Full text data of APOL1
APOL1
(APOL)
[Confidence: low (only semi-automatic identification from reviews)]
Apolipoprotein L1 (Apolipoprotein L; Apo-L; ApoL; Apolipoprotein L-I; ApoL-I; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Apolipoprotein L1 (Apolipoprotein L; Apo-L; ApoL; Apolipoprotein L-I; ApoL-I; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
O14791
ID APOL1_HUMAN Reviewed; 398 AA.
AC O14791; A5PLQ4; B4DU12; E9PF24; O60804; Q5R3P7; Q5R3P8; Q96AB8;
read moreAC Q96PM4; Q9BQ03;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 23-SEP-2008, sequence version 5.
DT 22-JAN-2014, entry version 126.
DE RecName: Full=Apolipoprotein L1;
DE AltName: Full=Apolipoprotein L;
DE Short=Apo-L;
DE Short=ApoL;
DE AltName: Full=Apolipoprotein L-I;
DE Short=ApoL-I;
DE Flags: Precursor;
GN Name=APOL1; Synonyms=APOL;
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 1), PROTEIN SEQUENCE OF 28-63, AND
RP VARIANTS LYS-150; ILE-228 AND LYS-255.
RC TISSUE=Pancreas;
RX PubMed=9325276; DOI=10.1074/jbc.272.41.25576;
RA Duchateau P.N., Pullinger C.R., Orellana R.E., Kunitake S.T.,
RA Naya-Vigne J., O'Connor P.M., Malloy M.J., Kane J.P.;
RT "Apolipoprotein L, a new human high density lipoprotein apolipoprotein
RT expressed by the pancreas. Identification, cloning, characterization,
RT and plasma distribution of apolipoprotein L.";
RL J. Biol. Chem. 272:25576-25582(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM
RP 2), SEQUENCE REVISION TO 155 AND 346, AND VARIANTS LYS-150; ILE-228
RP AND LYS-255.
RC TISSUE=Pancreas;
RX PubMed=11290834;
RA Duchateau P.N., Pullinger C.R., Cho M.H., Eng C., Kane J.P.;
RT "Apolipoprotein L gene family: tissue-specific expression, splicing,
RT promoter regions; discovery of a new gene.";
RL J. Lipid Res. 42:620-630(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=11374903; DOI=10.1006/geno.2001.6534;
RA Page N.M., Butlin D.J., Lomthaisong K., Lowry P.J.;
RT "The human apolipoprotein L gene cluster: identification,
RT classification, and sites of distribution.";
RL Genomics 74:71-78(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS ILE-228; LYS-255;
RP GLY-342 AND MET-384.
RX PubMed=11944986; DOI=10.1006/geno.2002.6729;
RA Monajemi H., Fontijn R.D., Pannekoek H., Horrevoets A.J.G.;
RT "The apolipoprotein L gene cluster has emerged recently in evolution
RT and is expressed in human vascular tissue.";
RL Genomics 79:539-546(2002).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), AND VARIANTS
RP LYS-150; ILE-228 AND LYS-255.
RC TISSUE=Placenta;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10591208; DOI=10.1038/990031;
RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M.,
RA Clamp M., Smink L.J., Ainscough R., Almeida J.P., Babbage A.K.,
RA Bagguley C., Bailey J., Barlow K.F., Bates K.N., Beasley O.P.,
RA Bird C.P., Blakey S.E., Bridgeman A.M., Buck D., Burgess J.,
RA Burrill W.D., Burton J., Carder C., Carter N.P., Chen Y., Clark G.,
RA Clegg S.M., Cobley V.E., Cole C.G., Collier R.E., Connor R.,
RA Conroy D., Corby N.R., Coville G.J., Cox A.V., Davis J., Dawson E.,
RA Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M., Ellington A.G.,
RA Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S.,
RA Hunt S.E., Jones M.C., Kershaw J., Kimberley A.M., King A.,
RA Laird G.K., Langford C.F., Leversha M.A., Lloyd C., Lloyd D.M.,
RA Martyn I.D., Mashreghi-Mohammadi M., Matthews L.H., Mccann O.T.,
RA Mcclay J., Mclaren S., McMurray A.A., Milne S.A., Mortimore B.J.,
RA Odell C.N., Pavitt R., Pearce A.V., Pearson D., Phillimore B.J.C.T.,
RA Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y., Rogers L., Ross M.T.,
RA Scott C.E., Sehra H.K., Skuce C.D., Smalley S., Smith M.L.,
RA Soderlund C., Spragon L., Steward C.A., Sulston J.E., Swann R.M.,
RA Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J.,
RA Shintani A., Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S.,
RA Roe B.A., Chen F., Chu L., Crabtree J., Deschamps S., Do A., Do T.,
RA Dorman A., Fang F., Fu Y., Hu P., Hua A., Kenton S., Lai H., Lao H.I.,
RA Lewis J., Lewis S., Lin S.-P., Loh P., Malaj E., Nguyen T., Pan H.,
RA Phan S., Qi S., Qian Y., Ray L., Ren Q., Shaull S., Sloan D., Song L.,
RA Wang Q., Wang Y., Wang Z., White J., Willingham D., Wu H., Yao Z.,
RA Zhan M., Zhang G., Chissoe S., Murray J., Miller N., Minx P.,
RA Fulton R., Johnson D., Bemis G., Bentley D., Bradshaw H., Bourne S.,
RA Cordes M., Du Z., Fulton L., Goela D., Graves T., Hawkins J.,
RA Hinds K., Kemp K., Latreille P., Layman D., Ozersky P., Rohlfing T.,
RA Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K., Nelson J.,
RA Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S.,
RA Budarf M.L., McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E.,
RA Edelmann L., Kim U.J., Shizuya H., Simon M.I., Dumanski J.P.,
RA Peyrard M., Kedra D., Seroussi E., Fransson I., Tapia I., Bruder C.E.,
RA O'Brien K.P., Wilkinson P., Bodenteich A., Hartman K., Hu X.,
RA Khan A.S., Lane L., Tilahun Y., Wright H.;
RT "The DNA sequence of human chromosome 22.";
RL Nature 402:489-495(1999).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [8]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-261, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [9]
RP VARIANT [LARGE SCALE ANALYSIS] THR-188.
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).
RN [10]
RP VARIANTS FSGS4 GLY-342 AND MET-384.
RX PubMed=20635188; DOI=10.1007/s00439-010-0861-0;
RA Tzur S., Rosset S., Shemer R., Yudkovsky G., Selig S., Tarekegn A.,
RA Bekele E., Bradman N., Wasser W.G., Behar D.M., Skorecki K.;
RT "Missense mutations in the APOL1 gene are highly associated with end
RT stage kidney disease risk previously attributed to the MYH9 gene.";
RL Hum. Genet. 128:345-350(2010).
RN [11]
RP VARIANTS FSGS4 GLY-342 AND MET-384.
RX PubMed=20647424; DOI=10.1126/science.1193032;
RA Genovese G., Friedman D.J., Ross M.D., Lecordier L., Uzureau P.,
RA Freedman B.I., Bowden D.W., Langefeld C.D., Oleksyk T.K.,
RA Uscinski Knob A.L., Bernhardy A.J., Hicks P.J., Nelson G.W.,
RA Vanhollebeke B., Winkler C.A., Kopp J.B., Pays E., Pollak M.R.;
RT "Association of trypanolytic ApoL1 variants with kidney disease in
RT African Americans.";
RL Science 329:841-845(2010).
CC -!- FUNCTION: May play a role in lipid exchange and transport
CC throughout the body. May participate in reverse cholesterol
CC transport from peripheral cells to the liver.
CC -!- SUBUNIT: In plasma, interacts with APOA1 and mainly associated
CC with large high density lipoprotein particles.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=A;
CC IsoId=O14791-1; Sequence=Displayed;
CC Note=Major isoform;
CC Name=2; Synonyms=B;
CC IsoId=O14791-2; Sequence=VSP_000292;
CC Name=3;
CC IsoId=O14791-3; Sequence=VSP_045077;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Plasma. Found on APOA-I-containing high
CC density lipoprotein (HDL3). Expressed in pancreas, lung, prostate,
CC liver, placenta and spleen.
CC -!- PTM: Phosphorylation sites are present in the extracellular
CC medium.
CC -!- DISEASE: Focal segmental glomerulosclerosis 4 (FSGS4)
CC [MIM:612551]: A renal pathology defined by the presence of
CC segmental sclerosis in glomeruli and resulting in proteinuria,
CC reduced glomerular filtration rate and progressive decline in
CC renal function. Renal insufficiency often progresses to end-stage
CC renal disease, a highly morbid state requiring either dialysis
CC therapy or kidney transplantation. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the apolipoprotein L family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB81218.2; Type=Erroneous initiation;
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DR EMBL; AF019225; AAB81218.2; ALT_INIT; mRNA.
DR EMBL; AF323540; AAG53690.1; -; mRNA.
DR EMBL; AF323548; AAK11591.1; -; Genomic_DNA.
DR EMBL; AF323543; AAK11591.1; JOINED; Genomic_DNA.
DR EMBL; AF323544; AAK11591.1; JOINED; Genomic_DNA.
DR EMBL; AF323545; AAK11591.1; JOINED; Genomic_DNA.
DR EMBL; AF323546; AAK11591.1; JOINED; Genomic_DNA.
DR EMBL; AF323547; AAK11591.1; JOINED; Genomic_DNA.
DR EMBL; AF305224; AAK20210.1; -; mRNA.
DR EMBL; AF305428; AAL09358.1; -; mRNA.
DR EMBL; AK300454; BAG62174.1; -; mRNA.
DR EMBL; Z82215; CAI22438.1; -; Genomic_DNA.
DR EMBL; Z82215; CAQ09089.1; -; Genomic_DNA.
DR EMBL; BC143039; AAI43040.1; -; mRNA.
DR RefSeq; NP_001130012.1; NM_001136540.1.
DR RefSeq; NP_001130013.1; NM_001136541.1.
DR RefSeq; NP_003652.2; NM_003661.3.
DR RefSeq; XP_005261853.1; XM_005261796.1.
DR UniGene; Hs.114309; -.
DR ProteinModelPortal; O14791; -.
DR IntAct; O14791; 1.
DR STRING; 9606.ENSP00000317674; -.
DR PhosphoSite; O14791; -.
DR PaxDb; O14791; -.
DR PRIDE; O14791; -.
DR Ensembl; ENST00000319136; ENSP00000317674; ENSG00000100342.
DR Ensembl; ENST00000397278; ENSP00000380448; ENSG00000100342.
DR Ensembl; ENST00000397279; ENSP00000380449; ENSG00000100342.
DR Ensembl; ENST00000422706; ENSP00000411507; ENSG00000100342.
DR Ensembl; ENST00000426053; ENSP00000388477; ENSG00000100342.
DR GeneID; 8542; -.
DR KEGG; hsa:8542; -.
DR UCSC; uc003apf.3; human.
DR CTD; 8542; -.
DR GeneCards; GC22P036649; -.
DR H-InvDB; HIX0016423; -.
DR HGNC; HGNC:618; APOL1.
DR HPA; CAB056156; -.
DR HPA; HPA018885; -.
DR MIM; 603743; gene.
DR MIM; 612551; phenotype.
DR neXtProt; NX_O14791; -.
