RBCC Red Blood Cell Collection

SLC12A6 (KCC3) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Solute carrier family 12 member 6 (Electroneutral potassium-chloride cotransporter 3; K-Cl cotransporter 3)

UniProt Q9UHW9
ID S12A6_HUMAN Reviewed; 1150 AA.
AC Q9UHW9; A0AV76; Q2VI00; Q7Z2E7; Q7Z4G5; Q8TDD4; Q9UFR2; Q9Y642;
read moreAC Q9Y665;
DT 13-DEC-2002, integrated into UniProtKB/Swiss-Prot.
DT 13-DEC-2002, sequence version 2.
DT 22-JAN-2014, entry version 135.
DE RecName: Full=Solute carrier family 12 member 6;
DE AltName: Full=Electroneutral potassium-chloride cotransporter 3;
DE AltName: Full=K-Cl cotransporter 3;
GN Name=SLC12A6; Synonyms=KCC3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TOPOLOGY.
RC TISSUE=Placenta;
RX PubMed=10600773;
RA Race J.E., Makhlouf F.N., Logue P.J., Wilson F.H., Dunham P.B.,
RA Holtzman E.J.;
RT "Molecular cloning and functional characterization of KCC3, a new K-Cl
RT cotransporter.";
RL Am. J. Physiol. 277:C1210-C1219(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), GLYCOSYLATION, AND REGULATION
RP BY VEGF AND TNF.
RC TISSUE=Umbilical vein;
RX PubMed=10187864; DOI=10.1074/jbc.274.15.10661;
RA Hiki K., D'Andrea R.J., Furze J., Crawford J., Woollatt E.,
RA Sutherland G.R., Vadas M.A., Gamble J.R.;
RT "Cloning, characterization, and chromosomal location of a novel human
RT K+-Cl- cotransporter.";
RL J. Biol. Chem. 274:10661-10667(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=10347194; DOI=10.1074/jbc.274.23.16355;
RA Mount D.B., Mercado A., Song L., Xu J., George A.L. Jr., Delpire E.,
RA Gamba G.;
RT "Cloning and characterization of KCC3 and KCC4, new members of the
RT cation-chloride cotransporter gene family.";
RL J. Biol. Chem. 274:16355-16362(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING (ISOFORMS 1
RP AND 2), GLYCOSYLATION, AND DISEASE.
RX PubMed=12368912; DOI=10.1038/ng1002;
RA Howard H.C., Mount D.B., Rochefort D., Byun N., Dupre N., Lu J.,
RA Fan X., Song L., Riviere J.-B., Prevost C., Horst J., Simonati A.,
RA Lemcke B., Welch R., England R., Zhan F.Q., Mercado A., Siesser W.B.,
RA George A.L. Jr., McDonald M.P., Bouchard J.-P., Mathieu J.,
RA Delpire E., Rouleau G.A.;
RT "The K-Cl cotransporter KCC3 is mutant in a severe peripheral
RT neuropathy associated with agenesis of the corpus callosum.";
RL Nat. Genet. 32:384-392(2002).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3; 4; 5), ALTERNATIVE SPLICING
RP (ISOFORM 6), ALTERNATIVE PROMOTER USAGE, TISSUE SPECIFICITY, AND
RP BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=16048901; DOI=10.1152/ajprenal.00464.2004;
RA Mercado A., Vazquez N., Song L., Cortes R., Enck A.H., Welch R.,
RA Delpire E., Gamba G., Mount D.B.;
RT "NH2-terminal heterogeneity in the KCC3 K+-Cl- cotransporter.";
RL Am. J. Physiol. 289:F1246-1261(2005).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Uterus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R.,
RA Fahey J., Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G.,
RA Johnson E., Jones C., Kamat A., Kaur A., Locke D.P., Madan A.,
RA Munson G., Jaffe D.B., Lui A., Macdonald P., Mauceli E., Naylor J.W.,
RA Nesbitt R., Nicol R., O'Leary S.B., Ratcliffe A., Rounsley S., She X.,
RA Sneddon K.M.B., Stewart S., Sougnez C., Stone S.M., Topham K.,
RA Vincent D., Wang S., Zimmer A.R., Birren B.W., Hood L., Lander E.S.,
RA Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human
RT chromosome 15.";
RL Nature 440:671-675(2006).
RN [8]
