Full text data of KCNJ1
KCNJ1
(ROMK1)
[Confidence: low (only semi-automatic identification from reviews)]
ATP-sensitive inward rectifier potassium channel 1 (ATP-regulated potassium channel ROM-K; Inward rectifier K(+) channel Kir1.1; Potassium channel, inwardly rectifying subfamily J member 1)
ATP-sensitive inward rectifier potassium channel 1 (ATP-regulated potassium channel ROM-K; Inward rectifier K(+) channel Kir1.1; Potassium channel, inwardly rectifying subfamily J member 1)
UniProt
P48048
ID IRK1_HUMAN Reviewed; 391 AA.
AC P48048; B2RMR4; Q6LD67;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-FEB-1996, sequence version 1.
DT 22-JAN-2014, entry version 141.
DE RecName: Full=ATP-sensitive inward rectifier potassium channel 1;
DE AltName: Full=ATP-regulated potassium channel ROM-K;
DE AltName: Full=Inward rectifier K(+) channel Kir1.1;
DE AltName: Full=Potassium channel, inwardly rectifying subfamily J member 1;
GN Name=KCNJ1; Synonyms=ROMK1;
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], AND ALTERNATIVE SPLICING.
RC TISSUE=Kidney;
RX PubMed=7929082;
RA Shuck M.E., Bock J.H., Benjamin C.W., Tsai T.-D., Lee K.S.,
RA Slightom J.L., Bienkowski M.J.;
RT "Cloning and characterization of multiple forms of the human kidney
RT ROM-K potassium channel.";
RL J. Biol. Chem. 269:24261-24270(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND ALTERNATIVE SPLICING.
RC TISSUE=Kidney;
RX PubMed=8190102;
RA Yano H., Philipson L.H., Kugler J.L., Tokuyama Y., Davis E.M.,
RA le Beau M.M., Nelson D.J., Bell G.I., Takeda J.;
RT "Alternative splicing of human inwardly rectifying K+ channel ROMK1
RT mRNA.";
RL Mol. Pharmacol. 45:854-860(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND ALTERNATIVE SPLICING.
RX PubMed=9099852; DOI=10.1016/S0378-1119(96)00759-7;
RA Bock J.H., Shuck M.E., Benjamin C.W., Chee M., Bienkowski M.J.,
RA Slightom J.L.;
RT "Nucleotide sequence analysis of the human KCNJ1 potassium channel
RT locus.";
RL Gene 188:9-16(1997).
RN [4]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 76-177, AND TISSUE SPECIFICITY.
RC TISSUE=Brain cortex;
RX PubMed=7635463; DOI=10.1007/BF00207372;
RA Krishnan S.N., Desai T., Ward D.C., Haddad G.G.;
RT "Isolation and chromosomal localization of a human ATP-regulated
RT potassium channel.";
RL Hum. Genet. 96:155-160(1995).
RN [7]
RP GLYCOSYLATION AT ASN-117.
RX PubMed=10889209; DOI=10.1074/jbc.M005338200;
RA Pabon A., Chan K.W., Sui J.L., Wu X., Logothetis D.E., Thornhill W.B.;
RT "Glycosylation of GIRK1 at Asn119 and ROMK1 at Asn117 has different
RT consequences in potassium channel function.";
RL J. Biol. Chem. 275:30677-30682(2000).
RN [8]
RP INTERACTION WITH SGK1 AND SLC9A3R2/NHERF2.
RX PubMed=14623317; DOI=10.1016/j.bbrc.2003.10.037;
RA Palmada M., Embark H.M., Yun C., Bohmer C., Lang F.;
RT "Molecular requirements for the regulation of the renal outer
RT medullary K(+) channel ROMK1 by the serum- and glucocorticoid-
RT inducible kinase SGK1.";
RL Biochem. Biophys. Res. Commun. 311:629-634(2003).
RN [9]
RP PHOSPHORYLATION AT SER-44 BY SGK1, AND SUBCELLULAR LOCATION.
RX PubMed=12684516; DOI=10.1074/jbc.M212301200;
RA Yoo D., Kim B.Y., Campo C., Nance L., King A., Maouyo D.,
RA Welling P.A.;
RT "Cell surface expression of the ROMK (Kir 1.1) channel is regulated by
RT the aldosterone-induced kinase, SGK-1, and protein kinase A.";
RL J. Biol. Chem. 278:23066-23075(2003).
RN [10]
RP ENZYME REGULATION.
RX PubMed=16357011; DOI=10.1113/jphysiol.2005.102202;
RA Leng Q., Kahle K.T., Rinehart J., MacGregor G.G., Wilson F.H.,
RA Canessa C.M., Lifton R.P., Hebert S.C.;
RT "WNK3, a kinase related to genes mutated in hereditary hypertension
RT with hyperkalaemia, regulates the K+ channel ROMK1 (Kir1.1).";
RL J. Physiol. (Lond.) 571:275-286(2006).
RN [11]
RP VARIANTS BS2 VAL-214; ARG-219 AND THR-357.
RX PubMed=8841184; DOI=10.1038/ng1096-152;
RA Simon D.B., Karet F.E., Rodriguez-Soriano J., Hamdan J.H.,
RA DiPietro A., Trachtman H., Sanjad S.A., Lifton R.P.;
RT "Genetic heterogeneity of Bartter's syndrome revealed by mutations in
RT the K+ channel, ROMK.";
RL Nat. Genet. 14:152-156(1996).
RN [12]
RP VARIANTS BS2 GLU-72; TYR-74; CYS-99; HIS-108; LEU-110; GLU-122;
RP GLU-167; THR-198 AND GLY-315.
RX PubMed=9002665;
RA Karolyi L., Konrad M., Koeckerling A., Ziegler A., Zimmermann D.K.,
RA Roth B., Wieg C., Grzeschik K.-H., Koch M.C., Seyberth H.W.,
RA Vargas R., Forestier L., Jean G., Deschaux M., Rizzoni G.F.,
RA Niaudet P., Antignac C., Feldmann D., Lorridon F., Cougoureux E.,
RA Laroze F., Alessandri J.-L., David L., Saunier P., Deschenes G.,
RA Hildebrandt F., Vollmer M., Proesmans W., Brandis M.,
RA van den Heuvel L.P.W.J., Lemmink H.H., Nillesen W., Monnens L.A.H.,
RA Knoers N.V.A.M., Guay-Woodford L.M., Wright C.J., Madrigal G.,
RA Hebert S.C.;
RT "Mutations in the gene encoding the inwardly-rectifying renal
RT potassium channel, ROMK, cause the antenatal variant of Bartter
RT syndrome: evidence for genetic heterogeneity.";
RL Hum. Mol. Genet. 6:17-26(1997).
RN [13]
RP VARIANT BS2 LYS-124.
RX PubMed=9727001; DOI=10.1074/jbc.273.37.23884;
RA Derst C., Wischmeyer E., Preisig-Mueller R., Spauschus A., Konrad M.,
RA Hensen P., Jeck N., Seyberth H.W., Daut J., Karschin A.;
RT "A hyperprostaglandin E syndrome mutation in Kir1.1 (renal outer
RT medullary potassium) channels reveals a crucial residue for channel
RT function in Kir1.3 channels.";
RL J. Biol. Chem. 273:23884-23891(1998).
RN [14]
RP VARIANT [LARGE SCALE ANALYSIS] PHE-115.
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: In the kidney, probably plays a major role in potassium
CC homeostasis. Inward rectifier potassium channels are characterized
CC by a greater tendency to allow potassium to flow into the cell
CC rather than out of it. Their voltage dependence is regulated by
CC the concentration of extracellular potassium; as external
CC potassium is raised, the voltage range of the channel opening
CC shifts to more positive voltages. The inward rectification is
CC mainly due to the blockage of outward current by internal
CC magnesium. This channel is activated by internal ATP and can be
CC blocked by external barium.
CC -!- ENZYME REGULATION: Inhibited by WNK3.
CC -!- SUBUNIT: Interacts with SGK1 and SLC9A3R2/NHERF2.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.
CC Note=Phosphorylation at Ser-44 by SGK1 is necessary for its
CC expression at the cell membrane.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=ROM-K1;
CC IsoId=P48048-1; Sequence=Displayed;
CC Name=2; Synonyms=2-4-5, ROM-K2, ROM-K4, ROM-K5, ROM-K6;
CC IsoId=P48048-2; Sequence=VSP_002797;
CC Name=3; Synonyms=ROM-K3;
CC IsoId=P48048-3; Sequence=VSP_002798;
CC -!- TISSUE SPECIFICITY: In the kidney and pancreatic islets. Lower
CC levels in skeletal muscle, pancreas, spleen, brain, heart and
CC liver.
CC -!- PTM: Phosphorylation at Ser-44 by SGK1 is necessary for its
CC expression at the cell membrane.
CC -!- DISEASE: Bartter syndrome 2 (BS2) [MIM:241200]: An autosomal
CC recessive disorder characterized by impaired salt reabsorption in
CC the thick ascending loop of Henle with pronounced salt wasting,
CC hypokalemic metabolic alkalosis, and varying degrees of
CC hypercalciuria. Bartter syndrome type 2 is a life-threatening
CC condition beginning in utero, with marked fetal polyuria that
CC leads to polyhydramnios and premature delivery. Another hallmark
CC is a marked hypercalciuria and, as a secondary consequence, the
CC development of nephrocalcinosis and osteopenia. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the inward rectifier-type potassium channel
CC (TC 1.A.2.1) family. KCNJ1 subfamily.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/KCNJ1";
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DR EMBL; U12541; AAA61712.1; -; mRNA.
DR EMBL; U12542; AAA61713.1; -; mRNA.
DR EMBL; U12543; AAA61714.1; -; mRNA.
DR EMBL; U12544; AAA61715.1; -; mRNA.
DR EMBL; U12545; AAA61716.1; -; mRNA.
DR EMBL; U03884; AAA20594.1; -; mRNA.
DR EMBL; U65406; AAC51220.1; -; Genomic_DNA.
DR EMBL; U65406; AAC51221.1; -; Genomic_DNA.
DR EMBL; U65406; AAC51222.1; -; Genomic_DNA.
DR EMBL; CH471065; EAW67724.1; -; Genomic_DNA.
DR EMBL; BC074752; AAH74752.1; -; mRNA.
DR EMBL; BC136360; AAI36361.1; -; mRNA.
DR EMBL; BC136361; AAI36362.1; -; mRNA.
DR EMBL; S78737; AAB35012.1; -; mRNA.
DR PIR; A55119; A55119.
DR RefSeq; NP_000211.1; NM_000220.4.
DR RefSeq; NP_722448.1; NM_153764.2.
DR RefSeq; NP_722449.3; NM_153765.2.
DR RefSeq; NP_722450.1; NM_153766.2.
DR RefSeq; NP_722451.1; NM_153767.3.
DR UniGene; Hs.527830; -.
DR ProteinModelPortal; P48048; -.
DR SMR; P48048; 39-356.
DR MINT; MINT-90062; -.
DR STRING; 9606.ENSP00000316136; -.
DR BindingDB; P48048; -.
DR ChEMBL; CHEMBL1293292; -.
DR DrugBank; DB00414; Acetohexamide.
DR DrugBank; DB00672; Chlorpropamide.
DR DrugBank; DB01016; Glibenclamide.
DR DrugBank; DB01120; Gliclazide.
DR DrugBank; DB00222; Glimepiride.
DR DrugBank; DB01067; Glipizide.
DR DrugBank; DB01382; Glycodiazine.
DR DrugBank; DB00350; Minoxidil.
DR DrugBank; DB00731; Nateglinide.
DR DrugBank; DB00912; Repaglinide.
DR DrugBank; DB00839; Tolazamide.
DR DrugBank; DB01124; Tolbutamide.
DR GuidetoPHARMACOLOGY; 429; -.
DR TCDB; 1.A.2.1.1; inward rectifier k(+) channel (irk-c) family.
DR PhosphoSite; P48048; -.
DR DMDM; 1352479; -.
DR PaxDb; P48048; -.
DR PRIDE; P48048; -.
DR Ensembl; ENST00000324003; ENSP00000316136; ENSG00000151704.
DR Ensembl; ENST00000324036; ENSP00000316233; ENSG00000151704.
DR Ensembl; ENST00000392664; ENSP00000376432; ENSG00000151704.
DR Ensembl; ENST00000392665; ENSP00000376433; ENSG00000151704.
DR Ensembl; ENST00000392666; ENSP00000376434; ENSG00000151704.
DR Ensembl; ENST00000440599; ENSP00000406320; ENSG00000151704.
DR GeneID; 3758; -.
DR KEGG; hsa:3758; -.
DR UCSC; uc001qeo.2; human.
DR CTD; 3758; -.
DR GeneCards; GC11M128706; -.
DR HGNC; HGNC:6255; KCNJ1.
DR HPA; HPA026962; -.
DR MIM; 241200; phenotype.
DR MIM; 600359; gene.
DR neXtProt; NX_P48048; -.
DR Orphanet; 93604; Antenatal Bartter syndrome.
DR PharmGKB; PA213; -.
DR eggNOG; NOG247934; -.
DR HOGENOM; HOG000237326; -.
DR HOVERGEN; HBG006178; -.
DR InParanoid; P48048; -.
DR KO; K04995; -.
DR OMA; DIWTTVL; -.
DR OrthoDB; EOG7XPZ5K; -.
DR PhylomeDB; P48048; -.
DR Reactome; REACT_13685; Neuronal System.
DR GeneWiki; ROMK; -.
DR GenomeRNAi; 3758; -.
DR NextBio; 14725; -.
DR PRO; PR:P48048; -.
DR Bgee; P48048; -.
DR CleanEx; HS_KCNJ1; -.
DR Genevestigator; P48048; -.
DR GO; GO:0008076; C:voltage-gated potassium channel complex; TAS:ProtInc.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005242; F:inward rectifier potassium channel activity; TAS:ProtInc.
DR GO; GO:0005546; F:phosphatidylinositol-4,5-bisphosphate binding; IDA:BHF-UCL.
DR GO; GO:0072358; P:cardiovascular system development; IEA:Ensembl.
DR GO; GO:0007588; P:excretion; TAS:ProtInc.
DR GO; GO:0001822; P:kidney development; IEA:Ensembl.