DR Orphanet; 93218; Sporadic idiopathic steroid-resistant nephrotic syndrome with focal segmental hyalinosis.
DR PharmGKB; PA24904; -.
DR eggNOG; NOG125779; -.
DR HOVERGEN; HBG074468; -.
DR InParanoid; O14791; -.
DR KO; K14480; -.
DR OMA; KGTTIAN; -.
DR OrthoDB; EOG7GXPBT; -.
DR Reactome; REACT_160300; Binding and Uptake of Ligands by Scavenger Receptors.
DR ChiTaRS; APOL1; human.
DR GeneWiki; APOL1; -.
DR GenomeRNAi; 8542; -.
DR NextBio; 31996; -.
DR PRO; PR:O14791; -.
DR ArrayExpress; O14791; -.
DR Bgee; O14791; -.
DR CleanEx; HS_APOL1; -.
DR Genevestigator; O14791; -.
DR GO; GO:0034364; C:high-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0031224; C:intrinsic to membrane; IC:BHF-UCL.
DR GO; GO:0034361; C:very-low-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0005254; F:chloride channel activity; IDA:BHF-UCL.
DR GO; GO:0008289; F:lipid binding; IDA:BHF-UCL.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0019835; P:cytolysis; IDA:BHF-UCL.
DR GO; GO:0045087; P:innate immune response; IDA:BHF-UCL.
DR GO; GO:0031640; P:killing of cells of other organism; IDA:BHF-UCL.
DR GO; GO:0006869; P:lipid transport; IEA:UniProtKB-KW.
DR GO; GO:0042157; P:lipoprotein metabolic process; IEA:InterPro.
DR InterPro; IPR008405; ApoL.
DR PANTHER; PTHR14096; PTHR14096; 1.
DR Pfam; PF05461; ApoL; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cholesterol metabolism; Complete proteome;
KW Direct protein sequencing; Disease mutation; Glycoprotein; HDL;
KW Lipid metabolism; Lipid transport; Phosphoprotein; Polymorphism;
KW Reference proteome; Secreted; Signal; Steroid metabolism;
KW Sterol metabolism; Transport.
FT SIGNAL 1 27
FT CHAIN 28 398 Apolipoprotein L1.
FT /FTId=PRO_0000002040.
FT CARBOHYD 261 261 N-linked (GlcNAc...).
FT VAR_SEQ 1 1 M -> MRFKSHTVELRRPCSDM (in isoform 2).
FT /FTId=VSP_000292.
FT VAR_SEQ 16 33 Missing (in isoform 3).
FT /FTId=VSP_045077.
FT VARIANT 150 150 E -> K (in dbSNP:rs2239785).
FT /FTId=VAR_011383.
FT VARIANT 188 188 I -> T (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036568.
FT VARIANT 228 228 M -> I (in dbSNP:rs136175).
FT /FTId=VAR_011384.
FT VARIANT 255 255 R -> K (in dbSNP:rs136176).
FT /FTId=VAR_011385.
FT VARIANT 337 337 D -> N (in dbSNP:rs16996616).
FT /FTId=VAR_046641.
FT VARIANT 342 342 S -> G (in FSGS4; dbSNP:rs73885319).
FT /FTId=VAR_063598.
FT VARIANT 384 384 I -> M (in FSGS4; dbSNP:rs60910145).
FT /FTId=VAR_061995.
FT CONFLICT 24 24 G -> R (in Ref. 1; AAG53690 and 2;
FT AAK11591).
FT CONFLICT 256 256 E -> G (in Ref. 3; AAK20210).
FT CONFLICT 346 346 V -> A (in Ref. 3; AAK20210).
SQ SEQUENCE 398 AA; 43974 MW; BD1A8F1D7C5A889F CRC64;
MEGAALLRVS VLCIWMSALF LGVGVRAEEA GARVQQNVPS GTDTGDPQSK PLGDWAAGTM
DPESSIFIED AIKYFKEKVS TQNLLLLLTD NEAWNGFVAA AELPRNEADE LRKALDNLAR
QMIMKDKNWH DKGQQYRNWF LKEFPRLKSE LEDNIRRLRA LADGVQKVHK GTTIANVVSG
SLSISSGILT LVGMGLAPFT EGGSLVLLEP GMELGITAAL TGITSSTMDY GKKWWTQAQA
HDLVIKSLDK LKEVREFLGE NISNFLSLAG NTYQLTRGIG KDIRALRRAR ANLQSVPHAS
ASRPRVTEPI SAESGEQVER VNEPSILEMS RGVKLTDVAP VSFFLVLDVV YLVYESKHLH
EGAKSETAEE LKKVAQELEE KLNILNNNYK ILQADQEL
//
ID APOL1_HUMAN Reviewed; 398 AA.
AC O14791; A5PLQ4; B4DU12; E9PF24; O60804; Q5R3P7; Q5R3P8; Q96AB8;
read moreAC Q96PM4; Q9BQ03;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 23-SEP-2008, sequence version 5.
DT 22-JAN-2014, entry version 126.
DE RecName: Full=Apolipoprotein L1;
DE AltName: Full=Apolipoprotein L;
DE Short=Apo-L;
DE Short=ApoL;
DE AltName: Full=Apolipoprotein L-I;
DE Short=ApoL-I;
DE Flags: Precursor;
GN Name=APOL1; Synonyms=APOL;
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 1), PROTEIN SEQUENCE OF 28-63, AND
RP VARIANTS LYS-150; ILE-228 AND LYS-255.
RC TISSUE=Pancreas;
RX PubMed=9325276; DOI=10.1074/jbc.272.41.25576;
RA Duchateau P.N., Pullinger C.R., Orellana R.E., Kunitake S.T.,
RA Naya-Vigne J., O'Connor P.M., Malloy M.J., Kane J.P.;
RT "Apolipoprotein L, a new human high density lipoprotein apolipoprotein
RT expressed by the pancreas. Identification, cloning, characterization,
RT and plasma distribution of apolipoprotein L.";
RL J. Biol. Chem. 272:25576-25582(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM
RP 2), SEQUENCE REVISION TO 155 AND 346, AND VARIANTS LYS-150; ILE-228
RP AND LYS-255.
RC TISSUE=Pancreas;
RX PubMed=11290834;
RA Duchateau P.N., Pullinger C.R., Cho M.H., Eng C., Kane J.P.;
RT "Apolipoprotein L gene family: tissue-specific expression, splicing,
RT promoter regions; discovery of a new gene.";
RL J. Lipid Res. 42:620-630(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=11374903; DOI=10.1006/geno.2001.6534;
RA Page N.M., Butlin D.J., Lomthaisong K., Lowry P.J.;
RT "The human apolipoprotein L gene cluster: identification,
RT classification, and sites of distribution.";
RL Genomics 74:71-78(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS ILE-228; LYS-255;
RP GLY-342 AND MET-384.
RX PubMed=11944986; DOI=10.1006/geno.2002.6729;
RA Monajemi H., Fontijn R.D., Pannekoek H., Horrevoets A.J.G.;
RT "The apolipoprotein L gene cluster has emerged recently in evolution
RT and is expressed in human vascular tissue.";
RL Genomics 79:539-546(2002).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), AND VARIANTS
RP LYS-150; ILE-228 AND LYS-255.
RC TISSUE=Placenta;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10591208; DOI=10.1038/990031;
RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M.,
RA Clamp M., Smink L.J., Ainscough R., Almeida J.P., Babbage A.K.,
RA Bagguley C., Bailey J., Barlow K.F., Bates K.N., Beasley O.P.,
RA Bird C.P., Blakey S.E., Bridgeman A.M., Buck D., Burgess J.,
RA Burrill W.D., Burton J., Carder C., Carter N.P., Chen Y., Clark G.,
RA Clegg S.M., Cobley V.E., Cole C.G., Collier R.E., Connor R.,
RA Conroy D., Corby N.R., Coville G.J., Cox A.V., Davis J., Dawson E.,
RA Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M., Ellington A.G.,
RA Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S.,
RA Hunt S.E., Jones M.C., Kershaw J., Kimberley A.M., King A.,
RA Laird G.K., Langford C.F., Leversha M.A., Lloyd C., Lloyd D.M.,
RA Martyn I.D., Mashreghi-Mohammadi M., Matthews L.H., Mccann O.T.,
RA Mcclay J., Mclaren S., McMurray A.A., Milne S.A., Mortimore B.J.,
RA Odell C.N., Pavitt R., Pearce A.V., Pearson D., Phillimore B.J.C.T.,
RA Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y., Rogers L., Ross M.T.,
RA Scott C.E., Sehra H.K., Skuce C.D., Smalley S., Smith M.L.,
RA Soderlund C., Spragon L., Steward C.A., Sulston J.E., Swann R.M.,
RA Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J.,
RA Shintani A., Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S.,
RA Roe B.A., Chen F., Chu L., Crabtree J., Deschamps S., Do A., Do T.,
RA Dorman A., Fang F., Fu Y., Hu P., Hua A., Kenton S., Lai H., Lao H.I.,
RA Lewis J., Lewis S., Lin S.-P., Loh P., Malaj E., Nguyen T., Pan H.,
RA Phan S., Qi S., Qian Y., Ray L., Ren Q., Shaull S., Sloan D., Song L.,
RA Wang Q., Wang Y., Wang Z., White J., Willingham D., Wu H., Yao Z.,
RA Zhan M., Zhang G., Chissoe S., Murray J., Miller N., Minx P.,
RA Fulton R., Johnson D., Bemis G., Bentley D., Bradshaw H., Bourne S.,
RA Cordes M., Du Z., Fulton L., Goela D., Graves T., Hawkins J.,
RA Hinds K., Kemp K., Latreille P., Layman D., Ozersky P., Rohlfing T.,
RA Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K., Nelson J.,
RA Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S.,
RA Budarf M.L., McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E.,
RA Edelmann L., Kim U.J., Shizuya H., Simon M.I., Dumanski J.P.,
RA Peyrard M., Kedra D., Seroussi E., Fransson I., Tapia I., Bruder C.E.,
RA O'Brien K.P., Wilkinson P., Bodenteich A., Hartman K., Hu X.,
RA Khan A.S., Lane L., Tilahun Y., Wright H.;
RT "The DNA sequence of human chromosome 22.";
RL Nature 402:489-495(1999).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [8]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-261, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [9]
RP VARIANT [LARGE SCALE ANALYSIS] THR-188.
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).
RN [10]
RP VARIANTS FSGS4 GLY-342 AND MET-384.
RX PubMed=20635188; DOI=10.1007/s00439-010-0861-0;
RA Tzur S., Rosset S., Shemer R., Yudkovsky G., Selig S., Tarekegn A.,
RA Bekele E., Bradman N., Wasser W.G., Behar D.M., Skorecki K.;
RT "Missense mutations in the APOL1 gene are highly associated with end
RT stage kidney disease risk previously attributed to the MYH9 gene.";
RL Hum. Genet. 128:345-350(2010).
RN [11]
RP VARIANTS FSGS4 GLY-342 AND MET-384.