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 [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
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 [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 70-1150 (ISOFORM 1).
RC TISSUE=Testis;
RA Guo J.H., Yu L.;
RL Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 137-1150 (ISOFORM 1).
RC TISSUE=Testis;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [12]
RP SUBUNIT.
RX PubMed=11551954; DOI=10.1074/jbc.M107155200;
RA Casula S., Shmukler B.E., Wilhelm S., Stuart-Tilley A.K., Su W.,
RA Chernova M.N., Brugnara C., Alper S.L.;
RT "A dominant negative mutant of the KCC1 K-Cl cotransporter: both N-
RT and C-terminal cytoplasmic domains are required for K-Cl cotransport
RT activity.";
RL J. Biol. Chem. 276:41870-41878(2001).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1032, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-32, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [15]
RP ENZYME REGULATION.
RX PubMed=21613606; DOI=10.1152/ajpcell.00070.2011;
RA Cruz-Rangel S., Melo Z., Vazquez N., Meade P., Bobadilla N.A.,
RA Pasantes-Morales H., Gamba G., Mercado A.;
RT "Similar Effects of all WNK3 Variants upon SLC12 Cotransporters.";
RL Am. J. Physiol. 301:C601-C608(2011).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1032, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
CC -!- FUNCTION: Mediates electroneutral potassium-chloride cotransport.
CC May be activated by cell swelling. May contribute to cell volume
CC homeostasis in single cells.
CC -!- ENZYME REGULATION: Activated by N-ethylmaleimide (NEM). Inhibited
CC by DIOA, bumetanide and furosemide. Inhibited by WNK3.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=10.7 mM for extracellular Rb(+) (isoform 1);
CC KM=7.3 mM for extracellular Cl(-) (isoform 1);
CC KM=17.2 mM for extracellular Rb(+) (isoform 2);
CC KM=8.2 mM for extracellular Cl(-) (isoform 2);
CC -!- SUBUNIT: Homomultimer and heteromultimer with other K-Cl
CC cotransporters (By similarity).
CC -!- SUBCELLULAR LOCATION: Basolateral cell membrane; Multi-pass
CC membrane protein (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative promoter usage, Alternative splicing; Named isoforms=6;
CC Name=1; Synonyms=KCC3a;
CC IsoId=Q9UHW9-1; Sequence=Displayed;
CC Name=2; Synonyms=KCC3b;
CC IsoId=Q9UHW9-2; Sequence=VSP_006115, VSP_006116;
CC Note=Produced by alternative promoter usage;
CC Name=3; Synonyms=KCC3a-X2M;
CC IsoId=Q9UHW9-3; Sequence=VSP_041389;
CC Note=Does not differ in the osmotic set point of swelling
CC activation but, activation is more rapid;
CC Name=4; Synonyms=KCC3a-S3;
CC IsoId=Q9UHW9-4; Sequence=VSP_041388;
CC Name=5; Synonyms=KCC3a-S, KCC3a-S1, KCC3a-S2;
CC IsoId=Q9UHW9-5; Sequence=VSP_041387;
CC Note=Does not differ in the osmotic set point of swelling
CC activation but, activation is more rapid;
CC Name=6; Synonyms=KCC3b-X2M;
CC IsoId=Q9UHW9-6; Sequence=VSP_006115, VSP_006116, VSP_041389;
CC -!- TISSUE SPECIFICITY: Highly expressed in heart, brain and kidney.
CC Detected at lower levels in skeletal muscle, placenta, lung and
CC pancreas. Detected in umbilical vein endothelial cells. Isoform 2
CC is more abundant in kidney. Isoform 5 is testis specific.
CC Expressed in the proximal tubule of the kidney (at protein level).
CC -!- INDUCTION: Up-regulated by VEGF. Down-regulated by TNF.
CC -!- PTM: N-glycosylated.
CC -!- DISEASE: Agenesis of the corpus callosum, with peripheral
CC neuropathy (ACCPN) [MIM:218000]: A disease that is characterized