DR GO; GO:0009791; P:post-embryonic development; IEA:Ensembl.
DR GO; GO:1900128; P:regulation of G-protein activated inward rectifier potassium channel activity; IEA:Ensembl.
DR GO; GO:0070294; P:renal sodium ion absorption; IEA:Ensembl.
DR GO; GO:0007268; P:synaptic transmission; TAS:Reactome.
DR GO; GO:0001894; P:tissue homeostasis; IEA:Ensembl.
DR Gene3D; 2.60.40.1400; -; 1.
DR InterPro; IPR014756; Ig_E-set.
DR InterPro; IPR016449; K_chnl_inward-rec_Kir.
DR InterPro; IPR003268; K_chnl_inward-rec_Kir1.1.
DR InterPro; IPR013518; K_chnl_inward-rec_Kir_cyto.
DR PANTHER; PTHR11767; PTHR11767; 1.
DR PANTHER; PTHR11767:SF6; PTHR11767:SF6; 1.
DR Pfam; PF01007; IRK; 1.
DR PIRSF; PIRSF005465; GIRK_kir; 1.
DR PRINTS; PR01321; KIR11CHANNEL.
DR PRINTS; PR01320; KIRCHANNEL.
DR SUPFAM; SSF81296; SSF81296; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Bartter syndrome; Cell membrane;
KW Complete proteome; Disease mutation; Glycoprotein; Ion channel;
KW Ion transport; Membrane; Nucleotide-binding; Phosphoprotein;
KW Polymorphism; Potassium; Potassium transport; Reference proteome;
KW Transmembrane; Transmembrane helix; Transport; Voltage-gated channel.
FT CHAIN 1 391 ATP-sensitive inward rectifier potassium
FT channel 1.
FT /FTId=PRO_0000154917.
FT TOPO_DOM 1 77 Cytoplasmic (By similarity).
FT TRANSMEM 78 102 Helical; Name=M1; (By similarity).
FT TOPO_DOM 103 127 Extracellular (By similarity).
FT INTRAMEM 128 139 Helical; Pore-forming; Name=H5; (By
FT similarity).
FT INTRAMEM 140 146 Pore-forming; (By similarity).
FT TOPO_DOM 147 155 Extracellular (By similarity).
FT TRANSMEM 156 177 Helical; Name=M2; (By similarity).
FT TOPO_DOM 178 391 Cytoplasmic (By similarity).
FT NP_BIND 223 230 ATP (Potential).
FT MOTIF 141 146 Selectivity filter (By similarity).
FT SITE 171 171 Role in the control of polyamine-mediated
FT channel gating and in the blocking by
FT intracellular magnesium (By similarity).
FT MOD_RES 44 44 Phosphoserine; by SGK1.
FT CARBOHYD 117 117 N-linked (GlcNAc...).
FT VAR_SEQ 1 19 Missing (in isoform 2).
FT /FTId=VSP_002797.
FT VAR_SEQ 1 12 MNASSRNVFDTL -> MPTVYLCSEQ (in isoform
FT 3).
FT /FTId=VSP_002798.
FT VARIANT 6 6 R -> W (in dbSNP:rs34191956).
FT /FTId=VAR_049668.
FT VARIANT 72 72 V -> E (in BS2).
FT /FTId=VAR_001548.
FT VARIANT 74 74 D -> Y (in BS2).
FT /FTId=VAR_001549.
FT VARIANT 99 99 W -> C (in BS2).
FT /FTId=VAR_001550.
FT VARIANT 108 108 D -> H (in BS2).
FT /FTId=VAR_001551.
FT VARIANT 110 110 P -> L (in BS2).
FT /FTId=VAR_001552.
FT VARIANT 115 115 S -> F (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036426.
FT VARIANT 122 122 V -> E (in BS2).
FT /FTId=VAR_001553.
FT VARIANT 124 124 N -> K (in BS2).
FT /FTId=VAR_019724.
FT VARIANT 167 167 G -> E (in BS2).
FT /FTId=VAR_001554.
FT VARIANT 198 198 A -> T (in BS2).
FT /FTId=VAR_001555.
FT VARIANT 214 214 A -> V (in BS2).
FT /FTId=VAR_019725.
FT VARIANT 219 219 S -> R (in BS2).
FT /FTId=VAR_019726.
FT VARIANT 315 315 V -> G (in BS2).
FT /FTId=VAR_001556.
FT VARIANT 357 357 M -> T (in BS2; dbSNP:rs59172778).
FT /FTId=VAR_019727.
SQ SEQUENCE 391 AA; 44795 MW; DF01C89B16BE6205 CRC64;
MNASSRNVFD TLIRVLTESM FKHLRKWVVT RFFGHSRQRA RLVSKDGRCN IEFGNVEAQS
RFIFFVDIWT TVLDLKWRYK MTIFITAFLG SWFFFGLLWY AVAYIHKDLP EFHPSANHTP
CVENINGLTS AFLFSLETQV TIGYGFRCVT EQCATAIFLL IFQSILGVII NSFMCGAILA
KISRPKKRAK TITFSKNAVI SKRGGKLCLL IRVANLRKSL LIGSHIYGKL LKTTVTPEGE
TIILDQININ FVVDAGNENL FFISPLTIYH VIDHNSPFFH MAAETLLQQD FELVVFLDGT
VESTSATCQV RTSYVPEEVL WGYRFAPIVS KTKEGKYRVD FHNFSKTVEV ETPHCAMCLY
NEKDVRARMK RGYDNPNFIL SEVNETDDTK M
//
ID IRK1_HUMAN Reviewed; 391 AA.
AC P48048; B2RMR4; Q6LD67;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-FEB-1996, sequence version 1.
DT 22-JAN-2014, entry version 141.
DE RecName: Full=ATP-sensitive inward rectifier potassium channel 1;
DE AltName: Full=ATP-regulated potassium channel ROM-K;
DE AltName: Full=Inward rectifier K(+) channel Kir1.1;
DE AltName: Full=Potassium channel, inwardly rectifying subfamily J member 1;
GN Name=KCNJ1; Synonyms=ROMK1;
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], AND ALTERNATIVE SPLICING.
RC TISSUE=Kidney;
RX PubMed=7929082;
RA Shuck M.E., Bock J.H., Benjamin C.W., Tsai T.-D., Lee K.S.,
RA Slightom J.L., Bienkowski M.J.;
RT "Cloning and characterization of multiple forms of the human kidney
RT ROM-K potassium channel.";
RL J. Biol. Chem. 269:24261-24270(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND ALTERNATIVE SPLICING.
RC TISSUE=Kidney;
RX PubMed=8190102;
RA Yano H., Philipson L.H., Kugler J.L., Tokuyama Y., Davis E.M.,
RA le Beau M.M., Nelson D.J., Bell G.I., Takeda J.;
RT "Alternative splicing of human inwardly rectifying K+ channel ROMK1
RT mRNA.";
RL Mol. Pharmacol. 45:854-860(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND ALTERNATIVE SPLICING.
RX PubMed=9099852; DOI=10.1016/S0378-1119(96)00759-7;
RA Bock J.H., Shuck M.E., Benjamin C.W., Chee M., Bienkowski M.J.,
RA Slightom J.L.;
RT "Nucleotide sequence analysis of the human KCNJ1 potassium channel
RT locus.";
RL Gene 188:9-16(1997).
RN [4]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 76-177, AND TISSUE SPECIFICITY.
RC TISSUE=Brain cortex;
RX PubMed=7635463; DOI=10.1007/BF00207372;
RA Krishnan S.N., Desai T., Ward D.C., Haddad G.G.;
RT "Isolation and chromosomal localization of a human ATP-regulated
RT potassium channel.";
RL Hum. Genet. 96:155-160(1995).
RN [7]
RP GLYCOSYLATION AT ASN-117.
RX PubMed=10889209; DOI=10.1074/jbc.M005338200;
RA Pabon A., Chan K.W., Sui J.L., Wu X., Logothetis D.E., Thornhill W.B.;
RT "Glycosylation of GIRK1 at Asn119 and ROMK1 at Asn117 has different
RT consequences in potassium channel function.";
RL J. Biol. Chem. 275:30677-30682(2000).
RN [8]
RP INTERACTION WITH SGK1 AND SLC9A3R2/NHERF2.
RX PubMed=14623317; DOI=10.1016/j.bbrc.2003.10.037;
RA Palmada M., Embark H.M., Yun C., Bohmer C., Lang F.;
RT "Molecular requirements for the regulation of the renal outer
RT medullary K(+) channel ROMK1 by the serum- and glucocorticoid-
RT inducible kinase SGK1.";
RL Biochem. Biophys. Res. Commun. 311:629-634(2003).
RN [9]
RP PHOSPHORYLATION AT SER-44 BY SGK1, AND SUBCELLULAR LOCATION.
RX PubMed=12684516; DOI=10.1074/jbc.M212301200;
RA Yoo D., Kim B.Y., Campo C., Nance L., King A., Maouyo D.,
RA Welling P.A.;
RT "Cell surface expression of the ROMK (Kir 1.1) channel is regulated by
RT the aldosterone-induced kinase, SGK-1, and protein kinase A.";
RL J. Biol. Chem. 278:23066-23075(2003).
RN [10]
RP ENZYME REGULATION.
RX PubMed=16357011; DOI=10.1113/jphysiol.2005.102202;
RA Leng Q., Kahle K.T., Rinehart J., MacGregor G.G., Wilson F.H.,
RA Canessa C.M., Lifton R.P., Hebert S.C.;
RT "WNK3, a kinase related to genes mutated in hereditary hypertension
RT with hyperkalaemia, regulates the K+ channel ROMK1 (Kir1.1).";
RL J. Physiol. (Lond.) 571:275-286(2006).
RN [11]
RP VARIANTS BS2 VAL-214; ARG-219 AND THR-357.
RX PubMed=8841184; DOI=10.1038/ng1096-152;
RA Simon D.B., Karet F.E., Rodriguez-Soriano J., Hamdan J.H.,
RA DiPietro A., Trachtman H., Sanjad S.A., Lifton R.P.;
RT "Genetic heterogeneity of Bartter's syndrome revealed by mutations in
RT the K+ channel, ROMK.";
RL Nat. Genet. 14:152-156(1996).
RN [12]
RP VARIANTS BS2 GLU-72; TYR-74; CYS-99; HIS-108; LEU-110; GLU-122;
RP GLU-167; THR-198 AND GLY-315.
RX PubMed=9002665;
RA Karolyi L., Konrad M., Koeckerling A., Ziegler A., Zimmermann D.K.,
RA Roth B., Wieg C., Grzeschik K.-H., Koch M.C., Seyberth H.W.,
RA Vargas R., Forestier L., Jean G., Deschaux M., Rizzoni G.F.,
RA Niaudet P., Antignac C., Feldmann D., Lorridon F., Cougoureux E.,
RA Laroze F., Alessandri J.-L., David L., Saunier P., Deschenes G.,
RA Hildebrandt F., Vollmer M., Proesmans W., Brandis M.,
RA van den Heuvel L.P.W.J., Lemmink H.H., Nillesen W., Monnens L.A.H.,
RA Knoers N.V.A.M., Guay-Woodford L.M., Wright C.J., Madrigal G.,
RA Hebert S.C.;
RT "Mutations in the gene encoding the inwardly-rectifying renal
RT potassium channel, ROMK, cause the antenatal variant of Bartter
RT syndrome: evidence for genetic heterogeneity.";
RL Hum. Mol. Genet. 6:17-26(1997).
RN [13]
RP VARIANT BS2 LYS-124.
RX PubMed=9727001; DOI=10.1074/jbc.273.37.23884;
RA Derst C., Wischmeyer E., Preisig-Mueller R., Spauschus A., Konrad M.,
RA Hensen P., Jeck N., Seyberth H.W., Daut J., Karschin A.;
RT "A hyperprostaglandin E syndrome mutation in Kir1.1 (renal outer
RT medullary potassium) channels reveals a crucial residue for channel
RT function in Kir1.3 channels.";
RL J. Biol. Chem. 273:23884-23891(1998).
RN [14]
RP VARIANT [LARGE SCALE ANALYSIS] PHE-115.
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: In the kidney, probably plays a major role in potassium
CC homeostasis. Inward rectifier potassium channels are characterized
CC by a greater tendency to allow potassium to flow into the cell
CC rather than out of it. Their voltage dependence is regulated by
CC the concentration of extracellular potassium; as external
CC potassium is raised, the voltage range of the channel opening
CC shifts to more positive voltages. The inward rectification is
CC mainly due to the blockage of outward current by internal
CC magnesium. This channel is activated by internal ATP and can be
CC blocked by external barium.
CC -!- ENZYME REGULATION: Inhibited by WNK3.
CC -!- SUBUNIT: Interacts with SGK1 and SLC9A3R2/NHERF2.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.
CC Note=Phosphorylation at Ser-44 by SGK1 is necessary for its
CC expression at the cell membrane.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=ROM-K1;
CC IsoId=P48048-1; Sequence=Displayed;
CC Name=2; Synonyms=2-4-5, ROM-K2, ROM-K4, ROM-K5, ROM-K6;
CC IsoId=P48048-2; Sequence=VSP_002797;
CC Name=3; Synonyms=ROM-K3;
CC IsoId=P48048-3; Sequence=VSP_002798;
CC -!- TISSUE SPECIFICITY: In the kidney and pancreatic islets. Lower
CC levels in skeletal muscle, pancreas, spleen, brain, heart and
CC liver.
CC -!- PTM: Phosphorylation at Ser-44 by SGK1 is necessary for its
CC expression at the cell membrane.
CC -!- DISEASE: Bartter syndrome 2 (BS2) [MIM:241200]: An autosomal
CC recessive disorder characterized by impaired salt reabsorption in
CC the thick ascending loop of Henle with pronounced salt wasting,
CC hypokalemic metabolic alkalosis, and varying degrees of
CC hypercalciuria. Bartter syndrome type 2 is a life-threatening
CC condition beginning in utero, with marked fetal polyuria that
CC leads to polyhydramnios and premature delivery. Another hallmark
CC is a marked hypercalciuria and, as a secondary consequence, the
CC development of nephrocalcinosis and osteopenia. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the inward rectifier-type potassium channel
CC (TC 1.A.2.1) family. KCNJ1 subfamily.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/KCNJ1";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
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DR EMBL; U12541; AAA61712.1; -; mRNA.