RX PubMed=20647424; DOI=10.1126/science.1193032;
RA Genovese G., Friedman D.J., Ross M.D., Lecordier L., Uzureau P.,
RA Freedman B.I., Bowden D.W., Langefeld C.D., Oleksyk T.K.,
RA Uscinski Knob A.L., Bernhardy A.J., Hicks P.J., Nelson G.W.,
RA Vanhollebeke B., Winkler C.A., Kopp J.B., Pays E., Pollak M.R.;
RT "Association of trypanolytic ApoL1 variants with kidney disease in
RT African Americans.";
RL Science 329:841-845(2010).
CC -!- FUNCTION: May play a role in lipid exchange and transport
CC throughout the body. May participate in reverse cholesterol
CC transport from peripheral cells to the liver.
CC -!- SUBUNIT: In plasma, interacts with APOA1 and mainly associated
CC with large high density lipoprotein particles.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=A;
CC IsoId=O14791-1; Sequence=Displayed;
CC Note=Major isoform;
CC Name=2; Synonyms=B;
CC IsoId=O14791-2; Sequence=VSP_000292;
CC Name=3;
CC IsoId=O14791-3; Sequence=VSP_045077;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Plasma. Found on APOA-I-containing high
CC density lipoprotein (HDL3). Expressed in pancreas, lung, prostate,
CC liver, placenta and spleen.
CC -!- PTM: Phosphorylation sites are present in the extracellular
CC medium.
CC -!- DISEASE: Focal segmental glomerulosclerosis 4 (FSGS4)
CC [MIM:612551]: A renal pathology defined by the presence of
CC segmental sclerosis in glomeruli and resulting in proteinuria,
CC reduced glomerular filtration rate and progressive decline in
CC renal function. Renal insufficiency often progresses to end-stage
CC renal disease, a highly morbid state requiring either dialysis
CC therapy or kidney transplantation. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the apolipoprotein L family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB81218.2; Type=Erroneous initiation;
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; AF019225; AAB81218.2; ALT_INIT; mRNA.
DR EMBL; AF323540; AAG53690.1; -; mRNA.
DR EMBL; AF323548; AAK11591.1; -; Genomic_DNA.
DR EMBL; AF323543; AAK11591.1; JOINED; Genomic_DNA.
DR EMBL; AF323544; AAK11591.1; JOINED; Genomic_DNA.
DR EMBL; AF323545; AAK11591.1; JOINED; Genomic_DNA.
DR EMBL; AF323546; AAK11591.1; JOINED; Genomic_DNA.
DR EMBL; AF323547; AAK11591.1; JOINED; Genomic_DNA.
DR EMBL; AF305224; AAK20210.1; -; mRNA.
DR EMBL; AF305428; AAL09358.1; -; mRNA.
DR EMBL; AK300454; BAG62174.1; -; mRNA.
DR EMBL; Z82215; CAI22438.1; -; Genomic_DNA.
DR EMBL; Z82215; CAQ09089.1; -; Genomic_DNA.
DR EMBL; BC143039; AAI43040.1; -; mRNA.
DR RefSeq; NP_001130012.1; NM_001136540.1.
DR RefSeq; NP_001130013.1; NM_001136541.1.
DR RefSeq; NP_003652.2; NM_003661.3.
DR RefSeq; XP_005261853.1; XM_005261796.1.
DR UniGene; Hs.114309; -.
DR ProteinModelPortal; O14791; -.
DR IntAct; O14791; 1.
DR STRING; 9606.ENSP00000317674; -.
DR PhosphoSite; O14791; -.
DR PaxDb; O14791; -.
DR PRIDE; O14791; -.
DR Ensembl; ENST00000319136; ENSP00000317674; ENSG00000100342.
DR Ensembl; ENST00000397278; ENSP00000380448; ENSG00000100342.
DR Ensembl; ENST00000397279; ENSP00000380449; ENSG00000100342.
DR Ensembl; ENST00000422706; ENSP00000411507; ENSG00000100342.
DR Ensembl; ENST00000426053; ENSP00000388477; ENSG00000100342.
DR GeneID; 8542; -.
DR KEGG; hsa:8542; -.
DR UCSC; uc003apf.3; human.
DR CTD; 8542; -.
DR GeneCards; GC22P036649; -.
DR H-InvDB; HIX0016423; -.
DR HGNC; HGNC:618; APOL1.
DR HPA; CAB056156; -.
DR HPA; HPA018885; -.
DR MIM; 603743; gene.
DR MIM; 612551; phenotype.
DR neXtProt; NX_O14791; -.
DR Orphanet; 93218; Sporadic idiopathic steroid-resistant nephrotic syndrome with focal segmental hyalinosis.
DR PharmGKB; PA24904; -.
DR eggNOG; NOG125779; -.
DR HOVERGEN; HBG074468; -.
DR InParanoid; O14791; -.
DR KO; K14480; -.
DR OMA; KGTTIAN; -.
DR OrthoDB; EOG7GXPBT; -.
DR Reactome; REACT_160300; Binding and Uptake of Ligands by Scavenger Receptors.
DR ChiTaRS; APOL1; human.
DR GeneWiki; APOL1; -.
DR GenomeRNAi; 8542; -.
DR NextBio; 31996; -.
DR PRO; PR:O14791; -.
DR ArrayExpress; O14791; -.
DR Bgee; O14791; -.
DR CleanEx; HS_APOL1; -.
DR Genevestigator; O14791; -.
DR GO; GO:0034364; C:high-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0031224; C:intrinsic to membrane; IC:BHF-UCL.
DR GO; GO:0034361; C:very-low-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0005254; F:chloride channel activity; IDA:BHF-UCL.
DR GO; GO:0008289; F:lipid binding; IDA:BHF-UCL.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0019835; P:cytolysis; IDA:BHF-UCL.
DR GO; GO:0045087; P:innate immune response; IDA:BHF-UCL.
DR GO; GO:0031640; P:killing of cells of other organism; IDA:BHF-UCL.
DR GO; GO:0006869; P:lipid transport; IEA:UniProtKB-KW.
DR GO; GO:0042157; P:lipoprotein metabolic process; IEA:InterPro.
DR InterPro; IPR008405; ApoL.
DR PANTHER; PTHR14096; PTHR14096; 1.
DR Pfam; PF05461; ApoL; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cholesterol metabolism; Complete proteome;
KW Direct protein sequencing; Disease mutation; Glycoprotein; HDL;
KW Lipid metabolism; Lipid transport; Phosphoprotein; Polymorphism;
KW Reference proteome; Secreted; Signal; Steroid metabolism;
KW Sterol metabolism; Transport.
FT SIGNAL 1 27
FT CHAIN 28 398 Apolipoprotein L1.
FT /FTId=PRO_0000002040.
FT CARBOHYD 261 261 N-linked (GlcNAc...).
FT VAR_SEQ 1 1 M -> MRFKSHTVELRRPCSDM (in isoform 2).
FT /FTId=VSP_000292.
FT VAR_SEQ 16 33 Missing (in isoform 3).
FT /FTId=VSP_045077.
FT VARIANT 150 150 E -> K (in dbSNP:rs2239785).
FT /FTId=VAR_011383.
FT VARIANT 188 188 I -> T (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036568.
FT VARIANT 228 228 M -> I (in dbSNP:rs136175).
FT /FTId=VAR_011384.
FT VARIANT 255 255 R -> K (in dbSNP:rs136176).
FT /FTId=VAR_011385.
FT VARIANT 337 337 D -> N (in dbSNP:rs16996616).
FT /FTId=VAR_046641.
FT VARIANT 342 342 S -> G (in FSGS4; dbSNP:rs73885319).
FT /FTId=VAR_063598.
FT VARIANT 384 384 I -> M (in FSGS4; dbSNP:rs60910145).
FT /FTId=VAR_061995.
FT CONFLICT 24 24 G -> R (in Ref. 1; AAG53690 and 2;
FT AAK11591).
FT CONFLICT 256 256 E -> G (in Ref. 3; AAK20210).
FT CONFLICT 346 346 V -> A (in Ref. 3; AAK20210).
SQ SEQUENCE 398 AA; 43974 MW; BD1A8F1D7C5A889F CRC64;
MEGAALLRVS VLCIWMSALF LGVGVRAEEA GARVQQNVPS GTDTGDPQSK PLGDWAAGTM
DPESSIFIED AIKYFKEKVS TQNLLLLLTD NEAWNGFVAA AELPRNEADE LRKALDNLAR
QMIMKDKNWH DKGQQYRNWF LKEFPRLKSE LEDNIRRLRA LADGVQKVHK GTTIANVVSG
SLSISSGILT LVGMGLAPFT EGGSLVLLEP GMELGITAAL TGITSSTMDY GKKWWTQAQA
HDLVIKSLDK LKEVREFLGE NISNFLSLAG NTYQLTRGIG KDIRALRRAR ANLQSVPHAS
ASRPRVTEPI SAESGEQVER VNEPSILEMS RGVKLTDVAP VSFFLVLDVV YLVYESKHLH
EGAKSETAEE LKKVAQELEE KLNILNNNYK ILQADQEL
//
MIM
603743
*RECORD*
*FIELD* NO
603743
*FIELD* TI
*603743 APOLIPOPROTEIN L-I; APOL1
;;APOL;;
APOL-I
*FIELD* TX
DESCRIPTION
The APOL1 gene encodes apolipoprotein L-I (apoL-I), a human-specific
read moreserum apolipoprotein bound to high-density lipoprotein (HDL) particles
(summary by Perez-Morga et al., 2005). This apolipoprotein kills the
African trypanosome Trypanosoma brucei brucei, except subspecies adapted
to humans (T. b. rhodesiense, T. b. gambiense). Genovese et al. (2010)
found that APOL1 carrying African population-specific mutations can lyse
T. b. rhodesiense; these mutations were also associated with increased
susceptibility to focal segmental glomerulosclerosis in African
Americans (see FSGS4, 612551).
CLONING
Based on peptide sequences of a novel high density lipoprotein,
Duchateau et al. (1997) cloned cDNAs encoding APOL. The cDNA encodes a
383-amino acid polypeptide that includes a 12-amino acid secretory
signal peptide. Northern blot analysis detected a 1.3-kb APOL transcript
in the pancreas but not in any other human tissues. Affinity
immunosorption showed that APOL is not free in the plasma, but is
associated with lipoproteins containing APOA1 (107680). APOL was found
in high density lipoprotein fractions.
By sequencing a number of APOL1 clones, Duchateau et al. (2001)
identified a minor splice variant that includes exon 2. This variant
predicts a protein that contains a 43-residue signal peptide. The more
common transcript, lacking exon 2, predicts a protein with a 27-residue
signal peptide. By mRNA dot blot analysis, they found APOL1 expressed in
a wide variety of tissues, the only exception being fetal brain.
Quantitative RT-PCR, reflecting the sum of both splice variants,
revealed highest expression in lung.
By genomic sequence analysis, Page et al. (2001) identified APOL1 within
the APOL gene cluster. The predicted 398-amino acid protein has a
calculated molecular mass of 43.9 kD. They noted that the APOL proteins
share significant identity within the predicted amphipathic alpha
helices. Semiquantitative RT-PCR revealed ubiquitous expression of
APOL1, with highest levels in lung, spleen, prostate, and placenta, and
weak expression in fetal brain and pancreas. In situ hybridization of
human placenta revealed expression in all 3 tissue layers, including the
basal plate, cytiotrophoblast, and chorionic plate.