CC by severe progressive sensorimotor neuropathy, mental retardation,
CC dysmorphic features and complete or partial agenesis of the corpus
CC callosum. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the SLC12A transporter family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/SLC12A6";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF116242; AAF24986.1; -; mRNA.
DR EMBL; AF108831; AAD25337.1; -; mRNA.
DR EMBL; AF105366; AAD39742.1; -; mRNA.
DR EMBL; AF314956; AAM96215.1; -; Genomic_DNA.
DR EMBL; AF314931; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314933; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314934; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314935; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314936; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314937; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314938; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314939; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314940; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314941; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314942; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314943; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314944; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314945; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314946; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314947; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314948; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314949; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314950; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314951; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314952; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314953; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314954; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314955; AAM96215.1; JOINED; Genomic_DNA.
DR EMBL; AF314956; AAM96216.1; -; Genomic_DNA.
DR EMBL; AF314932; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314933; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314934; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314935; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314936; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314937; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314938; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314939; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314940; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314941; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314942; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314943; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314944; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314945; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314946; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314947; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314948; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314949; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314950; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314951; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314952; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314953; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314954; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF314955; AAM96216.1; JOINED; Genomic_DNA.
DR EMBL; AF531258; AAQ10026.1; -; mRNA.
DR EMBL; AF531259; AAQ10027.1; -; mRNA.
DR EMBL; AF531260; AAQ10028.1; -; mRNA.