DR EMBL; U12542; AAA61713.1; -; mRNA.
DR EMBL; U12543; AAA61714.1; -; mRNA.
DR EMBL; U12544; AAA61715.1; -; mRNA.
DR EMBL; U12545; AAA61716.1; -; mRNA.
DR EMBL; U03884; AAA20594.1; -; mRNA.
DR EMBL; U65406; AAC51220.1; -; Genomic_DNA.
DR EMBL; U65406; AAC51221.1; -; Genomic_DNA.
DR EMBL; U65406; AAC51222.1; -; Genomic_DNA.
DR EMBL; CH471065; EAW67724.1; -; Genomic_DNA.
DR EMBL; BC074752; AAH74752.1; -; mRNA.
DR EMBL; BC136360; AAI36361.1; -; mRNA.
DR EMBL; BC136361; AAI36362.1; -; mRNA.
DR EMBL; S78737; AAB35012.1; -; mRNA.
DR PIR; A55119; A55119.
DR RefSeq; NP_000211.1; NM_000220.4.
DR RefSeq; NP_722448.1; NM_153764.2.
DR RefSeq; NP_722449.3; NM_153765.2.
DR RefSeq; NP_722450.1; NM_153766.2.
DR RefSeq; NP_722451.1; NM_153767.3.
DR UniGene; Hs.527830; -.
DR ProteinModelPortal; P48048; -.
DR SMR; P48048; 39-356.
DR MINT; MINT-90062; -.
DR STRING; 9606.ENSP00000316136; -.
DR BindingDB; P48048; -.
DR ChEMBL; CHEMBL1293292; -.
DR DrugBank; DB00414; Acetohexamide.
DR DrugBank; DB00672; Chlorpropamide.
DR DrugBank; DB01016; Glibenclamide.
DR DrugBank; DB01120; Gliclazide.
DR DrugBank; DB00222; Glimepiride.
DR DrugBank; DB01067; Glipizide.
DR DrugBank; DB01382; Glycodiazine.
DR DrugBank; DB00350; Minoxidil.
DR DrugBank; DB00731; Nateglinide.
DR DrugBank; DB00912; Repaglinide.
DR DrugBank; DB00839; Tolazamide.
DR DrugBank; DB01124; Tolbutamide.
DR GuidetoPHARMACOLOGY; 429; -.
DR TCDB; 1.A.2.1.1; inward rectifier k(+) channel (irk-c) family.
DR PhosphoSite; P48048; -.
DR DMDM; 1352479; -.
DR PaxDb; P48048; -.
DR PRIDE; P48048; -.
DR Ensembl; ENST00000324003; ENSP00000316136; ENSG00000151704.
DR Ensembl; ENST00000324036; ENSP00000316233; ENSG00000151704.
DR Ensembl; ENST00000392664; ENSP00000376432; ENSG00000151704.
DR Ensembl; ENST00000392665; ENSP00000376433; ENSG00000151704.
DR Ensembl; ENST00000392666; ENSP00000376434; ENSG00000151704.
DR Ensembl; ENST00000440599; ENSP00000406320; ENSG00000151704.
DR GeneID; 3758; -.
DR KEGG; hsa:3758; -.
DR UCSC; uc001qeo.2; human.
DR CTD; 3758; -.
DR GeneCards; GC11M128706; -.
DR HGNC; HGNC:6255; KCNJ1.
DR HPA; HPA026962; -.
DR MIM; 241200; phenotype.
DR MIM; 600359; gene.
DR neXtProt; NX_P48048; -.
DR Orphanet; 93604; Antenatal Bartter syndrome.
DR PharmGKB; PA213; -.
DR eggNOG; NOG247934; -.
DR HOGENOM; HOG000237326; -.
DR HOVERGEN; HBG006178; -.
DR InParanoid; P48048; -.
DR KO; K04995; -.
DR OMA; DIWTTVL; -.
DR OrthoDB; EOG7XPZ5K; -.
DR PhylomeDB; P48048; -.
DR Reactome; REACT_13685; Neuronal System.
DR GeneWiki; ROMK; -.
DR GenomeRNAi; 3758; -.
DR NextBio; 14725; -.
DR PRO; PR:P48048; -.
DR Bgee; P48048; -.
DR CleanEx; HS_KCNJ1; -.
DR Genevestigator; P48048; -.
DR GO; GO:0008076; C:voltage-gated potassium channel complex; TAS:ProtInc.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005242; F:inward rectifier potassium channel activity; TAS:ProtInc.
DR GO; GO:0005546; F:phosphatidylinositol-4,5-bisphosphate binding; IDA:BHF-UCL.
DR GO; GO:0072358; P:cardiovascular system development; IEA:Ensembl.
DR GO; GO:0007588; P:excretion; TAS:ProtInc.
DR GO; GO:0001822; P:kidney development; IEA:Ensembl.
DR GO; GO:0009791; P:post-embryonic development; IEA:Ensembl.
DR GO; GO:1900128; P:regulation of G-protein activated inward rectifier potassium channel activity; IEA:Ensembl.
DR GO; GO:0070294; P:renal sodium ion absorption; IEA:Ensembl.
DR GO; GO:0007268; P:synaptic transmission; TAS:Reactome.
DR GO; GO:0001894; P:tissue homeostasis; IEA:Ensembl.
DR Gene3D; 2.60.40.1400; -; 1.
DR InterPro; IPR014756; Ig_E-set.
DR InterPro; IPR016449; K_chnl_inward-rec_Kir.
DR InterPro; IPR003268; K_chnl_inward-rec_Kir1.1.
DR InterPro; IPR013518; K_chnl_inward-rec_Kir_cyto.
DR PANTHER; PTHR11767; PTHR11767; 1.
DR PANTHER; PTHR11767:SF6; PTHR11767:SF6; 1.
DR Pfam; PF01007; IRK; 1.
DR PIRSF; PIRSF005465; GIRK_kir; 1.
DR PRINTS; PR01321; KIR11CHANNEL.
DR PRINTS; PR01320; KIRCHANNEL.
DR SUPFAM; SSF81296; SSF81296; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Bartter syndrome; Cell membrane;
KW Complete proteome; Disease mutation; Glycoprotein; Ion channel;
KW Ion transport; Membrane; Nucleotide-binding; Phosphoprotein;
KW Polymorphism; Potassium; Potassium transport; Reference proteome;
KW Transmembrane; Transmembrane helix; Transport; Voltage-gated channel.
FT CHAIN 1 391 ATP-sensitive inward rectifier potassium
FT channel 1.
FT /FTId=PRO_0000154917.
FT TOPO_DOM 1 77 Cytoplasmic (By similarity).
FT TRANSMEM 78 102 Helical; Name=M1; (By similarity).
FT TOPO_DOM 103 127 Extracellular (By similarity).
FT INTRAMEM 128 139 Helical; Pore-forming; Name=H5; (By
FT similarity).
FT INTRAMEM 140 146 Pore-forming; (By similarity).
FT TOPO_DOM 147 155 Extracellular (By similarity).
FT TRANSMEM 156 177 Helical; Name=M2; (By similarity).
FT TOPO_DOM 178 391 Cytoplasmic (By similarity).
FT NP_BIND 223 230 ATP (Potential).
FT MOTIF 141 146 Selectivity filter (By similarity).
FT SITE 171 171 Role in the control of polyamine-mediated
FT channel gating and in the blocking by
FT intracellular magnesium (By similarity).
FT MOD_RES 44 44 Phosphoserine; by SGK1.
FT CARBOHYD 117 117 N-linked (GlcNAc...).
FT VAR_SEQ 1 19 Missing (in isoform 2).
FT /FTId=VSP_002797.
FT VAR_SEQ 1 12 MNASSRNVFDTL -> MPTVYLCSEQ (in isoform
FT 3).
FT /FTId=VSP_002798.
FT VARIANT 6 6 R -> W (in dbSNP:rs34191956).
FT /FTId=VAR_049668.
FT VARIANT 72 72 V -> E (in BS2).
FT /FTId=VAR_001548.
FT VARIANT 74 74 D -> Y (in BS2).
FT /FTId=VAR_001549.
FT VARIANT 99 99 W -> C (in BS2).
FT /FTId=VAR_001550.
FT VARIANT 108 108 D -> H (in BS2).
FT /FTId=VAR_001551.
FT VARIANT 110 110 P -> L (in BS2).
FT /FTId=VAR_001552.
FT VARIANT 115 115 S -> F (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036426.
FT VARIANT 122 122 V -> E (in BS2).
FT /FTId=VAR_001553.
FT VARIANT 124 124 N -> K (in BS2).
FT /FTId=VAR_019724.
FT VARIANT 167 167 G -> E (in BS2).
FT /FTId=VAR_001554.
FT VARIANT 198 198 A -> T (in BS2).
FT /FTId=VAR_001555.
FT VARIANT 214 214 A -> V (in BS2).
FT /FTId=VAR_019725.
FT VARIANT 219 219 S -> R (in BS2).
FT /FTId=VAR_019726.
FT VARIANT 315 315 V -> G (in BS2).
FT /FTId=VAR_001556.
FT VARIANT 357 357 M -> T (in BS2; dbSNP:rs59172778).
FT /FTId=VAR_019727.
SQ SEQUENCE 391 AA; 44795 MW; DF01C89B16BE6205 CRC64;
MNASSRNVFD TLIRVLTESM FKHLRKWVVT RFFGHSRQRA RLVSKDGRCN IEFGNVEAQS
RFIFFVDIWT TVLDLKWRYK MTIFITAFLG SWFFFGLLWY AVAYIHKDLP EFHPSANHTP
CVENINGLTS AFLFSLETQV TIGYGFRCVT EQCATAIFLL IFQSILGVII NSFMCGAILA
KISRPKKRAK TITFSKNAVI SKRGGKLCLL IRVANLRKSL LIGSHIYGKL LKTTVTPEGE
TIILDQININ FVVDAGNENL FFISPLTIYH VIDHNSPFFH MAAETLLQQD FELVVFLDGT
VESTSATCQV RTSYVPEEVL WGYRFAPIVS KTKEGKYRVD FHNFSKTVEV ETPHCAMCLY
NEKDVRARMK RGYDNPNFIL SEVNETDDTK M
//
MIM
241200
*RECORD*
*FIELD* NO
241200
*FIELD* TI
#241200 BARTTER SYNDROME, ANTENATAL, TYPE 2
;;HYPOKALEMIC ALKALOSIS WITH HYPERCALCIURIA, ANTENATAL, 2;;
read moreHYPERPROSTAGLANDIN E SYNDROME 2
*FIELD* TX
A number sign (#) is used with this entry because antenatal Bartter
syndrome type 2 is caused by mutation in the potassium channel ROMK gene
(KCNJ1; 600359).
Antenatal Bartter syndrome type 1 (601678) is caused by mutation in the
SLC12A1 gene (600839).
For a phenotypic description and discussion of genetic heterogeneity of
Bartter syndrome, see 'classic' Bartter syndrome, or Bartter syndrome
type 3 (607364).
CLINICAL FEATURES
The antenatal form of Bartter syndrome is a life-threatening disorder in
which both renal tubular hypokalemic alkalosis and profound systemic
symptoms are manifest (Seyberth et al., 1985; Deschenes et al., 1993;
Proesmans et al., 1985). The abnormalities begin in utero with marked
fetal polyuria that leads to polyhydramnios between 24 and 30 weeks of
gestation and, typically, premature delivery (Ohlsson et al., 1984). The
amniotic fluid contains high chloride levels but normal concentrations
of sodium, potassium, calcium, and prostaglandin E2. Affected neonates
have severe salt wasting and hyposthenuria, moderate hypokalemic
metabolic alkalosis, hyperprostaglandinuria, and failure to thrive. The
International Collaborative Study Group for Bartter-like Syndromes
(1997) noted that an essential manifestation of the antenatal variant is
marked hypercalciuria, and as a secondary consequence, affected infants
develop nephrocalcinosis and osteopenia.
Peters et al. (2002) found that 9 of 14 patients with antenatal Bartter
syndrome caused by mutations in the ROMK gene developed transient
hyperkalemia within the first month of life, which was in contrast to
those patients with NKCC2 mutations. The phenotype in the ROMK patients
resembled the clinical picture of pseudohypoaldosteronism type I
(264350). Finer et al. (2003) reported 12 infants with mutations in the
ROMK gene, affecting all 3 protein isoforms, who showed transient
hyperkalemia as high as 9.0 mmol/L without acidosis within the first few
weeks of life. Two patients developed ventricular arrhythmias and 1
patient died while hyperkalemic at age 8 days. The authors suggested
that postnatal maturation of potassium-regulating mechanisms, including
Na-K-ATPase, may explain the transient nature of the hyperkalemia. By
functional analysis of channel conductance defects caused by different
ROMK mutations, Jeck et al. (2001) suggested that patients with
mutations that affect all 3 ROMK isoforms may show transient neonatal
hyperkalemia, most likely due to defects affecting the cortical
collecting duct.
Fever, vomiting, and occasional diarrhea associated with the antenatal
Bartter syndrome have been attributed to the stimulation of renal and
systemic prostaglandin E2 activity in affected infants; these symptoms
are effectively treated with inhibitors of prostaglandin synthesis.
Based on these clinical features, the antenatal form of Bartter syndrome
has been referred to as the hyperprostaglandin E syndrome (Seyberth et
al., 1987).
Fellman et al. (1996) described an infant with severe hyperprostaglandin
E syndrome in whom hyperthyroidism was diagnosed at the age of 12 weeks.
The hyperthyroidism was thought to have been induced by PGE2. The PGE2
stimulus was also thought to explain the recurrent acute crises of
polyuria, dehydration, fever, and diarrhea in this patient. They
considered the extensive and abnormal crying of the patient to be an
indicator of pain caused by endogenous PGE2, since it could be abolished
with indomethacin or a very high dose of fentanyl.
There may be a form of hyperprostaglandin E syndrome that is separate
from the antenatal Bartter syndrome due to mutation of the SLC12A1 or
KCNJ1 gene. Kockerling et al. (1996) stated that hyperprostaglandin E
syndrome is characterized by its severe prenatal manifestation, leading
to fetal polyuria, development of polyhydramnios, and premature birth.