By Northern blot analysis, Monajemi et al. (2002) detected highest
expression of a 3-kb APOL1 transcript in placenta, lung, and liver, with
low expression in heart and minimal expression in pancreas. In situ
hybridization of human vascular tissue showed APOL1 expression in
endothelial cells and possibly in macrophages.
GENE STRUCTURE
Duchateau et al. (2001) determined that the APOL1 gene contains 7 exons
and spans 14 kb. The promoter regions of the APOL1, APOL2, APOL3
(607253), and APOL4 genes have at least 1 SP1 (189906) site, a number of
AP1 (165160) and AP4 (600743) sites, at least 1 GC box, multiple zinc
finger-binding sites, and at least 1 sterol regulatory element-binding
protein (see 184756) site. Each contains at least 2 conserved initiator
sequences. The most commonly used promoter regions are TATA-less with
multiple transcription initiation sites.
Noting homology within intronic sequences, Monajemi et al. (2002)
concluded that the APOL1, APOL2, APOL3, and APOL4 gene cluster is the
result of tandem gene duplication, whereas APOL5 (607255) and APOL6
(607256) are more distantly related.
MAPPING
By genomic sequence analysis, Duchateau et al. (2001) mapped APOL1 to
chromosome 22q12.1-q13.1. It is located in a cluster with APOL2, APOL3,
and APOL4 that spans 127 kb. APOL1 is in the opposite orientation to the
other 3. Page et al. (2001) found that the APOL cluster contains 6 genes
and spans 619 kb.
In their figure 3, Mimmack et al. (2002) diagrammed the genomic
organization of the APOL gene family on chromosome 22q12.3. The COMT
gene (116790) on chromosome 22q11 is 15.2 Mb from the APOL6 gene, which
is located at the telomeric end of the APOL gene cluster. The APOL1 gene
is at the telomeric end of the cluster.
GENE FUNCTION
Monajemi et al. (2002) detected a 10-fold upregulation of APOL1 in human
umbilical vein endothelial cells following stimulation with tumor
necrosis factor-alpha (TNFA; 191160).
In a microarray analysis of gene expression in the prefrontal cortex of
schizophrenia (181500) and control brains, Mimmack et al. (2002) found
significant upregulation of the APOL1, APOL2 (607252), and APOL4
(607254) genes.
Human sleeping sickness in east Africa is caused by the parasite
Trypanosoma brucei rhodesiense. The basis of this pathology is the
resistance of these parasites to lysis by normal human serum. Resistance
to normal human serum is conferred by a gene that encodes a truncated
form of the variant surface glycoprotein termed serum
resistance-associated protein (SRA). Vanhamme et al. (2003) showed that
SRA is a lysosomal protein, and that the N-terminal alpha-helix of SRA
is responsible for resistance to normal human serum. This domain
interacts strongly with a carboxy-terminal alpha-helix of APOL1.
Depleting normal human serum of APOL1 by incubation with SRA or
antibodies against APOL1 led to the complete loss of trypanolytic
activity. Addition of native or recombinant APOL1 either to
APOL1-depleted normal human serum or to fetal calf serum induced lysis
of normal human serum-sensitive, but not normal human serum-resistant,
trypanosomes. Confocal microscopy demonstrated that APOL1 is taken up
through the endocytic pathway into the lysosome. Vanhamme et al. (2003)
proposed that APOL1 is the trypanosome lytic factor of normal human
serum, and that SRA confers resistance to lysis by interaction with
APOL1 in the lysosome.
Perez-Morga et al. (2005) demonstrated that apolipoprotein L-1 contains
a membrane pore-forming domain functionally similar to that of bacterial
colicins, flanked by a membrane-addressing domain. In lipid bilayer
membranes, apolipoprotein L-1 formed anion channels. In Trypanosoma
brucei, apolipoprotein L-1 was targeted to the lysosomal membrane and
triggered depolarization of this membrane, continuous influx of
chloride, and subsequent osmotic swelling of the lysosome until the
trypanosome lysed.
MOLECULAR GENETICS
Genovese et al. (2010) showed that in African Americans, focal segmental
glomerulosclerosis (FSGS; 603278) and hypertension-attributed end-stage
renal disease (ESRD) are associated with 2 independent sequence variants
in the APOL1 gene on chromosome 22 (FSGS odds ratio = 10.5, 95% CI,
6.0-18.4; ESRD odds ratio = 7.3, 95% CI, 5.6-9.5). The 2 APOL1 variants
are common in African chromosomes but absent in European chromosomes,
and both reside within haplotypes that harbor signatures of positive
selection. APOL1 is a serum factor that lyses trypanosomes. In vitro
assays revealed that only the kidney disease-associated APOL1 variants
lysed Trypanosoma brucei rhodesiense. Genovese et al. (2010) speculated
that evolution of a critical survival factor in Africa may have
contributed to the high rates of renal disease in African Americans. The
strongest signal was obtained for a 2-locus allele, termed G1
(613743.0001), consisting of 2 derived nonsynonymous coding variants:
dbSNP rs73885319 (ser342 to gly) and dbSNP rs60910145 (ile384 to met),
both in the last exon of APOL1. These 2 alleles are in perfect linkage
disequilibrium. The G1 allele (342G:384M) had a frequency of 52% in 205
FSGS cases and 18% in 180 controls (p = 1.07 x 10(-23)). When Genovese
et al. (2010) performed logistic regression to control for G1, they
identified a second strong signal, a 6-bp deletion, dbSNP rs71785313,
which they termed G2 (613743.0002), close to G1, that removed amino
acids N388 and Y389. Because of the proximity of dbSNP rs73885319, dbSNP
rs60910145, and dbSNP rs71785313, alleles G1 and G2 are mutually
exclusive; recombination between them is very unlikely. Genovese et al.
(2010) found that G1 and G2 are in strong LD with variants in MYH9
(160775). In particular, the MYH9 E-1 haplotype, the best predictor of
renal disease in previous studies (see FSGS4, 612551), is present in
most haplotypes containing the G1 or G2 allele. Specifically, E-1 is
present in 89% of haplotypes carrying G1 and in 76% of haplotypes
carrying G2, explaining the association of MYH9 E-1 with renal disease.
Association of renal disease with the MYH9 haplotype disappeared after
controlling for the APOL1 risk variants. Comparing participants with
zero or 1 risk allele of APOL1 to participants with 2 risk alleles
provided an odds ratio for FSGS of 10.5 (CI, 6.0-18.4). This analysis
supported a completely recessive pattern of inheritance.
Parsa et al. (2013) performed 2 studies examining the effects of
variants in the APOL1 gene on the progression of chronic kidney disease.
In the African American Study of Kidney Disease and Hypertension (AASK),
693 black patients with chronic kidney disease attributed to
hypertension were examined for a primary outcome of composite end-stage
renal disease or doubling of the serum creatinine level. A total of 160
(23%) individuals carried 2 copies of APOL1 risk variants G1
(603743.0001) and/or G2 (603743.0002). Of these individuals in the
high-risk group, the primary outcome occurred in 58%; in the APOL1
low-risk group (all other genotypes), the primary outcome occurred in
37% (hazard ratio in the high-risk group, 1.88; p less than 0.001). In
the Chronic Renal Insufficiency Cohort (CRIC), Parsa et al. (2013)
evaluated 2,955 white patients and black patients with chronic kidney
disease (46% of whom had diabetes) for the primary outcomes of the slope
of the estimated glomerular filtration rate (eGFR) and the composite of
end-stage renal disease, or a reduction of 50% in the eGFR from
baseline. Black patients were genotyped for the G1 and G2 risk alleles.
In the CRIC study, black patients in the APOL1 high-risk group (270 of
1,411 total black patients) had a more rapid decline in the eGFR and a
higher risk of the composite renal outcome than did white patients, with
or without diabetes as a complication (p less than 0.001 for all
comparisons).
POPULATION GENETICS
Ko et al. (2013) sequenced a 1.4-kb APOL1 region that encompasses the
last exon, which encodes the pore-forming, membrane-addressing, and
SRA-interacting domains, in 187 individuals from 10 geographically and
ethnically diverse African populations. They identified 38 variants,
including 15 nonsynonymous SNPs and a 6-bp indel that removes 2 amino
acids (i.e., the G2 allele). Three of these 16 variants occurred in the
pore-forming domain, 5 occurred in the membrane-addressing domain, and
6, including the G1 and G2 variants, occurred in the SRA-interacting
domain. The allele frequencies of G2 were similar across all populations
(3% to 8%), whereas the G1 allele was only common in West African Yoruba
(39%). Ko et al. (2013) also identified 8 polymorphic sites in strong
linkage disequilibrium, which they called the G3 haplotype, in all
populations except for West African Yoruba. The G3 haplotype appeared to
be under strong selective pressure in the West African Fulani
population, who practice cattle herding and are likely to have been
subjected to severe infection by T. b. gambiense in the past. Weaker
selection for the G3 haplotype was found in East African Borana, Hadza,
and Iraqw populations, who are subject to infection by T. b.
rhodesiense.
*FIELD* AV
.0001
FOCAL SEGMENTAL GLOMERULOSCLEROSIS 4, SUSCEPTIBILITY TO
APOL1, SER342GLY, ILE384MET (dbSNP rs73885319, dbSNP rs60910145)
In an association analysis comparing 205 African Americans with
biopsy-proven focal segmental glomerulosclerosis (FSGS4; 612551) and no
family history of FSGS with 180 African American controls, Genovese et
al. (2010) identified association with FSGS of 2 nonsynonymous variants
in the last exon of the APOL1 gene that are in perfect linkage
disequilibrium (LD). One is ser-to-gly at codon 342 (S342G, dbSNP
rs73885319) and the other is ile-to-met at codon 384 (I384M, dbSNP
rs60910145). Genovese et al. (2010) termed the 342G-384M allele the G1
allele, which had a frequency of 52% in FSGS cases and 18% in controls
(P = 1.07 x 10(-23)). The G1 allele was present in about 40% of Yoruba
chromosomes but not in any chromosomes from European, Japanese, or
Chinese individuals, all from HapMap 1000 Genomes data. The 384M
substitution is located at the serum resistance-associated protein (SRA)
binding site in the APOL1 C-terminal helix. Genovese et al. (2010)
showed that human plasma samples and recombinant APOL1 protein carrying
the G1 allele lysed both SRA-negative and SRA-positive T. b. rhodesiense
parasites, but not T. b. gambiense. T. b. rhodesiense is a deadly
subspecies of Trypanosoma that is normally completely resistant to APOL1
lytic activity; Genovese et al. (2010) hypothesized that evolution of a
critical survival factor in Africa may have contributed to the high
rates of renal disease in African Americans.
.0002
FOCAL SEGMENTAL GLOMERULOSCLEROSIS 4, SUSCEPTIBILITY TO
APOL1, 6-BP DEL, N388/Y389 (dbSNP rs71785313)
In an association analysis comparing 205 African Americans with
biopsy-proven focal segmental glomerulosclerosis (FSGS4; 612551) and no
family history of FSGS with 180 African American controls, Genovese et
al. (2010) identified association with FSGS of a 6-bp deletion, dbSNP
rs71785313, which they termed allele G2, in the last exon of the APOL1
gene. This mutation resulted in the deletion of 6 basepairs and removal
of amino acids asparagine-388 (N388) and tyrosine-389 (Y389). The G2
allele was detected in 3 Yoruban participants but not in any patients
from Europe, Japan, or China, all from HapMap 1000 Genomes data. The
6-bp deletion occurs at the SRA binding site in the APOL1 C-terminal
helix. Genovese et al. (2010) showed that human plasma samples and
recombinant APOL1 protein carrying the G2 allele lysed both SRA-negative
and SRA-positive T. b. rhodesiense parasites, but not T. b. gambiense.