DR EMBL; DQ138323; ABA02873.1; -; mRNA.
DR EMBL; AK315283; BAG37692.1; -; mRNA.
DR EMBL; AC021822; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC079203; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471125; EAW92295.1; -; Genomic_DNA.
DR EMBL; CH471125; EAW92297.1; -; Genomic_DNA.
DR EMBL; CH471125; EAW92301.1; -; Genomic_DNA.
DR EMBL; BC126241; AAI26242.1; -; mRNA.
DR EMBL; BC126243; AAI26244.1; -; mRNA.
DR EMBL; AF477977; AAL85335.1; -; mRNA.
DR EMBL; AL117500; CAB55965.1; -; mRNA.
DR PIR; T17275; T17275.
DR RefSeq; NP_001035959.1; NM_001042494.1.
DR RefSeq; NP_001035960.1; NM_001042495.1.
DR RefSeq; NP_001035961.1; NM_001042496.1.
DR RefSeq; NP_001035962.1; NM_001042497.1.
DR RefSeq; NP_005126.1; NM_005135.2.
DR RefSeq; NP_598408.1; NM_133647.1.
DR RefSeq; XP_005254874.1; XM_005254817.1.
DR RefSeq; XP_005254875.1; XM_005254818.1.
DR RefSeq; XP_005254877.1; XM_005254820.1.
DR RefSeq; XP_005254878.1; XM_005254821.1.
DR UniGene; Hs.510939; -.
DR ProteinModelPortal; Q9UHW9; -.
DR SMR; Q9UHW9; 469-660.
DR IntAct; Q9UHW9; 2.
DR STRING; 9606.ENSP00000346112; -.
DR DrugBank; DB00761; Potassium Chloride.
DR GuidetoPHARMACOLOGY; 973; -.
DR TCDB; 2.A.30.5.3; the cation-chloride cotransporter (ccc) family.
DR PhosphoSite; Q9UHW9; -.
DR DMDM; 27151690; -.
DR PaxDb; Q9UHW9; -.
DR PRIDE; Q9UHW9; -.
DR Ensembl; ENST00000290209; ENSP00000290209; ENSG00000140199.
DR Ensembl; ENST00000354181; ENSP00000346112; ENSG00000140199.
DR Ensembl; ENST00000397702; ENSP00000380814; ENSG00000140199.
DR Ensembl; ENST00000397707; ENSP00000380819; ENSG00000140199.
DR Ensembl; ENST00000458406; ENSP00000387725; ENSG00000140199.
DR Ensembl; ENST00000558589; ENSP00000452776; ENSG00000140199.
DR Ensembl; ENST00000558667; ENSP00000453473; ENSG00000140199.
DR Ensembl; ENST00000560611; ENSP00000454168; ENSG00000140199.
DR GeneID; 9990; -.
DR KEGG; hsa:9990; -.
DR UCSC; uc001zhw.3; human.
DR CTD; 9990; -.
DR GeneCards; GC15M034522; -.
DR HGNC; HGNC:10914; SLC12A6.
DR HPA; HPA034563; -.
DR MIM; 218000; phenotype.
DR MIM; 604878; gene.
DR neXtProt; NX_Q9UHW9; -.
DR Orphanet; 1496; Corpus callosum agenesis - neuronopathy.
DR PharmGKB; PA35808; -.
DR eggNOG; COG0531; -.
DR HOGENOM; HOG000092644; -.
DR HOVERGEN; HBG052852; -.
DR InParanoid; Q9UHW9; -.
DR KO; K14427; -.
DR OMA; NNMTVPS; -.
DR OrthoDB; EOG78M01J; -.
DR PhylomeDB; Q9UHW9; -.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR ChiTaRS; SLC12A6; human.
DR GeneWiki; SLC12A6; -.
DR GenomeRNAi; 9990; -.
DR NextBio; 37729; -.
DR PRO; PR:Q9UHW9; -.
DR ArrayExpress; Q9UHW9; -.
DR Bgee; Q9UHW9; -.
DR CleanEx; HS_SLC12A6; -.
DR Genevestigator; Q9UHW9; -.
DR GO; GO:0016323; C:basolateral plasma membrane; ISS:UniProtKB.
DR GO; GO:0016021; C:integral to membrane; NAS:UniProtKB.
DR GO; GO:0015379; F:potassium:chloride symporter activity; IDA:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; NAS:UniProtKB.
DR GO; GO:0071477; P:cellular hypotonic salinity response; IDA:UniProtKB.
DR GO; GO:0006813; P:potassium ion transport; IEA:UniProtKB-KW.
DR InterPro; IPR004841; AA-permease/SLC12A_dom.
DR InterPro; IPR018491; K/Cl_cotranspt_1/3.
DR InterPro; IPR000076; KCL_cotranspt.
DR InterPro; IPR004842; Na/K/Cl_cotransptS.
DR Pfam; PF00324; AA_permease; 2.
DR Pfam; PF03522; KCl_Cotrans_1; 1.
DR PRINTS; PR01081; KCLTRNSPORT.
DR TIGRFAMs; TIGR00930; 2a30; 1.
PE 1: Evidence at protein level;
KW Alternative promoter usage; Alternative splicing; Cell membrane;
KW Complete proteome; Glycoprotein; Ion transport; Membrane;
