longo, I.; Bruttini, M.;
Moizard, M.-P.; Gomot, M.; Chelly, J.; des Portes, V.; Fryns, J.-P.;
Ropers, H.-H.; Magi, B.; Bellan, C.; Volpi, N.; Yntema, H. G.; Lewis,
S. E.; Schaffer, J. E.; Renieri, A.: FACL4, encoding fatty acid-CoA
ligase 4, is mutated in nonspecific X-linked mental retardation. Nature
Genet. 30: 436-440, 2002.
3. Meloni, I.; Vitelli, F.; Pucci, L.; Lowry, R. B.; Tonlorenzi, R.;
Rossi, E.; Ventura, M.; Rizzoni, G.; Kashtan, C. E.; Pober, B.; Renieri,
A.: Alport syndrome and mental retardation: clinical and genetic
dissection of the contiguous gene deletion syndrome in Xq22.3 (ATS-MR). J.
Med. Genet. 39: 359-365, 2002.
4. Piccini, M.; Vitelli, F.; Bruttini, M.; Pober, B. R.; Jonsson,
J. J.; Villanova, M.; Zollo, M.; Borsani, G.; Ballabio, A.; Renieri,
A.: FACL4, a new gene encoding long-chain acyl-CoA synthetase 4,
is deleted in a family with Alport syndrome, elliptocytosis, and mental
retardation. Genomics 47: 350-358, 1998.
5. Robson, W. L. M.; Lowry, R. B.; Leung, A. K. C.: X-linked recessive
nephritis with mental retardation, sensorineural hearing loss, and
macrocephaly. Clin. Genet. 45: 314-317, 1994.
6. Vitelli, F.; Piccini, M.; Caroli, F.; Franco, B.; Malandrini, A.;
Pober, B.; Jonsson, J.; Sorrentino, V.; Renieri, A.: Identification
and characterization of a highly conserved protein absent in the Alport
syndrome (A), mental retardation (M), midface hypoplasia (M), and
elliptocytosis (E) contiguous gene deletion syndrome (AMME). Genomics 55:
335-340, 1999.
*FIELD* CN
Victor A. McKusick - updated: 12/29/2003
Ada Hamosh - updated: 3/29/2002
*FIELD* CD
Victor A. McKusick: 6/1/1999
*FIELD* ED
carol: 05/26/2010
ckniffin: 5/26/2010
carol: 7/13/2004
cwells: 12/31/2003
terry: 12/29/2003
alopez: 4/2/2002
terry: 3/29/2002
carol: 6/3/1999
carol: 6/1/1999
MIM
300387
*RECORD*
*FIELD* NO
300387
*FIELD* TI
#300387 MENTAL RETARDATION, X-LINKED 63; MRX63
;;MENTAL RETARDATION, X-LINKED 68; MRX68
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that
X-linked mental retardation-63 can be caused by mutation in the ACSL4
(300157) gene.
CLINICAL FEATURES
Raynaud et al. (2000) reported a 4-generation family with nonspecific
nonsyndromic X-linked mental retardation. Affected males showed
nonprogressive mental retardation ranging from severe to moderate,
without seizures, whereas carrier females showed highly variable
cognitive capacities, ranging from moderate mental retardation to normal
intelligence.
MAPPING
Raynaud et al. (2000) reported a 4-generation family with nonspecific
nonsyndromic X-linked mental retardation mapped between DXS990 and
DXS1227 (Xq21.33-q27.1) with a maximum lod at theta = 0.0 of 2.14 at
DXS1001.
MOLECULAR GENETICS
In the proband of the family reported by Raynaud et al. (2000) as MRX63,
Meloni et al. (2002) identified a mutation in the ACSL4 gene
(300157.0001). The proband of a second affected family carried a
mutation in the 3-prime splice site of intron 10 of the ACSL4 gene
(300157.0002). Mental retardation was severe. Six of 6 informative
carrier females in family MRX63 showed completely skewed X inactivation
in leukocytes. Similarly, 3 of 3 carrier females from 2 different
families with ATS-MR (300194) showed completely skewed X inactivation in
leukocytes, as did the carrier mother of the proband of the second
family.
In a family with nonsyndromic X-linked mental retardation (MRX68), Longo
et al. (2003) identified a mutation in the ACSL4 gene (300157.0003).