*FIELD* RF
1. Duchateau, P. N.; Pullinger, C. R.; Cho, M. H.; Eng, C.; Kane,
J. P.: Apolipoprotein L gene family: tissue-specific expression,
splicing, promoter regions; discovery of a new gene. J. Lipid Res. 42:
620-630, 2001.
2. Duchateau, P. N.; Pullinger, C. R.; Orellana, R. E.; Kunitake,
S. T.; Naya-Vigne, J.; O'Connor, P. M.; Malloy, M. J.; Kane, J. P.
: Apolipoprotein L, a new human high density lipoprotein apolipoprotein
expressed by the pancreas: identification, cloning, characterization,
and plasma distribution of apolipoprotein L. J. Biol. Chem. 272:
25576-25582, 1997.
3. Genovese, G.; Friedman, D. J.; Ross, M. D.; Lecordier, L.; Uzureau,
P.; Freedman, B. I.; Bowden, D. W.; Langefeld, C. D.; Oleksyk, T.
K.; Uscinski Knob, A. L.; Bernhardy, A. J.; Hicks, P. J.; Nelson,
G. W.; Vanhollebeke, B.; Winkler, C. A.; Kopp, J. B.; Pays, E.; Pollak,
M. R.: Association of trypanolytic ApoL1 variants with kidney disease
in African Americans. Science 329: 841-845, 2010.
4. Ko, W.-Y.; Rajan, P.; Gomez, F.; Scheinfeldt, L.; An, P.; Winkler,
C. A.; Froment, A.; Nyambo, T. B.; Omar, S. A.; Wambebe, C.; Ranciaro,
A.; Hirbo, J. B.; Tishkoff, S. A.: Identifying Darwinian selection
acting on different human APOL1 variants among diverse African populations. Am.
J. Hum. Genet. 93: 54-66, 2013. Note: Erratum: Am. J. Hum. Genet.
93: 191 only, 2013.
5. Mimmack, M. L.; Ryan, M.; Baba, H.; Navarro-Ruiz, J.; Iritani,
S.; Faull, R. L. M.; McKenna, P. J.; Jones, P. B.; Arai, H.; Starkey,
M.; Emson, P. C.; Bahn, S.: Gene expression analysis in schizophrenia:
reproducible up-regulation of several members of the apolipoprotein
L family located in a high-susceptibility locus for schizophrenia
on chromosome 22. Proc. Nat. Acad. Sci. 99: 4680-4685, 2002.
6. Monajemi, H.; Fontijn, R. D.; Pannekoek, H.; Horrevoets, A. J.
G.: The apolipoprotein L gene cluster has emerged recently in evolution
and is expressed in human vascular tissue. Genomics 79: 539-546,
2002.
7. Page, N. M.; Butlin, D. J.; Lomthaisong, K.; Lowry, P. J.: The
human apolipoprotein L gene cluster: identification, classification,
and sites of distribution. Genomics 74: 71-78, 2001.
8. Parsa, A.; Kao, L.; Xie, D.; Astor, B. C.; Li, M.; Hsu, C.; Feldman,
H. I.; Parekh, R. S.; Kusek, J. W.; Greene, T. H.; Fink, J. C.; Anderson,
A. H.; and 13 others: APOL1 risk variants, race, and progression
of chronic kidney disease. New Eng. J. Med. 369: 2183-2196, 2013.
9. Perez-Morga, D.; Vanhollebeke, B.; Paturiaux-Hanocq, F.; Nolan,
D. P.; Lins, L.; Homble, F.; Vanhamme, L.; Tebabi, P.; Pays, A.; Poelvoorde,
P.; Jacquet, A.; Brasseur, R.; Pays, E.: Apolipoprotein L-1 promotes
trypanosome lysis by forming pores in lysosomal membranes. Science 309:
469-472, 2005.
10. Vanhamme, L.; Paturiaux,-Hanocq, F.; Poelvoorde, P.; Nolan, D.
P.; Lins, L.; Van Den Abbeele, J.; Pays, A.; Tebabi, P.; Van Xong,
H.; Jacquet, A.; Moguilevsky, N.; Dieu, M.; Kane, J. P.; De Baetselier,
P.; Brasseur, R.; Pays, E.: Apolipoprotein L-I is the trypanosome
lytic factor of human serum. Nature 422: 83-87, 2003.
*FIELD* CN
Ada Hamosh - updated: 12/19/2013
Patricia A. Hartz - updated: 9/4/2013
Ada Hamosh - updated: 9/1/2010
Ada Hamosh - updated: 8/15/2005
Ada Hamosh - updated: 4/1/2003
Patricia A. Hartz - updated: 9/25/2002
Victor A. McKusick - updated: 9/24/2002
Joanna S. Amberger - updated: 4/2/2001
*FIELD* CD
Jennifer P. Macke: 4/19/1999
*FIELD* ED
alopez: 12/19/2013
mcolton: 12/19/2013
mgross: 9/4/2013
carol: 10/25/2010
alopez: 9/7/2010
terry: 9/1/2010
carol: 8/16/2005
terry: 8/15/2005
alopez: 4/3/2003
terry: 4/1/2003
mgross: 9/25/2002
mgross: 9/24/2002
joanna: 4/2/2001
alopez: 4/19/1999
*RECORD*
*FIELD* NO
603743
*FIELD* TI
*603743 APOLIPOPROTEIN L-I; APOL1
;;APOL;;
APOL-I
*FIELD* TX
DESCRIPTION
The APOL1 gene encodes apolipoprotein L-I (apoL-I), a human-specific
read moreserum apolipoprotein bound to high-density lipoprotein (HDL) particles
(summary by Perez-Morga et al., 2005). This apolipoprotein kills the
African trypanosome Trypanosoma brucei brucei, except subspecies adapted
to humans (T. b. rhodesiense, T. b. gambiense). Genovese et al. (2010)
found that APOL1 carrying African population-specific mutations can lyse
T. b. rhodesiense; these mutations were also associated with increased
susceptibility to focal segmental glomerulosclerosis in African
Americans (see FSGS4, 612551).
CLONING
Based on peptide sequences of a novel high density lipoprotein,
Duchateau et al. (1997) cloned cDNAs encoding APOL. The cDNA encodes a
383-amino acid polypeptide that includes a 12-amino acid secretory
signal peptide. Northern blot analysis detected a 1.3-kb APOL transcript
in the pancreas but not in any other human tissues. Affinity
immunosorption showed that APOL is not free in the plasma, but is
associated with lipoproteins containing APOA1 (107680). APOL was found
in high density lipoprotein fractions.
By sequencing a number of APOL1 clones, Duchateau et al. (2001)
identified a minor splice variant that includes exon 2. This variant
predicts a protein that contains a 43-residue signal peptide. The more
common transcript, lacking exon 2, predicts a protein with a 27-residue
signal peptide. By mRNA dot blot analysis, they found APOL1 expressed in
a wide variety of tissues, the only exception being fetal brain.
Quantitative RT-PCR, reflecting the sum of both splice variants,
revealed highest expression in lung.
By genomic sequence analysis, Page et al. (2001) identified APOL1 within
the APOL gene cluster. The predicted 398-amino acid protein has a
calculated molecular mass of 43.9 kD. They noted that the APOL proteins
share significant identity within the predicted amphipathic alpha
helices. Semiquantitative RT-PCR revealed ubiquitous expression of
APOL1, with highest levels in lung, spleen, prostate, and placenta, and
weak expression in fetal brain and pancreas. In situ hybridization of
human placenta revealed expression in all 3 tissue layers, including the
basal plate, cytiotrophoblast, and chorionic plate.
By Northern blot analysis, Monajemi et al. (2002) detected highest
expression of a 3-kb APOL1 transcript in placenta, lung, and liver, with
low expression in heart and minimal expression in pancreas. In situ
hybridization of human vascular tissue showed APOL1 expression in
endothelial cells and possibly in macrophages.
GENE STRUCTURE
Duchateau et al. (2001) determined that the APOL1 gene contains 7 exons
and spans 14 kb. The promoter regions of the APOL1, APOL2, APOL3
(607253), and APOL4 genes have at least 1 SP1 (189906) site, a number of
AP1 (165160) and AP4 (600743) sites, at least 1 GC box, multiple zinc
finger-binding sites, and at least 1 sterol regulatory element-binding
protein (see 184756) site. Each contains at least 2 conserved initiator
sequences. The most commonly used promoter regions are TATA-less with
multiple transcription initiation sites.
Noting homology within intronic sequences, Monajemi et al. (2002)
concluded that the APOL1, APOL2, APOL3, and APOL4 gene cluster is the
result of tandem gene duplication, whereas APOL5 (607255) and APOL6
(607256) are more distantly related.
MAPPING
By genomic sequence analysis, Duchateau et al. (2001) mapped APOL1 to
chromosome 22q12.1-q13.1. It is located in a cluster with APOL2, APOL3,
and APOL4 that spans 127 kb. APOL1 is in the opposite orientation to the
other 3. Page et al. (2001) found that the APOL cluster contains 6 genes
and spans 619 kb.
In their figure 3, Mimmack et al. (2002) diagrammed the genomic
organization of the APOL gene family on chromosome 22q12.3. The COMT
gene (116790) on chromosome 22q11 is 15.2 Mb from the APOL6 gene, which
is located at the telomeric end of the APOL gene cluster. The APOL1 gene
is at the telomeric end of the cluster.
GENE FUNCTION
Monajemi et al. (2002) detected a 10-fold upregulation of APOL1 in human
umbilical vein endothelial cells following stimulation with tumor
necrosis factor-alpha (TNFA; 191160).
In a microarray analysis of gene expression in the prefrontal cortex of
schizophrenia (181500) and control brains, Mimmack et al. (2002) found
significant upregulation of the APOL1, APOL2 (607252), and APOL4
(607254) genes.
Human sleeping sickness in east Africa is caused by the parasite
Trypanosoma brucei rhodesiense. The basis of this pathology is the
resistance of these parasites to lysis by normal human serum. Resistance
to normal human serum is conferred by a gene that encodes a truncated
form of the variant surface glycoprotein termed serum
resistance-associated protein (SRA). Vanhamme et al. (2003) showed that
SRA is a lysosomal protein, and that the N-terminal alpha-helix of SRA
is responsible for resistance to normal human serum. This domain
interacts strongly with a carboxy-terminal alpha-helix of APOL1.
Depleting normal human serum of APOL1 by incubation with SRA or
antibodies against APOL1 led to the complete loss of trypanolytic
activity. Addition of native or recombinant APOL1 either to
APOL1-depleted normal human serum or to fetal calf serum induced lysis
of normal human serum-sensitive, but not normal human serum-resistant,
trypanosomes. Confocal microscopy demonstrated that APOL1 is taken up
through the endocytic pathway into the lysosome. Vanhamme et al. (2003)
proposed that APOL1 is the trypanosome lytic factor of normal human
serum, and that SRA confers resistance to lysis by interaction with
APOL1 in the lysosome.