The disorder mimics furosemide treatment with hypokalemic alkalosis,
hypochloremia, isosthenuria, and impaired renal conservation of both
calcium and magnesium. Therefore, the thick ascending limb of the loop
of Henle seems to be involved in the disorder. Kockerling et al. (1996)
demonstrated that sensitivity to furosemide is completely maintained in
patients with Bartter syndrome and Gitelman syndrome. The diuretic,
saluretic, and hormonal responses were similar to those of the control
group of healthy children, indicating an intact function of the thick
ascending limb of the loop of Henle in BS/GS. In contrast, however,
patients with hyperprostaglandin E syndrome had a marked resistance to
this loop diuretic. The authors concluded that a defect in electrolyte
reabsorption in the thick ascending limb of the loop of Henle plays a
major role in hyperprostaglandin E syndrome.
DIAGNOSIS
- Prenatal Diagnosis
For prenatal diagnosis, Matsushita et al. (1999) conducted biochemical
examinations of both amniotic fluid and the mother's urine. Except for
potassium, amniotic fluid electrolytes in a mother with a fetus with
Bartter syndrome were high. Urinary chloride, sodium, and calcium were
very low. The authors suggested that the latter parameters may allow
prediction of fetal Bartter syndrome during the prenatal period.
Konrad et al. (1999) reviewed the clinical and laboratory findings
during pregnancy and the neonatal period in 2 sibs affected with the
hyperprostaglandin E syndrome. Compound heterozygosity at the KCNJ1
(600359) locus (D74Y/P110L) confirmed the clinical diagnosis of
antenatal Bartter syndrome type 2 at 26 weeks of gestation (see
MOLECULAR GENETICS).
CLINICAL MANAGEMENT
In a 26-week-old fetus with a confirmed diagnosis of hyperprostaglandin
E syndrome, Konrad et al. (1999) found that indomethacin therapy from 26
to 31 weeks prevented further progression of polyhydramnios without
major side effects. In contrast to his elder brother, who had been
diagnosed at the age of 2 months, the neonatal course was uncomplicated.
Hypovolemic renal failure after excessive renal loss of salt and water
could be prevented and severe nephrocalcinosis did not occur. Thus,
progression of polyhydramnios with extreme prematurity can be prevented
by prenatal therapy; postnatally the early diagnosis allows the
effective water and electrolyte substitution before severe volume
depletion occurs.
Kleta et al. (2000) noted that the clinical problems in patients with
Bartter syndrome are to a large extent caused by elevated levels of
prostaglandins. Treatment options have included indomethacin, a
nonselective cyclooxygenase (COX) inhibitor, but this drug has a broad
range of side effects and therefore requires extensive monitoring. Kleta
et al. (2000) reported successful results with a selective and specific
inhibitor of COX2 (600262). This isoenzyme seems to be responsible for
the elevated levels of inducible prostaglandins from the macula densa
and the thick ascending limb of the loop of Henle.
MOLECULAR GENETICS
The potassium channel gene ROMK (KCNJ1; 600359) is believed to be a
regulator of cotransporter activity; it is an ATP-sensitive potassium
channel that 'recycles' reabsorbed potassium back to the tubule lumen.
In 4 kindreds, Simon et al. (1996) found mutations in the ROMK gene that
cosegregated with antenatal Bartter syndrome and disrupted ROMK function
(600359.0001-600359.0006). The disorder has since been designated
antenatal Bartter syndrome type 2. Thus, antenatal Bartter syndrome is
genetically heterogeneous.
The International Collaborative Study Group for Bartter-like Syndromes
(1997) reported mutations in the KCNJ1 gene (600359.0007-600359.0009) in
3 kindreds and 5 sporadic cases with antenatal Bartter syndrome type 2.
Functional coupling of ROMK and the luminal Na-K-2Cl cotransporter is
crucial for NaCl reabsorption. Therefore, loss of function in ROMK, as
well as in NKCC2, would be predicted to disrupt electrogenic chloride
reabsorption in the medullary thick ascending limb of the loop of Henle.
Using targeted mutations, Lopes et al. (2002) established that mutations
in KCNJ1 residues associated with Bartter syndrome decreased the
strength of channel interactions with phosphatidylinositol
4,5-bisphosphate (PIP2). They concluded that a decrease in channel-PIP2
interactions underlies the molecular mechanism of Bartter syndrome when
these mutations are present in patients.
*FIELD* RF
1. Deschenes, G.; Burguet, A.; Guyot, C.; Hubert, P.; Garabedian,
M.; Dechaux, M.; Loirat, C.; Broyer, M.: Forme antenatale de syndrome
de Bartter. Ann. Pediat. 40: 95-101, 1993.
2. Fellman, V.; Pihko, H.; Majander, A.; Seyberth, H. W.: Severe
hyperprostaglandin E syndrome with hyperthyroidism: studies of pathogenetic
mechanisms. J. Inherit. Metab. Dis. 19: 687-694, 1996.
3. Finer, G.; Shalev, H.; Birk, O. S.; Galron, D.; Jeck, N.; Sinai-Treiman,
L.; Landau, D.: Transient neonatal hyperkalemia in the antenatal
(ROMK defective) Bartter syndrome. J. Pediat. 142: 318-323, 2003.
4. International Collaborative Study Group for Bartter-like Syndromes
: Mutations in the gene encoding the inwardly-rectifying renal potassium
channel, ROMK, cause the antenatal variant of Bartter syndrome: evidence
for genetic heterogeneity. Hum. Molec. Genet. 6: 17-26, 1997. Note:
Erratum: Hum. Molec. Genet. 6: 650 only, 1997.
5. Jeck, N.; Derst, C.; Wischmeyer, E.; Ott, H.; Weber, S.; Rudin,
C.; Seyberth, H. W.; Daut, J.; Karschin, A.; Konrad, M.: Functional
heterogeneity of ROMK mutations linked to hyperprostaglandin E syndrome. Kidney
Int. 59: 1803-1811, 2001.
6. Kleta, R.; Basoglu, C.; Kuwertz-Broking, E.: New treatment options
for Bartter's syndrome. (Letter) New Eng. J. Med. 343: 661-662,
2000.
7. Kockerling, A.; Reinalter, S. C.; Seyberth, H. W.: Impaired response
to furosemide in hyperprostaglandin E syndrome: evidence for a tubular
defect in the loop of Henle. J. Pediat. 129: 519-528, 1996.
8. Konrad, M.; Leonhardt, A.; Hensen, P.; Seyberth, H. W.; Kockerling,
A.: Prenatal and postnatal management of hyperprostaglandin E syndrome
after genetic diagnosis from amniocytes. Pediatrics 103: 678-683,
1999.
9. Lopes, C. M. B.; Zhang, H.; Rohacs, T.; Jin, T.; Yang, J.; Logothetis,
D. E.: Alterations in conserved Kir channel-PIP(2) interactions underlie
channelopathies. Neuron 34: 933-944, 2002.
10. Matsushita, Y.; Suzuki, Y.; Oya, N.; Kajiura, S.; Okajima, K.;
Uemura, O.; Suzumori, K.: Biochemical examination of mother's urine
is useful for prenatal diagnosis of Bartter syndrome. Prenatal Diag. 19:
671-673, 1999.
11. Ohlsson, A.; Sieck, U.; Cumming, W.; Akhtar, M.; Serenius, F.
: A variant of Bartter's syndrome: Bartter's syndrome associated with
hydramnios, prematurity, hypercalciuria and nephrocalcinosis. Acta
Pediat. Scand. 73: 868-874, 1984.
12. Peters, M.; Jeck, N.; Reinalter, S.; Leonhardt, A.; Tonshoff,
B.; Klaus, G.; Konrad, M.; Seyberth, H. W.: Clinical presentation
of genetically defined patients with hypokalemic salt-losing tubulopathies. Am.
J. Med. 112: 183-190, 2002.
13. Proesmans, W.; Devlieger, H.; Van Assche, A.; Eggermont, E.; Vandenberghe,
K.; Lemmens, F.; Sieprath, P.; Lijnen, P.: Bartter syndrome in two
siblings: antenatal and neonatal observations. Int. J. Pediat. Nephrol. 6:
63-70, 1985.
14. Seyberth, H.; Koniger, S.; Rascher, W.; Kuhl, P.; Schweer, H.
: Role of prostaglandins in hyperprostaglandin E syndrome and in selected
renal tubular disorders. Pediat. Nephrol. 1: 491-497, 1987.
15. Seyberth, H. W.; Rascher, W.; Schweer, H.; Kuhl, P. G.; Mehls,
O.; Scharer, K.: Congenital hypokalemia and hypercalciuria in preterm
infants: a hyperprostaglandinuric tubular syndrome different from
Bartter syndrome. J. Pediat. 107: 694-701, 1985.
16. Simon, D. B.; Karet, F. E.; Rodriguez-Soriano, J.; Hamdan, J.
H.; DiPietro, A.; Trachtman, H.; Sanjad, S. A.: Lifton, R. P.: Genetic
heterogeneity of Bartter's syndrome revealed by mutations in the K+
channel, ROMK. Nature Genet. 14: 152-156, 1996.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature;
[Weight];
Low birth weight;
[Other];
Failure to thrive
HEAD AND NECK:
[Head];
Large head;
[Face];
Prominent forehead;
Triangular face;
[Ears];
Large pinnae;
[Eyes];
Large eyes
CARDIOVASCULAR:
[Vascular];
Low-to-normal blood pressure
ABDOMEN:
[Gastrointestinal];
Constipation;
Vomiting;
Diarrhea
GENITOURINARY:
[Kidneys];
Renal salt wasting;
Renal potassium wasting;
Nephrocalcinosis;
Renal juxtaglomerular cell hypertrophy/hyperplasia;
Polyuria
SKELETAL:
Osteopenia;
Chondrocalcinosis
MUSCLE, SOFT TISSUE:
Generalized weakness;
Muscle cramps;
Tetany
NEUROLOGIC:
[Central nervous system];
Developmental delay;
Mental retardation;
Seizures;
Paresthesias
METABOLIC FEATURES:
Dehydration;
Polydipsia;
Hypokalemic metabolic alkalosis;
Fever
ENDOCRINE FEATURES:
Hyperactive renin-angiotensin system;
Elevated plasma renin;
Elevated plasma aldosterone
HEMATOLOGY:
Platelet aggregation defect
PRENATAL MANIFESTATIONS:
[Amniotic fluid];
Fetal polyuria;
Polyhydramnios;
Elevated chloride levels;
[Delivery];
Premature delivery
LABORATORY ABNORMALITIES:
Hypokalemia;
Increased serum prostaglandin E2;
Hyperprostaglandinuria;
Hypercalciuria;
Occasional hypomagnesemia;
Hypochloremia;
Increased urinary potassium;
Increased urinary chloride;
Hyposthenuria
MISCELLANEOUS:
Genetic heterogeneity (see antenatal Bartter syndrome type 1, 601678)
MOLECULAR BASIS:
Caused by mutation in the potassium inwardly-rectifying channel, subfamily
J, member 1 gene (KCNJ1, 600359.0001)
*FIELD* CN
Cassandra L. Kniffin - revised: 12/18/2002
Kelly A. Przylepa - revised: 10/4/2000
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 07/02/2013
joanna: 3/1/2011
joanna: 3/4/2003
joanna: 12/20/2002
ckniffin: 12/18/2002
joanna: 12/3/2001
joanna: 11/8/2001
kayiaros: 10/4/2000
*FIELD* CN
Natalie E. Krasikov - updated: 3/22/2004
Cassandra L. Kniffin - updated: 3/17/2004
Cassandra L. Kniffin - reorganized: 12/2/2002
Dawn Watkins-Chow - updated: 11/18/2002
Victor A. McKusick - updated: 9/26/2000
Victor A. McKusick - updated: 11/1/1999
Victor A. McKusick - updated: 4/21/1999
Victor A. McKusick - edited: 10/1/1997
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
carol: 04/22/2013
terry: 4/28/2011
terry: 3/10/2011
mgross: 10/16/2009
tkritzer: 6/3/2005
alopez: 11/23/2004
ckniffin: 8/24/2004
joanna: 8/24/2004
carol: 3/22/2004
ckniffin: 3/17/2004
alopez: 12/3/2002
carol: 12/2/2002
ckniffin: 11/21/2002
cwells: 11/18/2002
carol: 11/18/2002
terry: 9/26/2000
carol: 11/10/1999
terry: 11/1/1999
mgross: 4/23/1999
terry: 4/21/1999
carol: 4/29/1998
terry: 3/27/1998
mark: 10/1/1997
terry: 9/30/1997
mark: 7/16/1997
mark: 9/30/1996
terry: 9/26/1996
mark: 5/31/1996
mark: 5/30/1996
terry: 5/28/1996
terry: 2/6/1996
mark: 1/17/1996
terry: 1/16/1996
mark: 10/5/1995
carol: 1/17/1995
terry: 5/7/1994
warfield: 4/15/1994
mimadm: 2/19/1994
carol: 8/27/1992
*RECORD*
*FIELD* NO
241200
*FIELD* TI
#241200 BARTTER SYNDROME, ANTENATAL, TYPE 2
;;HYPOKALEMIC ALKALOSIS WITH HYPERCALCIURIA, ANTENATAL, 2;;
read moreHYPERPROSTAGLANDIN E SYNDROME 2
*FIELD* TX
A number sign (#) is used with this entry because antenatal Bartter
syndrome type 2 is caused by mutation in the potassium channel ROMK gene
(KCNJ1; 600359).
Antenatal Bartter syndrome type 1 (601678) is caused by mutation in the
SLC12A1 gene (600839).
For a phenotypic description and discussion of genetic heterogeneity of
Bartter syndrome, see 'classic' Bartter syndrome, or Bartter syndrome
type 3 (607364).
CLINICAL FEATURES
The antenatal form of Bartter syndrome is a life-threatening disorder in
which both renal tubular hypokalemic alkalosis and profound systemic
symptoms are manifest (Seyberth et al., 1985; Deschenes et al., 1993;
Proesmans et al., 1985). The abnormalities begin in utero with marked
fetal polyuria that leads to polyhydramnios between 24 and 30 weeks of
gestation and, typically, premature delivery (Ohlsson et al., 1984). The
amniotic fluid contains high chloride levels but normal concentrations
of sodium, potassium, calcium, and prostaglandin E2. Affected neonates
have severe salt wasting and hyposthenuria, moderate hypokalemic
metabolic alkalosis, hyperprostaglandinuria, and failure to thrive. The
International Collaborative Study Group for Bartter-like Syndromes
(1997) noted that an essential manifestation of the antenatal variant is
marked hypercalciuria, and as a secondary consequence, affected infants
develop nephrocalcinosis and osteopenia.