KW Phosphoprotein; Polymorphism; Potassium; Potassium transport;
KW Reference proteome; Symport; Transmembrane; Transmembrane helix;
KW Transport.
FT CHAIN 1 1150 Solute carrier family 12 member 6.
FT /FTId=PRO_0000178037.
FT TOPO_DOM 1 185 Cytoplasmic (Potential).
FT TRANSMEM 186 208 Helical; (Potential).
FT TOPO_DOM 209 223 Extracellular (Potential).
FT TRANSMEM 224 245 Helical; (Potential).
FT TOPO_DOM 246 271 Cytoplasmic (Potential).
FT TRANSMEM 272 295 Helical; (Potential).
FT TOPO_DOM 296 318 Extracellular (Potential).
FT TRANSMEM 319 343 Helical; (Potential).
FT TOPO_DOM 344 346 Cytoplasmic (Potential).
FT TRANSMEM 347 371 Helical; (Potential).
FT TOPO_DOM 372 479 Extracellular (Potential).
FT TRANSMEM 480 501 Helical; (Potential).
FT TOPO_DOM 502 515 Cytoplasmic (Potential).
FT TRANSMEM 516 543 Helical; (Potential).
FT TOPO_DOM 544 557 Extracellular (Potential).
FT TRANSMEM 558 581 Helical; (Potential).
FT TOPO_DOM 582 620 Cytoplasmic (Potential).
FT TRANSMEM 621 644 Helical; (Potential).
FT TOPO_DOM 645 647 Extracellular (Potential).
FT TRANSMEM 648 670 Helical; (Potential).
FT TOPO_DOM 671 676 Cytoplasmic (Potential).
FT TRANSMEM 677 695 Helical; (Potential).
FT TOPO_DOM 696 696 Extracellular (Potential).
FT TRANSMEM 697 719 Helical; (Potential).
FT TOPO_DOM 720 1150 Cytoplasmic (Potential).
FT COMPBIAS 227 230 Poly-Cys.
FT MOD_RES 32 32 Phosphoserine.
FT MOD_RES 1032 1032 Phosphoserine.
FT CARBOHYD 379 379 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 398 398 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 411 411 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 428 428 N-linked (GlcNAc...) (Potential).
FT VAR_SEQ 1 59 Missing (in isoform 5).
FT /FTId=VSP_041387.
FT VAR_SEQ 1 51 Missing (in isoform 2 and isoform 6).
FT /FTId=VSP_006115.
FT VAR_SEQ 1 9 Missing (in isoform 4).
FT /FTId=VSP_041388.
FT VAR_SEQ 52 90 PETSRSEPMSEMSGATTSLATVALDPPSDRTSHPQDVIE
FT -> MPHFTVTKVEDPEEGAAASISQEPSLADIKARIQDSDE
FT P (in isoform 2 and isoform 6).
FT /FTId=VSP_006116.
FT VAR_SEQ 91 105 Missing (in isoform 3 and isoform 6).
FT /FTId=VSP_041389.
FT VARIANT 415 415 F -> S (in dbSNP:rs2705339).
FT /FTId=VAR_014960.
FT CONFLICT 802 802 E -> H (in Ref. 1; AAF24986).
SQ SEQUENCE 1150 AA; 127617 MW; F8BDD39181294EDD CRC64;
MHPPETTTKM ASVRFMVTPT KIDDIPGLSD TSPDLSSRSS SRVRFSSRES VPETSRSEPM
SEMSGATTSL ATVALDPPSD RTSHPQDVIE DLSQNSITGE HSQLLDDGHK KARNAYLNNS
NYEEGDEYFD KNLALFEEEM DTRPKVSSLL NRMANYTNLT QGAKEHEEAE NITEGKKKPT
KTPQMGTFMG VYLPCLQNIF GVILFLRLTW VVGTAGVLQA FAIVLICCCC TMLTAISMSA
IATNGVVPAG GSYFMISRAL GPEFGGAVGL CFYLGTTFAA AMYILGAIEI FLVYIVPRAA
IFHSDDALKE SAAMLNNMRV YGTAFLVLMV LVVFIGVRYV NKFASLFLAC VIVSILAIYA
GAIKSSFAPP HFPVCMLGNR TLSSRHIDVC SKTKEINNMT VPSKLWGFFC NSSQFFNATC
DEYFVHNNVT SIQGIPGLAS GIITENLWSN YLPKGEIIEK PSAKSSDVLG SLNHEYVLVD
ITTSFTLLVG IFFPSVTGIM AGSNRSGDLK DAQKSIPIGT ILAILTTSFV YLSNVVLFGA
CIEGVVLRDK FGDAVKGNLV VGTLSWPSPW VIVIGSFFST CGAGLQSLTG APRLLQAIAK
DNIIPFLRVF GHSKANGEPT WALLLTAAIA ELGILIASLD LVAPILSMFF LMCYLFVNLA
CALQTLLRTP NWRPRFRYYH WALSFMGMSI CLALMFISSW YYAIVAMVIA GMIYKYIEYQ
GAEKEWGDGI RGLSLSAARF ALLRLEEGPP HTKNWRPQLL VLLKLDEDLH VKHPRLLTFA
SQLKAGKGLT IVGSVIVGNF LENYGEALAA EQTIKHLMEA EKVKGFCQLV VAAKLREGIS
HLIQSCGLGG MKHNTVVMGW PNGWRQSEDA RAWKTFIGTV RVTTAAHLAL LVAKNISFFP
SNVEQFSEGN IDVWWIVHDG GMLMLLPFLL KQHKVWRKCS IRIFTVAQLE DNSIQMKKDL
ATFLYHLRIE AEVEVVEMHD SDISAYTYER TLMMEQRSQM LRHMRLSKTE RDREAQLVKD
RNSMLRLTSI GSDEDEETET YQEKVHMTWT KDKYMASRGQ KAKSMEGFQD LLNMRPDQSN
VRRMHTAVKL NEVIVNKSHE AKLVLLNMPG PPRNPEGDEN YMEFLEVLTE GLERVLLVRG
GGSEVITIYS
//