Perez-Morga et al. (2005) demonstrated that apolipoprotein L-1 contains
a membrane pore-forming domain functionally similar to that of bacterial
colicins, flanked by a membrane-addressing domain. In lipid bilayer
membranes, apolipoprotein L-1 formed anion channels. In Trypanosoma
brucei, apolipoprotein L-1 was targeted to the lysosomal membrane and
triggered depolarization of this membrane, continuous influx of
chloride, and subsequent osmotic swelling of the lysosome until the
trypanosome lysed.
MOLECULAR GENETICS
Genovese et al. (2010) showed that in African Americans, focal segmental
glomerulosclerosis (FSGS; 603278) and hypertension-attributed end-stage
renal disease (ESRD) are associated with 2 independent sequence variants
in the APOL1 gene on chromosome 22 (FSGS odds ratio = 10.5, 95% CI,
6.0-18.4; ESRD odds ratio = 7.3, 95% CI, 5.6-9.5). The 2 APOL1 variants
are common in African chromosomes but absent in European chromosomes,
and both reside within haplotypes that harbor signatures of positive
selection. APOL1 is a serum factor that lyses trypanosomes. In vitro
assays revealed that only the kidney disease-associated APOL1 variants
lysed Trypanosoma brucei rhodesiense. Genovese et al. (2010) speculated
that evolution of a critical survival factor in Africa may have
contributed to the high rates of renal disease in African Americans. The
strongest signal was obtained for a 2-locus allele, termed G1
(613743.0001), consisting of 2 derived nonsynonymous coding variants:
dbSNP rs73885319 (ser342 to gly) and dbSNP rs60910145 (ile384 to met),
both in the last exon of APOL1. These 2 alleles are in perfect linkage
disequilibrium. The G1 allele (342G:384M) had a frequency of 52% in 205
FSGS cases and 18% in 180 controls (p = 1.07 x 10(-23)). When Genovese
et al. (2010) performed logistic regression to control for G1, they
identified a second strong signal, a 6-bp deletion, dbSNP rs71785313,
which they termed G2 (613743.0002), close to G1, that removed amino
acids N388 and Y389. Because of the proximity of dbSNP rs73885319, dbSNP
rs60910145, and dbSNP rs71785313, alleles G1 and G2 are mutually
exclusive; recombination between them is very unlikely. Genovese et al.
(2010) found that G1 and G2 are in strong LD with variants in MYH9
(160775). In particular, the MYH9 E-1 haplotype, the best predictor of
renal disease in previous studies (see FSGS4, 612551), is present in
most haplotypes containing the G1 or G2 allele. Specifically, E-1 is
present in 89% of haplotypes carrying G1 and in 76% of haplotypes
carrying G2, explaining the association of MYH9 E-1 with renal disease.
Association of renal disease with the MYH9 haplotype disappeared after
controlling for the APOL1 risk variants. Comparing participants with
zero or 1 risk allele of APOL1 to participants with 2 risk alleles
provided an odds ratio for FSGS of 10.5 (CI, 6.0-18.4). This analysis
supported a completely recessive pattern of inheritance.
Parsa et al. (2013) performed 2 studies examining the effects of
variants in the APOL1 gene on the progression of chronic kidney disease.
In the African American Study of Kidney Disease and Hypertension (AASK),
693 black patients with chronic kidney disease attributed to
hypertension were examined for a primary outcome of composite end-stage
renal disease or doubling of the serum creatinine level. A total of 160
(23%) individuals carried 2 copies of APOL1 risk variants G1
(603743.0001) and/or G2 (603743.0002). Of these individuals in the
high-risk group, the primary outcome occurred in 58%; in the APOL1
low-risk group (all other genotypes), the primary outcome occurred in
37% (hazard ratio in the high-risk group, 1.88; p less than 0.001). In
the Chronic Renal Insufficiency Cohort (CRIC), Parsa et al. (2013)
evaluated 2,955 white patients and black patients with chronic kidney
disease (46% of whom had diabetes) for the primary outcomes of the slope
of the estimated glomerular filtration rate (eGFR) and the composite of
end-stage renal disease, or a reduction of 50% in the eGFR from
baseline. Black patients were genotyped for the G1 and G2 risk alleles.
In the CRIC study, black patients in the APOL1 high-risk group (270 of
1,411 total black patients) had a more rapid decline in the eGFR and a
higher risk of the composite renal outcome than did white patients, with
or without diabetes as a complication (p less than 0.001 for all
comparisons).
POPULATION GENETICS
Ko et al. (2013) sequenced a 1.4-kb APOL1 region that encompasses the
last exon, which encodes the pore-forming, membrane-addressing, and
SRA-interacting domains, in 187 individuals from 10 geographically and
ethnically diverse African populations. They identified 38 variants,
including 15 nonsynonymous SNPs and a 6-bp indel that removes 2 amino
acids (i.e., the G2 allele). Three of these 16 variants occurred in the
pore-forming domain, 5 occurred in the membrane-addressing domain, and
6, including the G1 and G2 variants, occurred in the SRA-interacting
domain. The allele frequencies of G2 were similar across all populations
(3% to 8%), whereas the G1 allele was only common in West African Yoruba
(39%). Ko et al. (2013) also identified 8 polymorphic sites in strong
linkage disequilibrium, which they called the G3 haplotype, in all
populations except for West African Yoruba. The G3 haplotype appeared to
be under strong selective pressure in the West African Fulani
population, who practice cattle herding and are likely to have been
subjected to severe infection by T. b. gambiense in the past. Weaker
selection for the G3 haplotype was found in East African Borana, Hadza,
and Iraqw populations, who are subject to infection by T. b.
rhodesiense.
*FIELD* AV
.0001
FOCAL SEGMENTAL GLOMERULOSCLEROSIS 4, SUSCEPTIBILITY TO
APOL1, SER342GLY, ILE384MET (dbSNP rs73885319, dbSNP rs60910145)
In an association analysis comparing 205 African Americans with
biopsy-proven focal segmental glomerulosclerosis (FSGS4; 612551) and no
family history of FSGS with 180 African American controls, Genovese et
al. (2010) identified association with FSGS of 2 nonsynonymous variants
in the last exon of the APOL1 gene that are in perfect linkage
disequilibrium (LD). One is ser-to-gly at codon 342 (S342G, dbSNP
rs73885319) and the other is ile-to-met at codon 384 (I384M, dbSNP
rs60910145). Genovese et al. (2010) termed the 342G-384M allele the G1
allele, which had a frequency of 52% in FSGS cases and 18% in controls
(P = 1.07 x 10(-23)). The G1 allele was present in about 40% of Yoruba
chromosomes but not in any chromosomes from European, Japanese, or
Chinese individuals, all from HapMap 1000 Genomes data. The 384M
substitution is located at the serum resistance-associated protein (SRA)
binding site in the APOL1 C-terminal helix. Genovese et al. (2010)
showed that human plasma samples and recombinant APOL1 protein carrying
the G1 allele lysed both SRA-negative and SRA-positive T. b. rhodesiense
parasites, but not T. b. gambiense. T. b. rhodesiense is a deadly
subspecies of Trypanosoma that is normally completely resistant to APOL1
lytic activity; Genovese et al. (2010) hypothesized that evolution of a
critical survival factor in Africa may have contributed to the high
rates of renal disease in African Americans.
.0002
FOCAL SEGMENTAL GLOMERULOSCLEROSIS 4, SUSCEPTIBILITY TO
APOL1, 6-BP DEL, N388/Y389 (dbSNP rs71785313)
In an association analysis comparing 205 African Americans with
biopsy-proven focal segmental glomerulosclerosis (FSGS4; 612551) and no
family history of FSGS with 180 African American controls, Genovese et
al. (2010) identified association with FSGS of a 6-bp deletion, dbSNP
rs71785313, which they termed allele G2, in the last exon of the APOL1
gene. This mutation resulted in the deletion of 6 basepairs and removal
of amino acids asparagine-388 (N388) and tyrosine-389 (Y389). The G2
allele was detected in 3 Yoruban participants but not in any patients
from Europe, Japan, or China, all from HapMap 1000 Genomes data. The
6-bp deletion occurs at the SRA binding site in the APOL1 C-terminal
helix. Genovese et al. (2010) showed that human plasma samples and
recombinant APOL1 protein carrying the G2 allele lysed both SRA-negative
and SRA-positive T. b. rhodesiense parasites, but not T. b. gambiense.
*FIELD* RF
1. Duchateau, P. N.; Pullinger, C. R.; Cho, M. H.; Eng, C.; Kane,
J. P.: Apolipoprotein L gene family: tissue-specific expression,
splicing, promoter regions; discovery of a new gene. J. Lipid Res. 42:
620-630, 2001.
2. Duchateau, P. N.; Pullinger, C. R.; Orellana, R. E.; Kunitake,
S. T.; Naya-Vigne, J.; O'Connor, P. M.; Malloy, M. J.; Kane, J. P.
: Apolipoprotein L, a new human high density lipoprotein apolipoprotein
expressed by the pancreas: identification, cloning, characterization,
and plasma distribution of apolipoprotein L. J. Biol. Chem. 272:
25576-25582, 1997.
3. Genovese, G.; Friedman, D. J.; Ross, M. D.; Lecordier, L.; Uzureau,
P.; Freedman, B. I.; Bowden, D. W.; Langefeld, C. D.; Oleksyk, T.
K.; Uscinski Knob, A. L.; Bernhardy, A. J.; Hicks, P. J.; Nelson,
G. W.; Vanhollebeke, B.; Winkler, C. A.; Kopp, J. B.; Pays, E.; Pollak,
M. R.: Association of trypanolytic ApoL1 variants with kidney disease
in African Americans. Science 329: 841-845, 2010.
4. Ko, W.-Y.; Rajan, P.; Gomez, F.; Scheinfeldt, L.; An, P.; Winkler,
C. A.; Froment, A.; Nyambo, T. B.; Omar, S. A.; Wambebe, C.; Ranciaro,
A.; Hirbo, J. B.; Tishkoff, S. A.: Identifying Darwinian selection
acting on different human APOL1 variants among diverse African populations. Am.
J. Hum. Genet. 93: 54-66, 2013. Note: Erratum: Am. J. Hum. Genet.
93: 191 only, 2013.
5. Mimmack, M. L.; Ryan, M.; Baba, H.; Navarro-Ruiz, J.; Iritani,
S.; Faull, R. L. M.; McKenna, P. J.; Jones, P. B.; Arai, H.; Starkey,
M.; Emson, P. C.; Bahn, S.: Gene expression analysis in schizophrenia:
reproducible up-regulation of several members of the apolipoprotein
L family located in a high-susceptibility locus for schizophrenia
on chromosome 22. Proc. Nat. Acad. Sci. 99: 4680-4685, 2002.
6. Monajemi, H.; Fontijn, R. D.; Pannekoek, H.; Horrevoets, A. J.
G.: The apolipoprotein L gene cluster has emerged recently in evolution
and is expressed in human vascular tissue. Genomics 79: 539-546,
2002.
7. Page, N. M.; Butlin, D. J.; Lomthaisong, K.; Lowry, P. J.: The
human apolipoprotein L gene cluster: identification, classification,
and sites of distribution. Genomics 74: 71-78, 2001.