Peters et al. (2002) found that 9 of 14 patients with antenatal Bartter
syndrome caused by mutations in the ROMK gene developed transient
hyperkalemia within the first month of life, which was in contrast to
those patients with NKCC2 mutations. The phenotype in the ROMK patients
resembled the clinical picture of pseudohypoaldosteronism type I
(264350). Finer et al. (2003) reported 12 infants with mutations in the
ROMK gene, affecting all 3 protein isoforms, who showed transient
hyperkalemia as high as 9.0 mmol/L without acidosis within the first few
weeks of life. Two patients developed ventricular arrhythmias and 1
patient died while hyperkalemic at age 8 days. The authors suggested
that postnatal maturation of potassium-regulating mechanisms, including
Na-K-ATPase, may explain the transient nature of the hyperkalemia. By
functional analysis of channel conductance defects caused by different
ROMK mutations, Jeck et al. (2001) suggested that patients with
mutations that affect all 3 ROMK isoforms may show transient neonatal
hyperkalemia, most likely due to defects affecting the cortical
collecting duct.
Fever, vomiting, and occasional diarrhea associated with the antenatal
Bartter syndrome have been attributed to the stimulation of renal and
systemic prostaglandin E2 activity in affected infants; these symptoms
are effectively treated with inhibitors of prostaglandin synthesis.
Based on these clinical features, the antenatal form of Bartter syndrome
has been referred to as the hyperprostaglandin E syndrome (Seyberth et
al., 1987).
Fellman et al. (1996) described an infant with severe hyperprostaglandin
E syndrome in whom hyperthyroidism was diagnosed at the age of 12 weeks.
The hyperthyroidism was thought to have been induced by PGE2. The PGE2
stimulus was also thought to explain the recurrent acute crises of
polyuria, dehydration, fever, and diarrhea in this patient. They
considered the extensive and abnormal crying of the patient to be an
indicator of pain caused by endogenous PGE2, since it could be abolished
with indomethacin or a very high dose of fentanyl.
There may be a form of hyperprostaglandin E syndrome that is separate
from the antenatal Bartter syndrome due to mutation of the SLC12A1 or
KCNJ1 gene. Kockerling et al. (1996) stated that hyperprostaglandin E
syndrome is characterized by its severe prenatal manifestation, leading
to fetal polyuria, development of polyhydramnios, and premature birth.
The disorder mimics furosemide treatment with hypokalemic alkalosis,
hypochloremia, isosthenuria, and impaired renal conservation of both
calcium and magnesium. Therefore, the thick ascending limb of the loop
of Henle seems to be involved in the disorder. Kockerling et al. (1996)
demonstrated that sensitivity to furosemide is completely maintained in
patients with Bartter syndrome and Gitelman syndrome. The diuretic,
saluretic, and hormonal responses were similar to those of the control
group of healthy children, indicating an intact function of the thick
ascending limb of the loop of Henle in BS/GS. In contrast, however,
patients with hyperprostaglandin E syndrome had a marked resistance to
this loop diuretic. The authors concluded that a defect in electrolyte
reabsorption in the thick ascending limb of the loop of Henle plays a
major role in hyperprostaglandin E syndrome.
DIAGNOSIS
- Prenatal Diagnosis
For prenatal diagnosis, Matsushita et al. (1999) conducted biochemical
examinations of both amniotic fluid and the mother's urine. Except for
potassium, amniotic fluid electrolytes in a mother with a fetus with
Bartter syndrome were high. Urinary chloride, sodium, and calcium were
very low. The authors suggested that the latter parameters may allow
prediction of fetal Bartter syndrome during the prenatal period.
Konrad et al. (1999) reviewed the clinical and laboratory findings
during pregnancy and the neonatal period in 2 sibs affected with the
hyperprostaglandin E syndrome. Compound heterozygosity at the KCNJ1
(600359) locus (D74Y/P110L) confirmed the clinical diagnosis of
antenatal Bartter syndrome type 2 at 26 weeks of gestation (see
MOLECULAR GENETICS).
CLINICAL MANAGEMENT
In a 26-week-old fetus with a confirmed diagnosis of hyperprostaglandin
E syndrome, Konrad et al. (1999) found that indomethacin therapy from 26
to 31 weeks prevented further progression of polyhydramnios without
major side effects. In contrast to his elder brother, who had been
diagnosed at the age of 2 months, the neonatal course was uncomplicated.
Hypovolemic renal failure after excessive renal loss of salt and water
could be prevented and severe nephrocalcinosis did not occur. Thus,
progression of polyhydramnios with extreme prematurity can be prevented
by prenatal therapy; postnatally the early diagnosis allows the
effective water and electrolyte substitution before severe volume
depletion occurs.
Kleta et al. (2000) noted that the clinical problems in patients with
Bartter syndrome are to a large extent caused by elevated levels of
prostaglandins. Treatment options have included indomethacin, a
nonselective cyclooxygenase (COX) inhibitor, but this drug has a broad
range of side effects and therefore requires extensive monitoring. Kleta
et al. (2000) reported successful results with a selective and specific
inhibitor of COX2 (600262). This isoenzyme seems to be responsible for
the elevated levels of inducible prostaglandins from the macula densa
and the thick ascending limb of the loop of Henle.
MOLECULAR GENETICS
The potassium channel gene ROMK (KCNJ1; 600359) is believed to be a
regulator of cotransporter activity; it is an ATP-sensitive potassium
channel that 'recycles' reabsorbed potassium back to the tubule lumen.
In 4 kindreds, Simon et al. (1996) found mutations in the ROMK gene that
cosegregated with antenatal Bartter syndrome and disrupted ROMK function
(600359.0001-600359.0006). The disorder has since been designated
antenatal Bartter syndrome type 2. Thus, antenatal Bartter syndrome is
genetically heterogeneous.
The International Collaborative Study Group for Bartter-like Syndromes
(1997) reported mutations in the KCNJ1 gene (600359.0007-600359.0009) in
3 kindreds and 5 sporadic cases with antenatal Bartter syndrome type 2.
Functional coupling of ROMK and the luminal Na-K-2Cl cotransporter is
crucial for NaCl reabsorption. Therefore, loss of function in ROMK, as
well as in NKCC2, would be predicted to disrupt electrogenic chloride
reabsorption in the medullary thick ascending limb of the loop of Henle.
Using targeted mutations, Lopes et al. (2002) established that mutations
in KCNJ1 residues associated with Bartter syndrome decreased the
strength of channel interactions with phosphatidylinositol
4,5-bisphosphate (PIP2). They concluded that a decrease in channel-PIP2
interactions underlies the molecular mechanism of Bartter syndrome when
these mutations are present in patients.
*FIELD* RF
1. Deschenes, G.; Burguet, A.; Guyot, C.; Hubert, P.; Garabedian,
M.; Dechaux, M.; Loirat, C.; Broyer, M.: Forme antenatale de syndrome
de Bartter. Ann. Pediat. 40: 95-101, 1993.
2. Fellman, V.; Pihko, H.; Majander, A.; Seyberth, H. W.: Severe
hyperprostaglandin E syndrome with hyperthyroidism: studies of pathogenetic
mechanisms. J. Inherit. Metab. Dis. 19: 687-694, 1996.
3. Finer, G.; Shalev, H.; Birk, O. S.; Galron, D.; Jeck, N.; Sinai-Treiman,
L.; Landau, D.: Transient neonatal hyperkalemia in the antenatal
(ROMK defective) Bartter syndrome. J. Pediat. 142: 318-323, 2003.
4. International Collaborative Study Group for Bartter-like Syndromes
: Mutations in the gene encoding the inwardly-rectifying renal potassium
channel, ROMK, cause the antenatal variant of Bartter syndrome: evidence
for genetic heterogeneity. Hum. Molec. Genet. 6: 17-26, 1997. Note:
Erratum: Hum. Molec. Genet. 6: 650 only, 1997.
5. Jeck, N.; Derst, C.; Wischmeyer, E.; Ott, H.; Weber, S.; Rudin,
C.; Seyberth, H. W.; Daut, J.; Karschin, A.; Konrad, M.: Functional
heterogeneity of ROMK mutations linked to hyperprostaglandin E syndrome. Kidney
Int. 59: 1803-1811, 2001.
6. Kleta, R.; Basoglu, C.; Kuwertz-Broking, E.: New treatment options
for Bartter's syndrome. (Letter) New Eng. J. Med. 343: 661-662,
2000.
7. Kockerling, A.; Reinalter, S. C.; Seyberth, H. W.: Impaired response
to furosemide in hyperprostaglandin E syndrome: evidence for a tubular
defect in the loop of Henle. J. Pediat. 129: 519-528, 1996.
8. Konrad, M.; Leonhardt, A.; Hensen, P.; Seyberth, H. W.; Kockerling,
A.: Prenatal and postnatal management of hyperprostaglandin E syndrome
after genetic diagnosis from amniocytes. Pediatrics 103: 678-683,
1999.
9. Lopes, C. M. B.; Zhang, H.; Rohacs, T.; Jin, T.; Yang, J.; Logothetis,
D. E.: Alterations in conserved Kir channel-PIP(2) interactions underlie
channelopathies. Neuron 34: 933-944, 2002.
10. Matsushita, Y.; Suzuki, Y.; Oya, N.; Kajiura, S.; Okajima, K.;
Uemura, O.; Suzumori, K.: Biochemical examination of mother's urine
is useful for prenatal diagnosis of Bartter syndrome. Prenatal Diag. 19:
671-673, 1999.
11. Ohlsson, A.; Sieck, U.; Cumming, W.; Akhtar, M.; Serenius, F.
: A variant of Bartter's syndrome: Bartter's syndrome associated with
hydramnios, prematurity, hypercalciuria and nephrocalcinosis. Acta
Pediat. Scand. 73: 868-874, 1984.
12. Peters, M.; Jeck, N.; Reinalter, S.; Leonhardt, A.; Tonshoff,
B.; Klaus, G.; Konrad, M.; Seyberth, H. W.: Clinical presentation
of genetically defined patients with hypokalemic salt-losing tubulopathies. Am.
J. Med. 112: 183-190, 2002.
13. Proesmans, W.; Devlieger, H.; Van Assche, A.; Eggermont, E.; Vandenberghe,
K.; Lemmens, F.; Sieprath, P.; Lijnen, P.: Bartter syndrome in two
siblings: antenatal and neonatal observations. Int. J. Pediat. Nephrol. 6:
63-70, 1985.
14. Seyberth, H.; Koniger, S.; Rascher, W.; Kuhl, P.; Schweer, H.
: Role of prostaglandins in hyperprostaglandin E syndrome and in selected
renal tubular disorders. Pediat. Nephrol. 1: 491-497, 1987.
15. Seyberth, H. W.; Rascher, W.; Schweer, H.; Kuhl, P. G.; Mehls,
O.; Scharer, K.: Congenital hypokalemia and hypercalciuria in preterm
infants: a hyperprostaglandinuric tubular syndrome different from
Bartter syndrome. J. Pediat. 107: 694-701, 1985.
16. Simon, D. B.; Karet, F. E.; Rodriguez-Soriano, J.; Hamdan, J.
H.; DiPietro, A.; Trachtman, H.; Sanjad, S. A.: Lifton, R. P.: Genetic
heterogeneity of Bartter's syndrome revealed by mutations in the K+
channel, ROMK. Nature Genet. 14: 152-156, 1996.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature;
[Weight];
Low birth weight;
[Other];
Failure to thrive
HEAD AND NECK:
[Head];
Large head;
[Face];
Prominent forehead;
Triangular face;
[Ears];
Large pinnae;
[Eyes];
Large eyes
CARDIOVASCULAR:
[Vascular];
Low-to-normal blood pressure
ABDOMEN:
[Gastrointestinal];
Constipation;
Vomiting;
Diarrhea
GENITOURINARY:
[Kidneys];
Renal salt wasting;
Renal potassium wasting;
Nephrocalcinosis;
Renal juxtaglomerular cell hypertrophy/hyperplasia;
Polyuria
SKELETAL:
Osteopenia;
Chondrocalcinosis
MUSCLE, SOFT TISSUE:
Generalized weakness;
Muscle cramps;
Tetany
NEUROLOGIC:
[Central nervous system];
Developmental delay;
Mental retardation;
Seizures;
Paresthesias
METABOLIC FEATURES:
Dehydration;
Polydipsia;
Hypokalemic metabolic alkalosis;
Fever
ENDOCRINE FEATURES:
Hyperactive renin-angiotensin system;
Elevated plasma renin;
Elevated plasma aldosterone
HEMATOLOGY:
Platelet aggregation defect
PRENATAL MANIFESTATIONS:
[Amniotic fluid];
Fetal polyuria;
Polyhydramnios;
Elevated chloride levels;
[Delivery];
Premature delivery
LABORATORY ABNORMALITIES:
Hypokalemia;
Increased serum prostaglandin E2;
Hyperprostaglandinuria;
Hypercalciuria;
Occasional hypomagnesemia;
Hypochloremia;
Increased urinary potassium;
Increased urinary chloride;
Hyposthenuria
MISCELLANEOUS:
Genetic heterogeneity (see antenatal Bartter syndrome type 1, 601678)
MOLECULAR BASIS:
Caused by mutation in the potassium inwardly-rectifying channel, subfamily
J, member 1 gene (KCNJ1, 600359.0001)
*FIELD* CN
Cassandra L. Kniffin - revised: 12/18/2002
Kelly A. Przylepa - revised: 10/4/2000
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 07/02/2013
joanna: 3/1/2011
joanna: 3/4/2003
joanna: 12/20/2002
ckniffin: 12/18/2002
joanna: 12/3/2001
joanna: 11/8/2001
kayiaros: 10/4/2000
*FIELD* CN
Natalie E. Krasikov - updated: 3/22/2004
Cassandra L. Kniffin - updated: 3/17/2004
Cassandra L. Kniffin - reorganized: 12/2/2002
Dawn Watkins-Chow - updated: 11/18/2002
Victor A. McKusick - updated: 9/26/2000
Victor A. McKusick - updated: 11/1/1999
Victor A. McKusick - updated: 4/21/1999
Victor A. McKusick - edited: 10/1/1997
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
carol: 04/22/2013
terry: 4/28/2011
terry: 3/10/2011
mgross: 10/16/2009
tkritzer: 6/3/2005
alopez: 11/23/2004
ckniffin: 8/24/2004
joanna: 8/24/2004
carol: 3/22/2004
ckniffin: 3/17/2004
alopez: 12/3/2002
carol: 12/2/2002
ckniffin: 11/21/2002
cwells: 11/18/2002
carol: 11/18/2002
terry: 9/26/2000
carol: 11/10/1999
terry: 11/1/1999
mgross: 4/23/1999
terry: 4/21/1999
carol: 4/29/1998
terry: 3/27/1998
mark: 10/1/1997
terry: 9/30/1997
mark: 7/16/1997
mark: 9/30/1996
terry: 9/26/1996
mark: 5/31/1996
mark: 5/30/1996
terry: 5/28/1996
terry: 2/6/1996
mark: 1/17/1996
terry: 1/16/1996
mark: 10/5/1995
carol: 1/17/1995
terry: 5/7/1994
warfield: 4/15/1994
mimadm: 2/19/1994
carol: 8/27/1992
MIM
600359
*RECORD*
*FIELD* NO
600359
*FIELD* TI
*600359 POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 1; KCNJ1
;;RENAL OUTER-MEDULLARY POTASSIUM CHANNEL; ROMK; ROMK1;;
read moreKIR1.1
*FIELD* TX
DESCRIPTION
The inward rectifier class of potassium channels controls the resting
potential and membrane excitability. KCNJ1 is an inward-rectifying
apical potassium channel expressed in the thick ascending limb of Henle
and throughout the distal nephron of the kidney.