Neurocognitive levels ranged from mild to moderate in affected males and
were borderline in female carriers. X-inactivation studies in the female
carriers showed 100% skewed inactivation in all of them.
ANIMAL MODEL
Zhang et al. (2009) demonstrated that the Drosophila ACSL-like protein,
Acsl, and ACSL4 are highly conserved, allowing ACSL4 to substitute for
Acsl in organismal viability, lipid storage, and the neural wiring in
the visual center. In neurodevelopment, production of decapentaplegic
(Dpp), a BMP-like protein in Drosophila, diminished specifically in the
larval brain of Drosophila Acsl mutants. Consistent with the Dpp
reduction, the number of glial cells and neurons dramatically decreased
and the retinal axons mistargeted in the visual cortex. All of these
defects in Drosophila brain were rescued by the wildtype ACSL4 but not
by the mutant products found in nonsyndromic X-linked mental retardation
patients. Expression of an MRX63-associated ACSL4 mutant form in a
wildtype background led to lesions in the visual center, suggesting a
dominant-negative effect. Zhang et al. (2009) proposed a connection
between ACSL4 and the BMP pathway in neurodevelopment.
*FIELD* RF
1. Longo, I.; Frints, S. G. M.; Fryns, J.-P.; Meloni, I.; Pescucci,
C.; Ariani, F.; Borghgraef, M.; Raynaud, M.; Marynen, P.; Schwartz,
C.; Renieri, A.; Froyen, G.: A third MRX family (MRX68) is the result
of mutation in the long chain fatty acid-CoA ligase 4 (FACL4) gene:
proposal of a rapid enzymatic assay for screening mentally retarded
patients. J. Med. Genet. 40: 11-17, 2003.
2. Meloni, I.; Muscettola, M.; Raynaud, M.; Longo, I.; Bruttini, M.;
Moizard, M.-P.; Gomot, M.; Chelly, J.; des Portes, V.; Fryns, J.-P.;
Ropers, H.-H.; Magi, B.; Bellan, C.; Volpi, N.; Yntema, H. G.; Lewis,
S. E.; Schaffer, J. E.; Renieri, A.: FACL4, encoding fatty acid-CoA
ligase 4, is mutated in nonspecific X-linked mental retardation. Nature
Genet. 30: 436-440, 2002.
3. Raynaud, M.; Moizard, M.-P.; Dessay, B.; Briault, S.; Toutain,
A.; Gendrot, C.; Ronce, N.; Moraine, C.: Systematic analysis of X-inactivation
in 19 XLMR families: extremely skewed profiles in carriers in three
families. Europ. J. Hum. Genet. 8: 253-258, 2000.
4. Zhang, Y.; Chen, D.; Wang, Z.: Analyses of mental dysfunction-related
ACSl4 (sic) in Drosophila reveal its requirement for Dpp/BMP production
and visual wiring in the brain. Hum. Molec. Genet. 18: 3894-3905,
2009.
*FIELD* CN
George E. Tiller - updated: 8/6/2010
Cassandra L. Kniffin - updated: 12/12/2003
*FIELD* CD
Ada Hamosh: 4/2/2002
*FIELD* ED
carol: 03/29/2012
wwang: 8/10/2010
terry: 8/6/2010
carol: 12/12/2003
ckniffin: 12/8/2003
terry: 4/28/2003
alopez: 4/2/2002
*RECORD*
*FIELD* NO
300387
*FIELD* TI
#300387 MENTAL RETARDATION, X-LINKED 63; MRX63
;;MENTAL RETARDATION, X-LINKED 68; MRX68
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that
X-linked mental retardation-63 can be caused by mutation in the ACSL4
(300157) gene.
CLINICAL FEATURES
Raynaud et al. (2000) reported a 4-generation family with nonspecific
nonsyndromic X-linked mental retardation. Affected males showed
nonprogressive mental retardation ranging from severe to moderate,
without seizures, whereas carrier females showed highly variable
cognitive capacities, ranging from moderate mental retardation to normal
intelligence.
MAPPING
Raynaud et al. (2000) reported a 4-generation family with nonspecific
nonsyndromic X-linked mental retardation mapped between DXS990 and
DXS1227 (Xq21.33-q27.1) with a maximum lod at theta = 0.0 of 2.14 at
DXS1001.