8. Parsa, A.; Kao, L.; Xie, D.; Astor, B. C.; Li, M.; Hsu, C.; Feldman,
H. I.; Parekh, R. S.; Kusek, J. W.; Greene, T. H.; Fink, J. C.; Anderson,
A. H.; and 13 others: APOL1 risk variants, race, and progression
of chronic kidney disease. New Eng. J. Med. 369: 2183-2196, 2013.
9. Perez-Morga, D.; Vanhollebeke, B.; Paturiaux-Hanocq, F.; Nolan,
D. P.; Lins, L.; Homble, F.; Vanhamme, L.; Tebabi, P.; Pays, A.; Poelvoorde,
P.; Jacquet, A.; Brasseur, R.; Pays, E.: Apolipoprotein L-1 promotes
trypanosome lysis by forming pores in lysosomal membranes. Science 309:
469-472, 2005.
10. Vanhamme, L.; Paturiaux,-Hanocq, F.; Poelvoorde, P.; Nolan, D.
P.; Lins, L.; Van Den Abbeele, J.; Pays, A.; Tebabi, P.; Van Xong,
H.; Jacquet, A.; Moguilevsky, N.; Dieu, M.; Kane, J. P.; De Baetselier,
P.; Brasseur, R.; Pays, E.: Apolipoprotein L-I is the trypanosome
lytic factor of human serum. Nature 422: 83-87, 2003.
*FIELD* CN
Ada Hamosh - updated: 12/19/2013
Patricia A. Hartz - updated: 9/4/2013
Ada Hamosh - updated: 9/1/2010
Ada Hamosh - updated: 8/15/2005
Ada Hamosh - updated: 4/1/2003
Patricia A. Hartz - updated: 9/25/2002
Victor A. McKusick - updated: 9/24/2002
Joanna S. Amberger - updated: 4/2/2001
*FIELD* CD
Jennifer P. Macke: 4/19/1999
*FIELD* ED
alopez: 12/19/2013
mcolton: 12/19/2013
mgross: 9/4/2013
carol: 10/25/2010
alopez: 9/7/2010
terry: 9/1/2010
carol: 8/16/2005
terry: 8/15/2005
alopez: 4/3/2003
terry: 4/1/2003
mgross: 9/25/2002
mgross: 9/24/2002
joanna: 4/2/2001
alopez: 4/19/1999
MIM
612551
*RECORD*
*FIELD* NO
612551
*FIELD* TI
#612551 FOCAL SEGMENTAL GLOMERULOSCLEROSIS 4, SUSCEPTIBILITY TO; FSGS4
;;END-STAGE RENAL DISEASE, NONDIABETIC, SUSCEPTIBILITY TO, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because susceptibility to this
form of renal disease, referred to here as focal segmental
glomerulosclerosis-4 (FSGS4), is conferred by variation in the APOL1
gene (603743) on chromosome 22q12.3. These APOL1 variants confer
protection against infection with T. b. rhodesiense, a human-specific
Trypanosoma subspecies. Susceptibility to this form of FSGS is prevalent
in populations of African ancestry.
DESCRIPTION
Focal segmental glomerulosclerosis (FSGS) is a pathologic entity
associated clinically with proteinuria, the nephrotic syndrome (NPHS),
and progressive loss of renal function. It is a common cause of
end-stage renal disease (ESRD) (Meyrier, 2005).
For a general phenotypic description and a discussion of genetic
heterogeneity of focal segmental glomerulosclerosis and nephrotic
syndrome, see FSGS1 (603278).
MAPPING
To identify genetic variants predisposing to idiopathic and
HIV-1-associated focal segmental glomerulosclerosis (FSGS), Kopp et al.
(2008) carried out an admixture mapping linkage disequilibrium genome
scan in 190 African American individuals with FSGS and 222 controls.
They identified a chromosome 22q12 region with a genomewide lod score of
9.2 and a peak lod of 12.4 centered on MYH9 (160775), a functional
candidate gene expressed in kidney podocytes. Multiple MYH9 SNPs and
haplotypes were recessively associated with FSGS, most strongly in
haplotypes spanning exons 14 through 23 (odds ratio = 5.0, 95%
confidence interval = 3.5-7.1; P = 4 x 10(-23), n = 852). Kopp et al.
(2008) found that their association extended to hypertensive end-stage
renal disease (ESRD) (odds ratio = 2.2, 95% confidence interval =
1.5-3.4; n = 433), but not type 2 diabetic ESRD (n = 476). Kopp et al.
(2008) concluded that genetic variation at the MYH9 locus substantially
explains the increased burden of FSGS and hypertensive ESRD among
African Americans. For 3 MYH9 intron 23 SNPs in strong linkage
disequilibrium (dbSNP rs4821480, dbSNP rs2032487, and dbSNP rs4821481),
79 to 83% of the association was attributable to the SNPs alone, with
the remaining fraction attributable to chromosomal ancestry. The single
strongest risk allele within MYH9 was at dbSNP rs2032487, which had a P
value for idiopathic FSGS of 7 x 10(-12) and a P value for
HIV-1-associated FSGS of 8 x 10(-8).
Kao et al. (2008) independently performed a genomewide admixture scan in
1,372 end-stage renal disease (ESRD) cases and 806 controls and found a
highly significant association between excess African ancestry and
nondiabetic ESRD (lod score = 5.70) but not diabetic ESRD (lod = 0.47)
on chromosome 22q12. Each copy of the European ancestral allele
conferred a relative risk of 0.50 (95% confidence interval = 0.39-0.63)
compared to African ancestry. Multiple common SNPs (allele frequencies
ranging from 0.02 to 0.06) in MYH9, the gene encoding nonmuscle myosin
heavy chain type II isoform A, were associated with 2 to 4 times greater
risk of nondiabetic ESRD and accounted for a large proportion of the
excess risk of ESRD observed in African compared to European Americans.
This risk was associated with all nondiabetes ESRD with a lod score of
4.55 and also with hypertensive ESRD at 1.79, FSGS at 2.47, and
HIV-related ESRD at 2.09. Kao et al. (2008) showed that any of the 3
SNPs, dbSNP rs4821480, dbSNP rs2032487, and dbSNP rs4821481, in strong
linkage disequilibrium is sufficient to account for all of the
association between the excess African ancestry observed on chromosome
22q12 and nondiabetic ESRD.
MOLECULAR GENETICS
Although genetic variation in or near the MYH9 gene on chromosome 22 was
associated with increased risk of FSGS, causal mutations in MHY9 had not
been identified. Genomewide analyses showed a strong signal of natural
selection in the region containing the MHY9 and APOL1 (603743) genes.
The longer patterns of linkage disequilibrium (LD) associated with
variants undergoing natural selection suggested to Genovese et al.
(2010) that a positively selected risk variant could be in a larger
interval containing the APOL genes rather than be confined to MYH9. In
an association analysis comparing 205 African Americans with
biopsy-proven FSGS and no family history of FSGS with 180 African
American controls, Genovese et al. (2010) identified association of
kidney disease with 2 independent sequence variants in the last exon of
the APOL1 gene (FSGS odds ratio = 10.5, 95% confidence interval 6.0 to
18.4; ESRD odds ratio = 7.3, 95% confidence interval 5.6 to 9.5).
Association with renal disease was confirmed in a larger cohort of 1,030
African American cases with ESRD and 1,025 geographically matched
African American controls. The 2 APOL1 variants, which Genovese et al.
(2010) referred to as G1 (603743.0001) and G2 (603743.0002), are common
in African chromosomes but absent in European chromosomes, and both
reside within haplotypes that harbor signatures of positive selection.
APOL1 is a serum factor that lyses trypanosomes. In vitro assays
revealed that only the kidney disease-associated APOL1 variants lysed
Trypanosoma brucei rhodesiense. Association of renal disease with MYH9
sequence variants disappeared after controlling for the APOL1 risk
variants. Comparing participants with zero or 1 risk allele of APOL1 to
participants with 2 risk alleles provided an odds ratio for FSGS of 10.5
(confidence interval 6.0 to 18.4). This analysis supported a completely
recessive pattern of inheritance. Genovese et al. (2010) speculated that
evolution of a critical survival factor in Africa may have contributed
to the high rates of renal disease in African Americans.
Parsa et al. (2013) performed 2 studies examining the effects of
variants in the APOL1 gene on the progression of chronic kidney disease.
In the African American Study of Kidney Disease and Hypertension (AASK),
693 black patients with chronic kidney disease attributed to
hypertension were examined for a primary outcome of composite end-stage
renal disease or doubling of the serum creatinine level. A total of 160
(23%) individuals carried 2 copies of APOL1 risk variants G1
(603743.0001) and/or G2 (603743.0002). Of these individuals in the
high-risk group, the primary outcome occurred in 58%; in the APOL1
low-risk group (all other genotypes), the primary outcome occurred in
37% (hazard ratio in the high-risk group, 1.88; p less than 0.001). In
the Chronic Renal Insufficiency Cohort (CRIC), Parsa et al. (2013)
evaluated 2,955 white patients and black patients with chronic kidney
disease (46% of whom had diabetes) for the primary outcomes of the slope
of the estimated glomerular filtration rate (eGFR) and the composite of
end-stage renal disease, or a reduction of 50% in the eGFR from
baseline. Black patients were genotyped for the G1 and G2 risk alleles.
In the CRIC study, black patients in the APOL1 high-risk group (270 of
1,411 total black patients) had a more rapid decline in the eGFR and a
higher risk of the composite renal outcome than did white patients, with
or without diabetes as a complication (p less than 0.001 for all
comparisons).
NOMENCLATURE
In the literature, the clinical term 'nephrotic syndrome' (NPHS) and the
pathologic term 'focal segmental glomerulosclerosis' (FSGS) have often
been used to refer to the same disease entity. In OMIM, these disorders
are designated as NPHS or FSGS according to how they were first
described in the literature.
*FIELD* RF
1. Genovese, G.; Friedman, D. J.; Ross, M. D.; Lecordier, L.; Uzureau,
P.; Freedman, B. I.; Bowden, D. W.; Langefeld, C. D.; Oleksyk, T.
K.; Uscinski Knob, A. L.; Bernhardy, A. J.; Hicks, P. J.; Nelson,
G. W.; Vanhollebeke, B.; Winkler, C. A.; Kopp, J. B.; Pays, E.; Pollak,
M. R.: Association of trypanolytic ApoL1 variants with kidney disease
in African Americans. Science 329: 841-845, 2010.
2. Kao, W. H. L.; Klag, M. J.; Meoni, L. A.; Reich, D.; Berthier-Schaad,
Y.; Li, M.; Coresh, J.; Patterson, N.; Tandon, A.; Powe, N. R.; Fink,
N. E.; Sadler, J. H.; and 19 others: MYH9 is associated with nondiabetic
end-stage renal disease in African Americans. Nature Genet. 40:
1185-1192, 2008.
3. Kopp, J. B.; Smith, M. W.; Nelson, G. W.; Johnson, R. C.; Freedman,
B. I.; Bowden, D. W.; Oleksyk, T.; McKenzie, L. M.; Kajiyama, H.;
Ahuja, T. S.; Berns, J. S.; Briggs, W.; and 10 others: MYH9 is
a major-effect risk gene for focal segmental glomerulosclerosis. Nature
Genet. 40: 1175-1184, 2008.