CLONING
Ho et al. (1993) cloned the rat Romk1 cDNA from kidney and showed that
the predicted protein had only 2 transmembrane domains, in contrast to
the 6 seen in other potassium channels.
Yano et al. (1994) used PCR with primers based on the rat Romk1 sequence
to create a probe from a human kidney cDNA library. The library was then
screened and 2 classes of cDNA were isolated. Two isoforms of KCNJ1,
which they termed ROMK1A (with 389 codons) and ROMK1B (with 372 codons),
differ at their 5-prime ends as a consequence of alternative splicing.
Both isoforms of KCNJ1 were detected in the kidney, but other tissues
only showed the A form. ROMK1A shows 93% similarity to the rat homolog.
Shuck et al. (1994) used the rat kidney Romk1 potassium channel cDNA to
clone the homolog from human kidney. In addition to the human species
homolog of the rat gene, 4 additional transcripts formed by alternative
splicing of a single human gene were also characterized. All 5
transcripts share a common 3-prime exon that encodes the majority of the
channel protein, and in 3 of the isoforms translation is initiated at a
start codon contained within this exon.
Krishnan et al. (1995) identified a novel 308-bp PCR product from human
cerebral cortex mRNA, the expression of which was found to be restricted
to a 3.0-kb band in the kidney by probing a human multiple tissue
Northern blot.
GENE FUNCTION
Inwardly rectifying potassium (Kir) channels are important regulators of
resting membrane potential and cell excitability. The activity of Kir
channels is critically dependent on the integrity of channel
interactions with phosphatidylinositol 4,5-bisphosphate (PIP2). Using
targeted mutations in KCNJ2 (600681) and KCNJ1, which the authors called
Kir2.1 and Kir1.1, Lopes et al. (2002) identified residues important for
PIP2 interaction. Mutations in residues associated with Andersen
syndrome (170390) and Bartter syndrome (241200) decreased the strength
of channel-PIP2 interactions. Lopes et al. (2002) concluded that a
decrease in channel-PIP2 interactions underlies the molecular mechanism
of Andersen and Bartter syndromes when these mutations are present in
patients.
Lin et al. (2005) found that Romk1 immunoprecipitated from rat kidney
cortex and outer medulla was monoubiquitinated. Mutation analysis
indicated that lys22 was the modified residue. Lin et al. (2005)
presented evidence that monoubiquitination of ROMK1 regulates channel
activity by reducing expression of ROMK1 at the cell surface.
He et al. (2007) showed that mammalian Wnk1 (605232) and Wnk4 (601844)
interacted with the endocytic scaffold protein intersectin-1 (ITSN1;
602442) and that these interactions were crucial for stimulation of
Romk1 endocytosis. Stimulation of Romk1 endocytosis by Wnk1 and Wnk4
required their proline-rich motifs, but it did not require their kinase
activities. Pseudohypoaldosteronism II (PHA2B; 614491)-causing mutations
in Wnk4 enhanced the interactions of Wnk4 with Itsn1 and Romk1, leading
to increased endocytosis of Romk1.
MAPPING
Yano et al. (1994) used fluorescence in situ hybridization to map the
ROMK1 gene to chromosome 11q24. Using fluorescence in situ hybridization
to human metaphase chromosomes, Krishnan et al. (1995) confirmed the
mapping of the KCNJ1 gene to 11q.
MOLECULAR GENETICS
Mutations in the sodium/potassium/chloride transporter-2 gene, (SLC12A1;
600839), a mediator of renal salt reabsorption, cause antenatal Bartter
syndrome type 1 (601678), featuring salt wasting, hypokalemic alkalosis,
hypercalciuria, and low blood pressure. SLC12A1 mutations had been
excluded in some Bartter kindreds, prompting examination of regulators
of cotransporter activity. ROMK is believed to be one such regulator; it
is an ATP-sensitive potassium channel that 'recycles' reabsorbed
potassium back to the tubule lumen. In 4 kindreds, Simon et al. (1996)
found mutations in the ROMK gene that cosegregated with antenatal
Bartter syndrome and disrupted ROMK function (600359.0001-600359.0006).
The disorder has since been designated antenatal Bartter syndrome type 2
(241200).
The International Collaborative Study Group for Bartter-like Syndromes
(1997) reported mutations in the KCNJ1 gene (600359.0007-600359.0009) in
3 kindreds and 5 sporadic cases with antenatal Bartter syndrome type 2.
Functional coupling of ROMK and the luminal Na-K-2Cl cotransporter is
crucial for NaCl reabsorption. Therefore, loss of function in ROMK, as
well as in NKCC2, would be predicted to disrupt electrogenic chloride
reabsorption in the medullary thick ascending limb of the loop of Henle.
Schwalbe et al. (1998) introduced 4 mutations associated with antenatal
Bartter syndrome into rat Kcnj1 and characterized the channels expressed
in Sf9 insect cells. Three of the mutations produced channels with
significantly reduced K(+) fluxes; however, the mechanisms in each case
were different and included abnormalities in phosphorylation,
proteolytic processing, and protein trafficking.
Jeck et al. (2001) assessed the functional consequences of 9 different
mutations in the ROMK gene categorized by location: within the core
region, truncation at the cytosolic C terminus, and within putative
promoter elements. Although the majority of the core mutations exhibited
a dominant-negative effect, there was a variable effect on channel
conductance, suggesting a spectrum of mechanisms involved in loss of
channel function.
ANIMAL MODEL
Lorenz et al. (2002) developed Kcnj1-null mice. Young null mutants had
hydronephrosis, were severely dehydrated, and about 95% died before 3
weeks of age. Those that survived beyond weaning grew to adulthood;
however, they had metabolic acidosis, elevated blood concentrations of
Na(+) and Cl(-), reduced blood pressure, polydipsia, polyuria, and poor
urinary concentrating ability. Whole kidney glomerular filtration rate
was reduced, apparently as a result of hydronephrosis, and fractional
excretion of electrolytes was elevated. Micropuncture analysis revealed
that the single nephron glomerular filtration rate was relatively
normal, absorption of NaCl in thick ascending limb of Henle was reduced,
and tubuloglomerular feedback was impaired.
Lu et al. (2002) bred surviving null males from the work reported by
Lorenz et al. (2002) with heterozygous females to enhance survival.
These Kcnj1-null mice showed 25% survival to adulthood. Those that died
showed significant hydronephrosis, whereas surviving null mice did not.
Mutant mice were polyuric and natriuretic with an elevated hematocrit
consistent with mild extracellular volume depletion. Patch-clamp
analysis of cortical collecting ducts and thick ascending limb of
wildtype mice revealed the presence of small-conductance K(+) channel
activity that was missing in mutant mice. Despite the loss of Kcnj1
expression, the normokalemic null mice exhibited significantly increased
kaliuresis, indicating alternative mechanisms for K(+)
absorption/secretion in the nephron.
*FIELD* AV
.0001
BARTTER SYNDROME, ANTENATAL, TYPE 2
KCNJ1, TYR60TER
In a family with antenatal Bartter syndrome type 2 (241200) in which
linkage to the NKCC2 gene was excluded, Simon et al. (1996) found a
tyr60-to-ter nonsense mutation in the KCNJ1 gene. The mutation truncated
the protein prior to the first transmembrane domain. In this family with
first-cousin parents, there were 2 affected children who were homozygous
for the mutation.
.0002
BARTTER SYNDROME, ANTENATAL, TYPE 2
KCNJ1, 1-BP INS, CODON 15
In a consanguineous family in which linkage of antenatal Bartter
syndrome (241200) to the NKCC2 gene was excluded, Simon et al. (1996)
found homozygosity for insertion of a single T into a sequence of 6
consecutive T residues spanning codons 13 and 14, resulting in a
frameshift mutation changing the encoded protein from amino acid 15
onward and resulting in premature termination at codon 54.
.0003
BARTTER SYNDROME, ANTENATAL, TYPE 2
KCNJ1, SER200ARG
By screening 7 antenatal Bartter syndrome (241200) kindreds for ROMK
variants, Simon et al. (1996) found 2 variants in each of 2 outbred
kindreds that had revealed no variants in screening of NKCC2. The
affected individuals were compound heterozygotes. In the BAR208 family,
1 variant resulted in a missense mutation, substituting arginine for
serine at codon 200. The second variant in this kindred was a premature
termination codon at codon 58 (600359.0004), truncating the encoded
protein prior to the first transmembrane domain.
Schwalbe et al. (1998) characterized this mutation in rat Kcnj1
expressed in Sf9 insect cells. Patch clamp recordings indicated a lack
of whole-cell currents, and Western blot analysis revealed 2 proteins
with significantly reduced apparent molecular masses. Schwalbe et al.
(1998) proposed that the introduction of arginine at this site creates a
potential cleavage site for trypsin-like proteases.
.0004
BARTTER SYNDROME, ANTENATAL, TYPE 2
KCNJ1, TRP58TER
See 600359.0004 and Simon et al. (1996).
.0005
BARTTER SYNDROME, ANTENATAL, TYPE 2
KCNJ1, ALA195VAL
In nonconsanguineous family BAR206, Simon et al. (1996) found compound
heterozygosity for mutations in the KCNJ1 gene in members affected by
antenatal Bartter syndrome (241200). One variant represented a 4-bp
deletion, spanning the last base of codon 313 and all of codon 314,
resulting in a frameshift mutation and altering the encoded protein from
amino acid 315 onward and ending at a new stop codon at position 350.
The second variant in this kindred arose from substitution of valine for
alanine at amino acid 195 in the cytoplasmic C-terminal region of ROMK.
Schwalbe et al. (1998) studied this mutation in rat Kcnj1 and determined
that it hindered phosphorylation of a nearby serine and lead to fast
channel rundown.
.0006
BARTTER SYNDROME, ANTENATAL, TYPE 2
KCNJ1, MET338THR
In outbred Bartter syndrome (241200) kindred BAR139 in which no NKCC2
variant had been identified, Simon et al. (1996) identified a single
ROMK variant, substituting threonine for methionine at amino acid 338;
this variant had not been seen on 80 chromosomes from unaffected
subjects. No mutation had been identified on the other ROMK allele in
the affected subject.
.0007
BARTTER SYNDROME, ANTENATAL, TYPE 2
KCNJ1, ALA198THR
In a North African family with antenatal Bartter syndrome (241200)
studied in Paris, the International Collaborative Study Group for
Bartter-like Syndromes (1997) identified a G-to-A transition at
nucleotide 1153 of the KCNJ1 gene, resulting in an ala198-to-thr amino
acid substitution.
.0008
BARTTER SYNDROME, ANTENATAL, TYPE 2
KCNJ1, GLY167GLU
In a family of Indian origin studied in Marburg, Germany, the
International Collaborative Study Group for Bartter-like Syndromes
(1997) found the cause of antenatal Bartter syndrome (241200) to be a
G-to-A transition at nucleotide 1062 of the KCNJ1 gene, resulting in a
gly167-to-glu amino acid substitution.
.0009
BARTTER SYNDROME, ANTENATAL, TYPE 2
KCNJ1, ASP108HIS
In a Turkish family with antenatal Bartter syndrome (241200) studied in
Marburg, Germany, the International Collaborative Study Group for
Bartter-like Syndromes (1997) identified a G-to-C transversion at
nucleotide 883 of the KCNJ1 gene, resulting in an asp108-to-his (D108H)
amino acid substitution, as the cause of antenatal Bartter syndrome.
Derst et al. (1997) analyzed the electrophysiologic function of this
D108H ROMK channel mutation and 4 others: val72glu (V72E), pro110leu
(P110L), ala198-to-thr (A198T; 600359.0007), and val315gly (V315G). In
whole-cell patch-clamp recordings, mutated ROMK1 cDNAs transfected into
COS-7 kidney cells showed either no or only infrequently small currents.
Loss of tubular potassium channel function probably prevents apical
membrane potassium recycling with secondary inhibition of
Na-K-2Cl-cotransport in the thick ascending limb of the Henle loop
(TALH). Derst et al. (1997) concluded that mutations in the potassium
channel ROMK are the primary events causing renal salt wasting in the
subset of patients with the antenatal variant of Bartter syndrome.