MOLECULAR GENETICS
In the proband of the family reported by Raynaud et al. (2000) as MRX63,
Meloni et al. (2002) identified a mutation in the ACSL4 gene
(300157.0001). The proband of a second affected family carried a
mutation in the 3-prime splice site of intron 10 of the ACSL4 gene
(300157.0002). Mental retardation was severe. Six of 6 informative
carrier females in family MRX63 showed completely skewed X inactivation
in leukocytes. Similarly, 3 of 3 carrier females from 2 different
families with ATS-MR (300194) showed completely skewed X inactivation in
leukocytes, as did the carrier mother of the proband of the second
family.
In a family with nonsyndromic X-linked mental retardation (MRX68), Longo
et al. (2003) identified a mutation in the ACSL4 gene (300157.0003).
Neurocognitive levels ranged from mild to moderate in affected males and
were borderline in female carriers. X-inactivation studies in the female
carriers showed 100% skewed inactivation in all of them.
ANIMAL MODEL
Zhang et al. (2009) demonstrated that the Drosophila ACSL-like protein,
Acsl, and ACSL4 are highly conserved, allowing ACSL4 to substitute for
Acsl in organismal viability, lipid storage, and the neural wiring in
the visual center. In neurodevelopment, production of decapentaplegic
(Dpp), a BMP-like protein in Drosophila, diminished specifically in the
larval brain of Drosophila Acsl mutants. Consistent with the Dpp
reduction, the number of glial cells and neurons dramatically decreased
and the retinal axons mistargeted in the visual cortex. All of these
defects in Drosophila brain were rescued by the wildtype ACSL4 but not
by the mutant products found in nonsyndromic X-linked mental retardation
patients. Expression of an MRX63-associated ACSL4 mutant form in a
wildtype background led to lesions in the visual center, suggesting a
dominant-negative effect. Zhang et al. (2009) proposed a connection
between ACSL4 and the BMP pathway in neurodevelopment.
*FIELD* RF
1. Longo, I.; Frints, S. G. M.; Fryns, J.-P.; Meloni, I.; Pescucci,
C.; Ariani, F.; Borghgraef, M.; Raynaud, M.; Marynen, P.; Schwartz,
C.; Renieri, A.; Froyen, G.: A third MRX family (MRX68) is the result
of mutation in the long chain fatty acid-CoA ligase 4 (FACL4) gene:
proposal of a rapid enzymatic assay for screening mentally retarded
patients. J. Med. Genet. 40: 11-17, 2003.
2. Meloni, I.; Muscettola, M.; Raynaud, M.; Longo, I.; Bruttini, M.;
Moizard, M.-P.; Gomot, M.; Chelly, J.; des Portes, V.; Fryns, J.-P.;
Ropers, H.-H.; Magi, B.; Bellan, C.; Volpi, N.; Yntema, H. G.; Lewis,
S. E.; Schaffer, J. E.; Renieri, A.: FACL4, encoding fatty acid-CoA
ligase 4, is mutated in nonspecific X-linked mental retardation. Nature
Genet. 30: 436-440, 2002.
3. Raynaud, M.; Moizard, M.-P.; Dessay, B.; Briault, S.; Toutain,
A.; Gendrot, C.; Ronce, N.; Moraine, C.: Systematic analysis of X-inactivation
in 19 XLMR families: extremely skewed profiles in carriers in three
families. Europ. J. Hum. Genet. 8: 253-258, 2000.
4. Zhang, Y.; Chen, D.; Wang, Z.: Analyses of mental dysfunction-related
ACSl4 (sic) in Drosophila reveal its requirement for Dpp/BMP production
and visual wiring in the brain. Hum. Molec. Genet. 18: 3894-3905,
2009.
*FIELD* CN
George E. Tiller - updated: 8/6/2010
Cassandra L. Kniffin - updated: 12/12/2003
*FIELD* CD
Ada Hamosh: 4/2/2002
*FIELD* ED
carol: 03/29/2012
wwang: 8/10/2010
terry: 8/6/2010
carol: 12/12/2003
ckniffin: 12/8/2003
terry: 4/28/2003
alopez: 4/2/2002