4. Meyrier, A.: Mechanisms of disease: focal segmental glomerulosclerosis. Nature
Clin. Prac.:Nephrol. 1: 44-54, 2005.
5. Parsa, A.; Kao, L.; Xie, D.; Astor, B. C.; Li, M.; Hsu, C.; Feldman,
H. I.; Parekh, R. S.; Kusek, J. W.; Greene, T. H.; Fink, J. C.; Anderson,
A. H.; and 13 others: APOL1 risk variants, race, and progression
of chronic kidney disease. New Eng. J. Med. 369: 2183-2196, 2013.
*FIELD* CN
Ada Hamosh - updated: 12/19/2013
Cassandra L. Kniffin - updated: 10/21/2010
Ada Hamosh - updated: 9/1/2010
*FIELD* CD
Ada Hamosh: 1/22/2009
*FIELD* ED
alopez: 12/19/2013
alopez: 12/6/2011
terry: 12/1/2011
carol: 10/29/2010
carol: 10/25/2010
ckniffin: 10/21/2010
ckniffin: 10/8/2010
alopez: 9/7/2010
terry: 9/1/2010
alopez: 1/22/2009
*RECORD*
*FIELD* NO
612551
*FIELD* TI
#612551 FOCAL SEGMENTAL GLOMERULOSCLEROSIS 4, SUSCEPTIBILITY TO; FSGS4
;;END-STAGE RENAL DISEASE, NONDIABETIC, SUSCEPTIBILITY TO, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because susceptibility to this
form of renal disease, referred to here as focal segmental
glomerulosclerosis-4 (FSGS4), is conferred by variation in the APOL1
gene (603743) on chromosome 22q12.3. These APOL1 variants confer
protection against infection with T. b. rhodesiense, a human-specific
Trypanosoma subspecies. Susceptibility to this form of FSGS is prevalent
in populations of African ancestry.
DESCRIPTION
Focal segmental glomerulosclerosis (FSGS) is a pathologic entity
associated clinically with proteinuria, the nephrotic syndrome (NPHS),
and progressive loss of renal function. It is a common cause of
end-stage renal disease (ESRD) (Meyrier, 2005).
For a general phenotypic description and a discussion of genetic
heterogeneity of focal segmental glomerulosclerosis and nephrotic
syndrome, see FSGS1 (603278).
MAPPING
To identify genetic variants predisposing to idiopathic and
HIV-1-associated focal segmental glomerulosclerosis (FSGS), Kopp et al.
(2008) carried out an admixture mapping linkage disequilibrium genome
scan in 190 African American individuals with FSGS and 222 controls.
They identified a chromosome 22q12 region with a genomewide lod score of
9.2 and a peak lod of 12.4 centered on MYH9 (160775), a functional
candidate gene expressed in kidney podocytes. Multiple MYH9 SNPs and
haplotypes were recessively associated with FSGS, most strongly in
haplotypes spanning exons 14 through 23 (odds ratio = 5.0, 95%
confidence interval = 3.5-7.1; P = 4 x 10(-23), n = 852). Kopp et al.
(2008) found that their association extended to hypertensive end-stage
renal disease (ESRD) (odds ratio = 2.2, 95% confidence interval =
1.5-3.4; n = 433), but not type 2 diabetic ESRD (n = 476). Kopp et al.
(2008) concluded that genetic variation at the MYH9 locus substantially
explains the increased burden of FSGS and hypertensive ESRD among
African Americans. For 3 MYH9 intron 23 SNPs in strong linkage
disequilibrium (dbSNP rs4821480, dbSNP rs2032487, and dbSNP rs4821481),
79 to 83% of the association was attributable to the SNPs alone, with
the remaining fraction attributable to chromosomal ancestry. The single
strongest risk allele within MYH9 was at dbSNP rs2032487, which had a P
value for idiopathic FSGS of 7 x 10(-12) and a P value for
HIV-1-associated FSGS of 8 x 10(-8).
Kao et al. (2008) independently performed a genomewide admixture scan in
1,372 end-stage renal disease (ESRD) cases and 806 controls and found a
highly significant association between excess African ancestry and
nondiabetic ESRD (lod score = 5.70) but not diabetic ESRD (lod = 0.47)
on chromosome 22q12. Each copy of the European ancestral allele
conferred a relative risk of 0.50 (95% confidence interval = 0.39-0.63)
compared to African ancestry. Multiple common SNPs (allele frequencies
ranging from 0.02 to 0.06) in MYH9, the gene encoding nonmuscle myosin
heavy chain type II isoform A, were associated with 2 to 4 times greater
risk of nondiabetic ESRD and accounted for a large proportion of the
excess risk of ESRD observed in African compared to European Americans.
This risk was associated with all nondiabetes ESRD with a lod score of
4.55 and also with hypertensive ESRD at 1.79, FSGS at 2.47, and
HIV-related ESRD at 2.09. Kao et al. (2008) showed that any of the 3
SNPs, dbSNP rs4821480, dbSNP rs2032487, and dbSNP rs4821481, in strong
linkage disequilibrium is sufficient to account for all of the
association between the excess African ancestry observed on chromosome
22q12 and nondiabetic ESRD.
MOLECULAR GENETICS
Although genetic variation in or near the MYH9 gene on chromosome 22 was
associated with increased risk of FSGS, causal mutations in MHY9 had not
been identified. Genomewide analyses showed a strong signal of natural
selection in the region containing the MHY9 and APOL1 (603743) genes.
The longer patterns of linkage disequilibrium (LD) associated with
variants undergoing natural selection suggested to Genovese et al.
(2010) that a positively selected risk variant could be in a larger
interval containing the APOL genes rather than be confined to MYH9. In
an association analysis comparing 205 African Americans with
biopsy-proven FSGS and no family history of FSGS with 180 African
American controls, Genovese et al. (2010) identified association of
kidney disease with 2 independent sequence variants in the last exon of
the APOL1 gene (FSGS odds ratio = 10.5, 95% confidence interval 6.0 to
18.4; ESRD odds ratio = 7.3, 95% confidence interval 5.6 to 9.5).
Association with renal disease was confirmed in a larger cohort of 1,030
African American cases with ESRD and 1,025 geographically matched
African American controls. The 2 APOL1 variants, which Genovese et al.
(2010) referred to as G1 (603743.0001) and G2 (603743.0002), are common
in African chromosomes but absent in European chromosomes, and both
reside within haplotypes that harbor signatures of positive selection.
APOL1 is a serum factor that lyses trypanosomes. In vitro assays
revealed that only the kidney disease-associated APOL1 variants lysed
Trypanosoma brucei rhodesiense. Association of renal disease with MYH9
sequence variants disappeared after controlling for the APOL1 risk
variants. Comparing participants with zero or 1 risk allele of APOL1 to
participants with 2 risk alleles provided an odds ratio for FSGS of 10.5
(confidence interval 6.0 to 18.4). This analysis supported a completely
recessive pattern of inheritance. Genovese et al. (2010) speculated that
evolution of a critical survival factor in Africa may have contributed
to the high rates of renal disease in African Americans.
Parsa et al. (2013) performed 2 studies examining the effects of
variants in the APOL1 gene on the progression of chronic kidney disease.
In the African American Study of Kidney Disease and Hypertension (AASK),
693 black patients with chronic kidney disease attributed to
hypertension were examined for a primary outcome of composite end-stage
renal disease or doubling of the serum creatinine level. A total of 160
(23%) individuals carried 2 copies of APOL1 risk variants G1
(603743.0001) and/or G2 (603743.0002). Of these individuals in the
high-risk group, the primary outcome occurred in 58%; in the APOL1
low-risk group (all other genotypes), the primary outcome occurred in
37% (hazard ratio in the high-risk group, 1.88; p less than 0.001). In
the Chronic Renal Insufficiency Cohort (CRIC), Parsa et al. (2013)
evaluated 2,955 white patients and black patients with chronic kidney
disease (46% of whom had diabetes) for the primary outcomes of the slope
of the estimated glomerular filtration rate (eGFR) and the composite of
end-stage renal disease, or a reduction of 50% in the eGFR from
baseline. Black patients were genotyped for the G1 and G2 risk alleles.
In the CRIC study, black patients in the APOL1 high-risk group (270 of
1,411 total black patients) had a more rapid decline in the eGFR and a
higher risk of the composite renal outcome than did white patients, with
or without diabetes as a complication (p less than 0.001 for all
comparisons).
NOMENCLATURE
In the literature, the clinical term 'nephrotic syndrome' (NPHS) and the
pathologic term 'focal segmental glomerulosclerosis' (FSGS) have often
been used to refer to the same disease entity. In OMIM, these disorders
are designated as NPHS or FSGS according to how they were first
described in the literature.
*FIELD* RF
1. Genovese, G.; Friedman, D. J.; Ross, M. D.; Lecordier, L.; Uzureau,
P.; Freedman, B. I.; Bowden, D. W.; Langefeld, C. D.; Oleksyk, T.
K.; Uscinski Knob, A. L.; Bernhardy, A. J.; Hicks, P. J.; Nelson,
G. W.; Vanhollebeke, B.; Winkler, C. A.; Kopp, J. B.; Pays, E.; Pollak,
M. R.: Association of trypanolytic ApoL1 variants with kidney disease
in African Americans. Science 329: 841-845, 2010.
2. Kao, W. H. L.; Klag, M. J.; Meoni, L. A.; Reich, D.; Berthier-Schaad,
Y.; Li, M.; Coresh, J.; Patterson, N.; Tandon, A.; Powe, N. R.; Fink,
N. E.; Sadler, J. H.; and 19 others: MYH9 is associated with nondiabetic
end-stage renal disease in African Americans. Nature Genet. 40:
1185-1192, 2008.
3. Kopp, J. B.; Smith, M. W.; Nelson, G. W.; Johnson, R. C.; Freedman,
B. I.; Bowden, D. W.; Oleksyk, T.; McKenzie, L. M.; Kajiyama, H.;
Ahuja, T. S.; Berns, J. S.; Briggs, W.; and 10 others: MYH9 is
a major-effect risk gene for focal segmental glomerulosclerosis. Nature
Genet. 40: 1175-1184, 2008.
4. Meyrier, A.: Mechanisms of disease: focal segmental glomerulosclerosis. Nature
Clin. Prac.:Nephrol. 1: 44-54, 2005.
5. Parsa, A.; Kao, L.; Xie, D.; Astor, B. C.; Li, M.; Hsu, C.; Feldman,
H. I.; Parekh, R. S.; Kusek, J. W.; Greene, T. H.; Fink, J. C.; Anderson,
A. H.; and 13 others: APOL1 risk variants, race, and progression
of chronic kidney disease. New Eng. J. Med. 369: 2183-2196, 2013.
*FIELD* CN
Ada Hamosh - updated: 12/19/2013
Cassandra L. Kniffin - updated: 10/21/2010
Ada Hamosh - updated: 9/1/2010
*FIELD* CD
Ada Hamosh: 1/22/2009
*FIELD* ED
alopez: 12/19/2013
alopez: 12/6/2011
terry: 12/1/2011
carol: 10/29/2010
carol: 10/25/2010
ckniffin: 10/21/2010
ckniffin: 10/8/2010
alopez: 9/7/2010
terry: 9/1/2010
alopez: 1/22/2009