.0010
BARTTER SYNDROME, ANTENATAL, TYPE 2
KCNJ1, LYS124ASN
In a sporadic case of the hyperprostaglandin E syndrome (241200), Derst
et al. (1998) described a lys124-to-asn (K124N) missense mutation
located in the extracellular M1-H5 linker region of the KCNJ1 gene. When
heterologously expressed in Xenopus oocytes and mammalian cells, current
amplitudes from mutant Kir1.1a channels were reduced by a factor of
approximately 12 as compared with wildtype. A lysine at the equivalent
position is present in only 1 of the known Kir subunits, the newly
identified Kir1.3, which is also fully expressed in the recombinant
system. When the lysine residue in guinea pig Kir1.3 isolated from a
genomic library was changed to an asparagine, mutant channels yielded
macroscopic currents with amplitudes increased 6 fold. From single
channel analysis, it became apparent that the decrease in mutant Kir1.1
channels and the increase in guinea pig Kir1.3 macroscopic currents were
mainly due to the number of expressed functional channels. Coexpression
experiments revealed a dominant-negative effect of the mutant Kir1.1a on
macroscopic current amplitudes when fully expressed with wildtype
Kir1.1a. Thus, Derst et al. (1998) postulated that in Kir1.3 channels
the extracellular positively charged lysine is of crucial functional
importance. The hyperprostaglandin E syndrome phenotype in man can be
explained by the lower expression of functional channels by the Kir1.1a
unit.
*FIELD* RF
1. Derst, C.; Konrad, M.; Kockerling, A.; Karolyi, L.; Deschenes,
G.; Daut, J.; Karschin, A.; Seyberth, H. W.: Mutations in the ROMK
gene in antenatal Bartter syndrome are associated with impaired K(+)
channel function. Biochem. Biophys. Res. Commun. 203: 641-645, 1997.
2. Derst, C.; Wischmeyer, E.; Preisig-Muller, R.; Spauschus, A.; Konrad,
M.; Hensen, P.; Jeck, N.; Seyberth, H. W.; Daut, J.; Karschin, A.
: A hyperprostaglandin E syndrome mutation in Kir1.1 (renal outer
medullary potassium) channels reveals a crucial residue for channel
function in Kir1.3 channels. J. Biol. Chem. 273: 23884-23891, 1998.
3. He, G.; Wang, H.-R.; Huang, S.-K.; Huang, C.-L.: Intersectin links
WNK kinases to endocytosis of ROMK1. J. Clin. Invest. 117: 1078-1087,
2007.
4. Ho, K.; Nichols, C. G.; Lederer, W. J.; Lytton, J.; Vassilev, P.
M.; Kanazirska, M. V.; Hebert, S. C.: Cloning and expression of an
inwardly rectifying ATP-regulated potassium channel. Nature 362:
31-38, 1993.
5. International Collaborative Study Group for Bartter-like Syndromes
: Mutations in the gene encoding the inwardly-rectifying renal potassium
channel, ROMK, cause the antenatal variant of Bartter syndrome: evidence
for genetic heterogeneity. Hum. Molec. Genet. 6: 17-26, 1997. Note:
Erratum: Hum. Molec. Genet. 6: 650 only, 1997.
6. Jeck, N.; Derst, C.; Wischmeyer, E.; Ott, H.; Weber, S.; Rudin,
C.; Seyberth, H. W.; Daut, J.; Karschin, A.; Konrad, M.: Functional
heterogeneity of ROMK mutations linked to hyperprostaglandin E syndrome. Kidney
Int. 59: 1803-1811, 2001.
7. Krishnan, S. N.; Desai, T.; Ward, D. C.; Haddad, G. G.: Isolation
and chromosomal localization of a human ATP-regulated potassium channel. Hum.
Genet. 96: 155-160, 1995.
8. Lin, D.-H.; Sterling, H.; Wang, Z.; Babilonia, E.; Yang, B.; Dong,
K.; Hebert, S. C.; Giebisch, G.; Wang, W.-H.: ROMK1 channel activity
is regulated by monoubiquitination. Proc. Nat. Acad. Sci. 102: 4306-4311,
2005.
9. Lopes, C. M. B.; Zhang, H.; Rohacs, T.; Jin, T.; Yang, J.; Logothetis,
D. E.: Alterations in conserved Kir channel-PIP(2) interactions underlie
channelopathies. Neuron 34: 933-944, 2002.
10. Lorenz, J. N.; Baird, N. R.; Judd, L. M.; Noonan, W. T.; Andringa,
A.; Doetschman, T.; Manning, P. A.; Liu, L. H.; Miller, M. L.; Shull,
G. E.: Impaired renal NaCl absorption in mice lacking the ROMK potassium
channel, a model for type II Bartter's syndrome. J. Biol. Chem. 277:
37871-37880, 2002.
11. Lu, M.; Wang, T.; Yan, Q.; Yang, X.; Dong, K.; Knepper, M. A.;
Wang, W.; Giebisch, G.; Shull, G. E.; Hebert, S. C.: Absence of small
conductance K(+) channel (SK) activity in apical membranes of thick
ascending limb and cortical collecting duct in ROMK (Bartter's) knockout
mice. J. Biol. Chem. 277: 37881-37887, 2002.
12. Schwalbe, R. A.; Bianchi, L.; Accili, E. A.; Brown, A. M.: Functional
consequences of ROMK mutants linked to antenatal Bartter's syndrome
and implications for treatment. Hum. Molec. Genet. 7: 975-980, 1998.
13. Shuck, M. E.; Bock, J. H.; Benjamin, C. W.; Tsai, T.-D.; Lee,
K. S.; Slightom, J. L.; Bienkowski, M. J.: Cloning and characterization
of multiple forms of the human kidney ROM-K potassium channel. J.
Biol. Chem. 269: 24261-24270, 1994.
14. Simon, D. B.; Karet, F. E.; Rodriguez-Soriano, J.; Hamdan, J.
H.; DiPietro, A.; Trachtman, H.; Sanjad, S. A.: Lifton, R. P.: Genetic
heterogeneity of Bartter's syndrome revealed by mutations in the K(+)
channel, ROMK. Nature Genet. 14: 152-156, 1996.
15. Yano, H.; Philipson, L. H.; Kugler, J. L.; Tokuyama, Y.; Davis,
E. M.; Le Beau, M. M.; Nelson, D. J.; Bell, G. I.; Takeda, J.: Alternative
splicing of human inwardly rectifying K+ channel ROMK1 mRNA. Molec.
Pharm. 45: 854-860, 1994.
*FIELD* CN
Patricia A. Hartz - updated: 10/18/2007
Patricia A. Hartz - updated: 5/9/2005
Cassandra L. Kniffin - updated: 3/17/2004
Patricia A. Hartz - updated: 1/30/2003
Dawn Watkins-Chow - updated: 11/14/2002
Victor A. McKusick - updated: 10/13/1998
Victor A. McKusick - updated: 2/27/1998
Victor A. McKusick - updated: 2/12/1997
Alan F. Scott - updated: 7/10/1995
*FIELD* CD
Victor A. McKusick: 1/31/1995
*FIELD* ED
carol: 12/20/2013
carol: 4/22/2013
alopez: 2/27/2012
alopez: 4/6/2011
terry: 7/29/2008
mgross: 10/18/2007
terry: 10/18/2007
tkritzer: 6/3/2005
mgross: 5/10/2005
terry: 5/9/2005
terry: 4/4/2005
carol: 3/22/2004
ckniffin: 3/17/2004
mgross: 2/4/2003
terry: 1/30/2003
alopez: 12/3/2002
carol: 12/2/2002
ckniffin: 11/21/2002
cwells: 11/14/2002
carol: 3/14/2002
alopez: 10/27/1998
carol: 10/18/1998
terry: 10/13/1998
alopez: 3/23/1998
terry: 2/27/1998
mark: 1/10/1998
alopez: 7/30/1997
alopez: 7/10/1997
alopez: 7/8/1997
jenny: 4/1/1997
terry: 3/27/1997
terry: 2/12/1997
terry: 2/7/1997
mark: 9/30/1996
terry: 9/26/1996
mark: 10/10/1995
terry: 7/28/1995
mark: 5/23/1995
carol: 2/1/1995
*RECORD*
*FIELD* NO
600359
*FIELD* TI
*600359 POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 1; KCNJ1
;;RENAL OUTER-MEDULLARY POTASSIUM CHANNEL; ROMK; ROMK1;;
read moreKIR1.1
*FIELD* TX
DESCRIPTION
The inward rectifier class of potassium channels controls the resting
potential and membrane excitability. KCNJ1 is an inward-rectifying
apical potassium channel expressed in the thick ascending limb of Henle
and throughout the distal nephron of the kidney.
CLONING
Ho et al. (1993) cloned the rat Romk1 cDNA from kidney and showed that
the predicted protein had only 2 transmembrane domains, in contrast to
the 6 seen in other potassium channels.
Yano et al. (1994) used PCR with primers based on the rat Romk1 sequence
to create a probe from a human kidney cDNA library. The library was then
screened and 2 classes of cDNA were isolated. Two isoforms of KCNJ1,
which they termed ROMK1A (with 389 codons) and ROMK1B (with 372 codons),
differ at their 5-prime ends as a consequence of alternative splicing.
Both isoforms of KCNJ1 were detected in the kidney, but other tissues
only showed the A form. ROMK1A shows 93% similarity to the rat homolog.
Shuck et al. (1994) used the rat kidney Romk1 potassium channel cDNA to
clone the homolog from human kidney. In addition to the human species
homolog of the rat gene, 4 additional transcripts formed by alternative
splicing of a single human gene were also characterized. All 5
transcripts share a common 3-prime exon that encodes the majority of the
channel protein, and in 3 of the isoforms translation is initiated at a
start codon contained within this exon.
Krishnan et al. (1995) identified a novel 308-bp PCR product from human
cerebral cortex mRNA, the expression of which was found to be restricted
to a 3.0-kb band in the kidney by probing a human multiple tissue
Northern blot.
GENE FUNCTION
Inwardly rectifying potassium (Kir) channels are important regulators of
resting membrane potential and cell excitability. The activity of Kir
channels is critically dependent on the integrity of channel
interactions with phosphatidylinositol 4,5-bisphosphate (PIP2). Using
targeted mutations in KCNJ2 (600681) and KCNJ1, which the authors called
Kir2.1 and Kir1.1, Lopes et al. (2002) identified residues important for
PIP2 interaction. Mutations in residues associated with Andersen
syndrome (170390) and Bartter syndrome (241200) decreased the strength
of channel-PIP2 interactions. Lopes et al. (2002) concluded that a
decrease in channel-PIP2 interactions underlies the molecular mechanism
of Andersen and Bartter syndromes when these mutations are present in
patients.
Lin et al. (2005) found that Romk1 immunoprecipitated from rat kidney
cortex and outer medulla was monoubiquitinated. Mutation analysis
indicated that lys22 was the modified residue. Lin et al. (2005)
presented evidence that monoubiquitination of ROMK1 regulates channel
activity by reducing expression of ROMK1 at the cell surface.
He et al. (2007) showed that mammalian Wnk1 (605232) and Wnk4 (601844)
interacted with the endocytic scaffold protein intersectin-1 (ITSN1;
602442) and that these interactions were crucial for stimulation of
Romk1 endocytosis. Stimulation of Romk1 endocytosis by Wnk1 and Wnk4
required their proline-rich motifs, but it did not require their kinase
activities. Pseudohypoaldosteronism II (PHA2B; 614491)-causing mutations
in Wnk4 enhanced the interactions of Wnk4 with Itsn1 and Romk1, leading
to increased endocytosis of Romk1.
MAPPING
Yano et al. (1994) used fluorescence in situ hybridization to map the
ROMK1 gene to chromosome 11q24. Using fluorescence in situ hybridization
to human metaphase chromosomes, Krishnan et al. (1995) confirmed the
mapping of the KCNJ1 gene to 11q.
MOLECULAR GENETICS
Mutations in the sodium/potassium/chloride transporter-2 gene, (SLC12A1;
600839), a mediator of renal salt reabsorption, cause antenatal Bartter
syndrome type 1 (601678), featuring salt wasting, hypokalemic alkalosis,
hypercalciuria, and low blood pressure. SLC12A1 mutations had been
excluded in some Bartter kindreds, prompting examination of regulators
of cotransporter activity. ROMK is believed to be one such regulator; it
is an ATP-sensitive potassium channel that 'recycles' reabsorbed
potassium back to the tubule lumen. In 4 kindreds, Simon et al. (1996)
found mutations in the ROMK gene that cosegregated with antenatal
Bartter syndrome and disrupted ROMK function (600359.0001-600359.0006).
The disorder has since been designated antenatal Bartter syndrome type 2
(241200).
The International Collaborative Study Group for Bartter-like Syndromes
(1997) reported mutations in the KCNJ1 gene (600359.0007-600359.0009) in
3 kindreds and 5 sporadic cases with antenatal Bartter syndrome type 2.
Functional coupling of ROMK and the luminal Na-K-2Cl cotransporter is
crucial for NaCl reabsorption. Therefore, loss of function in ROMK, as
well as in NKCC2, would be predicted to disrupt electrogenic chloride
reabsorption in the medullary thick ascending limb of the loop of Henle.
Schwalbe et al. (1998) introduced 4 mutations associated with antenatal
Bartter syndrome into rat Kcnj1 and characterized the channels expressed
in Sf9 insect cells. Three of the mutations produced channels with
significantly reduced K(+) fluxes; however, the mechanisms in each case
were different and included abnormalities in phosphorylation,
proteolytic processing, and protein trafficking.
Jeck et al. (2001) assessed the functional consequences of 9 different
mutations in the ROMK gene categorized by location: within the core
region, truncation at the cytosolic C terminus, and within putative
promoter elements. Although the majority of the core mutations exhibited
a dominant-negative effect, there was a variable effect on channel
conductance, suggesting a spectrum of mechanisms involved in loss of
channel function.
ANIMAL MODEL
Lorenz et al. (2002) developed Kcnj1-null mice. Young null mutants had
hydronephrosis, were severely dehydrated, and about 95% died before 3
weeks of age. Those that survived beyond weaning grew to adulthood;
however, they had metabolic acidosis, elevated blood concentrations of
Na(+) and Cl(-), reduced blood pressure, polydipsia, polyuria, and poor
urinary concentrating ability. Whole kidney glomerular filtration rate
was reduced, apparently as a result of hydronephrosis, and fractional
excretion of electrolytes was elevated. Micropuncture analysis revealed
that the single nephron glomerular filtration rate was relatively
normal, absorption of NaCl in thick ascending limb of Henle was reduced,
and tubuloglomerular feedback was impaired.
Lu et al. (2002) bred surviving null males from the work reported by
Lorenz et al. (2002) with heterozygous females to enhance survival.
These Kcnj1-null mice showed 25% survival to adulthood. Those that died
showed significant hydronephrosis, whereas surviving null mice did not.
Mutant mice were polyuric and natriuretic with an elevated hematocrit
consistent with mild extracellular volume depletion. Patch-clamp
analysis of cortical collecting ducts and thick ascending limb of
wildtype mice revealed the presence of small-conductance K(+) channel
activity that was missing in mutant mice. Despite the loss of Kcnj1
expression, the normokalemic null mice exhibited significantly increased
kaliuresis, indicating alternative mechanisms for K(+)
absorption/secretion in the nephron.
*FIELD* AV
.0001
BARTTER SYNDROME, ANTENATAL, TYPE 2
KCNJ1, TYR60TER
In a family with antenatal Bartter syndrome type 2 (241200) in which
linkage to the NKCC2 gene was excluded, Simon et al. (1996) found a
tyr60-to-ter nonsense mutation in the KCNJ1 gene. The mutation truncated
the protein prior to the first transmembrane domain. In this family with
first-cousin parents, there were 2 affected children who were homozygous
for the mutation.
.0002
BARTTER SYNDROME, ANTENATAL, TYPE 2
KCNJ1, 1-BP INS, CODON 15
In a consanguineous family in which linkage of antenatal Bartter
syndrome (241200) to the NKCC2 gene was excluded, Simon et al. (1996)
found homozygosity for insertion of a single T into a sequence of 6
consecutive T residues spanning codons 13 and 14, resulting in a
frameshift mutation changing the encoded protein from amino acid 15
onward and resulting in premature termination at codon 54.
.0003
BARTTER SYNDROME, ANTENATAL, TYPE 2
KCNJ1, SER200ARG
By screening 7 antenatal Bartter syndrome (241200) kindreds for ROMK
variants, Simon et al. (1996) found 2 variants in each of 2 outbred
kindreds that had revealed no variants in screening of NKCC2. The
affected individuals were compound heterozygotes. In the BAR208 family,
1 variant resulted in a missense mutation, substituting arginine for
serine at codon 200. The second variant in this kindred was a premature
termination codon at codon 58 (600359.0004), truncating the encoded
protein prior to the first transmembrane domain.
Schwalbe et al. (1998) characterized this mutation in rat Kcnj1
expressed in Sf9 insect cells. Patch clamp recordings indicated a lack
of whole-cell currents, and Western blot analysis revealed 2 proteins
with significantly reduced apparent molecular masses. Schwalbe et al.
(1998) proposed that the introduction of arginine at this site creates a
potential cleavage site for trypsin-like proteases.
.0004
BARTTER SYNDROME, ANTENATAL, TYPE 2
KCNJ1, TRP58TER
See 600359.0004 and Simon et al. (1996).
.0005
BARTTER SYNDROME, ANTENATAL, TYPE 2
KCNJ1, ALA195VAL
In nonconsanguineous family BAR206, Simon et al. (1996) found compound
heterozygosity for mutations in the KCNJ1 gene in members affected by
antenatal Bartter syndrome (241200). One variant represented a 4-bp
deletion, spanning the last base of codon 313 and all of codon 314,
resulting in a frameshift mutation and altering the encoded protein from
amino acid 315 onward and ending at a new stop codon at position 350.
The second variant in this kindred arose from substitution of valine for
alanine at amino acid 195 in the cytoplasmic C-terminal region of ROMK.
Schwalbe et al. (1998) studied this mutation in rat Kcnj1 and determined
that it hindered phosphorylation of a nearby serine and lead to fast
channel rundown.
.0006
BARTTER SYNDROME, ANTENATAL, TYPE 2
KCNJ1, MET338THR
In outbred Bartter syndrome (241200) kindred BAR139 in which no NKCC2
variant had been identified, Simon et al. (1996) identified a single
ROMK variant, substituting threonine for methionine at amino acid 338;
this variant had not been seen on 80 chromosomes from unaffected
subjects. No mutation had been identified on the other ROMK allele in
the affected subject.
.0007
BARTTER SYNDROME, ANTENATAL, TYPE 2
KCNJ1, ALA198THR
In a North African family with antenatal Bartter syndrome (241200)
studied in Paris, the International Collaborative Study Group for
Bartter-like Syndromes (1997) identified a G-to-A transition at
nucleotide 1153 of the KCNJ1 gene, resulting in an ala198-to-thr amino
acid substitution.
.0008
BARTTER SYNDROME, ANTENATAL, TYPE 2
KCNJ1, GLY167GLU
In a family of Indian origin studied in Marburg, Germany, the
International Collaborative Study Group for Bartter-like Syndromes
(1997) found the cause of antenatal Bartter syndrome (241200) to be a
G-to-A transition at nucleotide 1062 of the KCNJ1 gene, resulting in a
gly167-to-glu amino acid substitution.
.0009
BARTTER SYNDROME, ANTENATAL, TYPE 2
KCNJ1, ASP108HIS
In a Turkish family with antenatal Bartter syndrome (241200) studied in
Marburg, Germany, the International Collaborative Study Group for
Bartter-like Syndromes (1997) identified a G-to-C transversion at
nucleotide 883 of the KCNJ1 gene, resulting in an asp108-to-his (D108H)
amino acid substitution, as the cause of antenatal Bartter syndrome.
Derst et al. (1997) analyzed the electrophysiologic function of this
D108H ROMK channel mutation and 4 others: val72glu (V72E), pro110leu
(P110L), ala198-to-thr (A198T; 600359.0007), and val315gly (V315G). In
whole-cell patch-clamp recordings, mutated ROMK1 cDNAs transfected into
COS-7 kidney cells showed either no or only infrequently small currents.
Loss of tubular potassium channel function probably prevents apical
membrane potassium recycling with secondary inhibition of
Na-K-2Cl-cotransport in the thick ascending limb of the Henle loop
(TALH). Derst et al. (1997) concluded that mutations in the potassium
channel ROMK are the primary events causing renal salt wasting in the
subset of patients with the antenatal variant of Bartter syndrome.
.0010
BARTTER SYNDROME, ANTENATAL, TYPE 2
KCNJ1, LYS124ASN
In a sporadic case of the hyperprostaglandin E syndrome (241200), Derst
et al. (1998) described a lys124-to-asn (K124N) missense mutation
located in the extracellular M1-H5 linker region of the KCNJ1 gene. When
heterologously expressed in Xenopus oocytes and mammalian cells, current
amplitudes from mutant Kir1.1a channels were reduced by a factor of
approximately 12 as compared with wildtype. A lysine at the equivalent
position is present in only 1 of the known Kir subunits, the newly
identified Kir1.3, which is also fully expressed in the recombinant
system. When the lysine residue in guinea pig Kir1.3 isolated from a
genomic library was changed to an asparagine, mutant channels yielded
macroscopic currents with amplitudes increased 6 fold. From single
channel analysis, it became apparent that the decrease in mutant Kir1.1
channels and the increase in guinea pig Kir1.3 macroscopic currents were
mainly due to the number of expressed functional channels. Coexpression
experiments revealed a dominant-negative effect of the mutant Kir1.1a on
macroscopic current amplitudes when fully expressed with wildtype
Kir1.1a. Thus, Derst et al. (1998) postulated that in Kir1.3 channels
the extracellular positively charged lysine is of crucial functional
importance. The hyperprostaglandin E syndrome phenotype in man can be
explained by the lower expression of functional channels by the Kir1.1a
unit.
*FIELD* RF
1. Derst, C.; Konrad, M.; Kockerling, A.; Karolyi, L.; Deschenes,
G.; Daut, J.; Karschin, A.; Seyberth, H. W.: Mutations in the ROMK
gene in antenatal Bartter syndrome are associated with impaired K(+)
channel function. Biochem. Biophys. Res. Commun. 203: 641-645, 1997.
2. Derst, C.; Wischmeyer, E.; Preisig-Muller, R.; Spauschus, A.; Konrad,
M.; Hensen, P.; Jeck, N.; Seyberth, H. W.; Daut, J.; Karschin, A.
: A hyperprostaglandin E syndrome mutation in Kir1.1 (renal outer
medullary potassium) channels reveals a crucial residue for channel
function in Kir1.3 channels. J. Biol. Chem. 273: 23884-23891, 1998.
3. He, G.; Wang, H.-R.; Huang, S.-K.; Huang, C.-L.: Intersectin links
WNK kinases to endocytosis of ROMK1. J. Clin. Invest. 117: 1078-1087,
2007.
4. Ho, K.; Nichols, C. G.; Lederer, W. J.; Lytton, J.; Vassilev, P.
M.; Kanazirska, M. V.; Hebert, S. C.: Cloning and expression of an
inwardly rectifying ATP-regulated potassium channel. Nature 362:
31-38, 1993.
5. International Collaborative Study Group for Bartter-like Syndromes
: Mutations in the gene encoding the inwardly-rectifying renal potassium
channel, ROMK, cause the antenatal variant of Bartter syndrome: evidence
for genetic heterogeneity. Hum. Molec. Genet. 6: 17-26, 1997. Note:
Erratum: Hum. Molec. Genet. 6: 650 only, 1997.
6. Jeck, N.; Derst, C.; Wischmeyer, E.; Ott, H.; Weber, S.; Rudin,
C.; Seyberth, H. W.; Daut, J.; Karschin, A.; Konrad, M.: Functional
heterogeneity of ROMK mutations linked to hyperprostaglandin E syndrome. Kidney
Int. 59: 1803-1811, 2001.
7. Krishnan, S. N.; Desai, T.; Ward, D. C.; Haddad, G. G.: Isolation
and chromosomal localization of a human ATP-regulated potassium channel. Hum.
Genet. 96: 155-160, 1995.
8. Lin, D.-H.; Sterling, H.; Wang, Z.; Babilonia, E.; Yang, B.; Dong,
K.; Hebert, S. C.; Giebisch, G.; Wang, W.-H.: ROMK1 channel activity
is regulated by monoubiquitination. Proc. Nat. Acad. Sci. 102: 4306-4311,
2005.
9. Lopes, C. M. B.; Zhang, H.; Rohacs, T.; Jin, T.; Yang, J.; Logothetis,
D. E.: Alterations in conserved Kir channel-PIP(2) interactions underlie
channelopathies. Neuron 34: 933-944, 2002.
10. Lorenz, J. N.; Baird, N. R.; Judd, L. M.; Noonan, W. T.; Andringa,
A.; Doetschman, T.; Manning, P. A.; Liu, L. H.; Miller, M. L.; Shull,
G. E.: Impaired renal NaCl absorption in mice lacking the ROMK potassium
channel, a model for type II Bartter's syndrome. J. Biol. Chem. 277:
37871-37880, 2002.
11. Lu, M.; Wang, T.; Yan, Q.; Yang, X.; Dong, K.; Knepper, M. A.;
Wang, W.; Giebisch, G.; Shull, G. E.; Hebert, S. C.: Absence of small
conductance K(+) channel (SK) activity in apical membranes of thick
ascending limb and cortical collecting duct in ROMK (Bartter's) knockout
mice. J. Biol. Chem. 277: 37881-37887, 2002.
12. Schwalbe, R. A.; Bianchi, L.; Accili, E. A.; Brown, A. M.: Functional
consequences of ROMK mutants linked to antenatal Bartter's syndrome
and implications for treatment. Hum. Molec. Genet. 7: 975-980, 1998.
13. Shuck, M. E.; Bock, J. H.; Benjamin, C. W.; Tsai, T.-D.; Lee,
K. S.; Slightom, J. L.; Bienkowski, M. J.: Cloning and characterization
of multiple forms of the human kidney ROM-K potassium channel. J.
Biol. Chem. 269: 24261-24270, 1994.
14. Simon, D. B.; Karet, F. E.; Rodriguez-Soriano, J.; Hamdan, J.
H.; DiPietro, A.; Trachtman, H.; Sanjad, S. A.: Lifton, R. P.: Genetic
heterogeneity of Bartter's syndrome revealed by mutations in the K(+)
channel, ROMK. Nature Genet. 14: 152-156, 1996.
15. Yano, H.; Philipson, L. H.; Kugler, J. L.; Tokuyama, Y.; Davis,
E. M.; Le Beau, M. M.; Nelson, D. J.; Bell, G. I.; Takeda, J.: Alternative
splicing of human inwardly rectifying K+ channel ROMK1 mRNA. Molec.
Pharm. 45: 854-860, 1994.
*FIELD* CN
Patricia A. Hartz - updated: 10/18/2007
Patricia A. Hartz - updated: 5/9/2005
Cassandra L. Kniffin - updated: 3/17/2004
Patricia A. Hartz - updated: 1/30/2003
Dawn Watkins-Chow - updated: 11/14/2002
Victor A. McKusick - updated: 10/13/1998
Victor A. McKusick - updated: 2/27/1998
Victor A. McKusick - updated: 2/12/1997
Alan F. Scott - updated: 7/10/1995
*FIELD* CD
Victor A. McKusick: 1/31/1995
*FIELD* ED
carol: 12/20/2013
carol: 4/22/2013
alopez: 2/27/2012
alopez: 4/6/2011
terry: 7/29/2008
mgross: 10/18/2007
terry: 10/18/2007
tkritzer: 6/3/2005
mgross: 5/10/2005
terry: 5/9/2005
terry: 4/4/2005
carol: 3/22/2004
ckniffin: 3/17/2004
mgross: 2/4/2003
terry: 1/30/2003
alopez: 12/3/2002
carol: 12/2/2002
ckniffin: 11/21/2002
cwells: 11/14/2002
carol: 3/14/2002
alopez: 10/27/1998
carol: 10/18/1998
terry: 10/13/1998
alopez: 3/23/1998
terry: 2/27/1998
mark: 1/10/1998
alopez: 7/30/1997
alopez: 7/10/1997
alopez: 7/8/1997
jenny: 4/1/1997
terry: 3/27/1997
terry: 2/12/1997
terry: 2/7/1997
mark: 9/30/1996
terry: 9/26/1996
mark: 10/10/1995
terry: 7/28/1995
mark: 5/23/1995
carol: 2/1/1995