MIM 218000
*RECORD*
*FIELD* NO
218000
*FIELD* TI
#218000 AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY; ACCPN
;;CHARLEVOIX DISEASE;;
read moreANDERMANN SYNDROME;;
POLYNEUROPATHY, SENSORIMOTOR, WITH OR WITHOUT AGENESIS OF THE CORPUS
CALLOSUM;;
CORPUS CALLOSUM, AGENESIS OF, WITH NEURONOPATHY
*FIELD* TX
A number sign (#) is used with this entry because autosomal recessive
agenesis of the corpus callosum with peripheral neuropathy (ACCPN), also
known as Andermann syndrome, is caused by mutations in the SLC12A6 gene
(604878).

DESCRIPTION

Andermann syndrome is an autosomal recessive motor and sensory
neuropathy with agenesis of the corpus callosum associated with
developmental and neurodegenerative defects and dysmorphic features. It
has a high prevalence in the French Canadian population in the
Charlevoix and Saguenay-Lac-Saint-Jean region of Quebec (Uyanik et al.,
2006).

Dupre et al. (2003) provided a comprehensive review of the disorder.
Dobyns (1996) reviewed the many genetic causes of agenesis of the corpus
callosum.

CLINICAL FEATURES

Naiman and Fraser (1955) described 2 sisters, and Ziegler (1958)
described 2 brothers with agenesis of the corpus callosum associated
with mental and physical retardation. Andermann et al. (1972) observed 2
brothers with mental retardation, areflexia and paraparesis. The authors
postulated an anterior horn cell disease. The clinical picture was the
same as in the sisters reported by Naiman and Fraser (1955) and the 2
families were French Canadian from the Charlevoix County in Quebec.
Andermann et al. (1977) extended these studies to identify 45 patients
in 24 sibships, descendants from a couple married in Quebec City,
Charlevoix County, in 1657. Brain CT imaging demonstrated agenesis of
the corpus callosum.

Cao et al. (1977) reported 3 sibs, a male and 2 females, with severe
mental retardation, spastic quadriplegia, microcephaly, and infantile
spasms. Two sibs had agenesis of the corpus callosum on
pneumoencephalogram. Other reports of familial agenesis of the corpus
callosum consistent with autosomal recessive inheritance were published
by Shapira and Cohen (1973) and Castro Gago et al. (1982). The former
report concerned 2 affected sisters whose parents were more closely
related than first cousins. The latter report concerned 2 sisters and 2
daughters of a paternal uncle of their father. The 2 sisters, studied at
6 years and 15 months of age, respectively, had progressive psychomotor
regression, microcephaly, optic atrophy and seizures. CT scan showed
absence of the corpus callosum, subcortical atrophy and gray substance
heterotopy at the level of the ventricles.

Larbrisseau et al. (1984) studied 15 cases and described a
characteristic dysmorphic facies. The authors observed that progressive
motor neuropathy led to loss of ambulation by adolescence and
progressive scoliosis. Hauser et al. (1993) reported cases of agenesis
of the corpus callosum with neuronopathy in a brother and sister in
Vienna.

Uyanik et al. (2006) reported 3 unrelated patients with Andermann
syndrome; 1 was German and 2 Turkish. The German child presented at age
13 days with feeding difficulties and hypotonia. Over the next few
months, she was found to have complete absence of the corpus callosum
with ventricular enlargement and areflexia with an axonal and
demyelinating peripheral neuropathy. Lumbar puncture showed increased
CSF protein. At age 3 years, she had marked psychomotor retardation with
inability to walk or speak. Mild facial dysmorphism was present,
including hypertelorism, short nose, broad nasal root, and downplaced
first toe and thumb. The second child, born of consanguineous Turkish
parents, presented with diffuse hypotonic weakness, psychomotor
retardation, and afebrile seizures. She had mild mental retardation,
high-arched palate, elongated facies, esotropia of the right eye,
ptosis, facial diplegia, areflexia, and distal wasting of the limbs. She
had complete ACC and an axonal/demyelinating motor and sensory
neuropathy with decreased nerve conduction velocities. The third child,
born of second-degree Turkish cousins, had hypotonia and psychomotor
retardation. He could walk with support at age 5 years and developed
some speech. He had complete ACC and peripheral neuropathy but was less
severely affected in the upper limbs. He also had bilateral diffuse
white matter abnormalities, which had not previously been reported in
this syndrome.

MAPPING

Casaubon et al. (1996) performed linkage studies with 120 microsatellite
DNA markers to position the ACCPN gene to a 5-cM region on 15q13-q15,
flanked by markers D15S1040 and D15S118. A maximum 2-point lod score of
11.1 was obtained with the markers D15S971 at a recombination fraction
of 0.0. Haplotype analysis and linkage disequilibrium supported the
existence of the previously suspected founder effect. The authors stated
that this finding was the first step in the identification of the gene
responsible for ACCPN, which may shed light on numerous conditions
associated with progressive peripheral neuropathy or agenesis of the
corpus callosum.

Howard et al. (2002) typed 11 polymorphic markers on chromosome 15 in
231 individuals from 50 seemingly unrelated French Canadian ACCPN
families. Haplotype analysis confirmed the presence of a founder
haplotype, and recombination events reduced the ACCPN candidate interval
to a region of approximately 2 cM or 1000 kb between markers D15S1040
and ACTC.

MOLECULAR GENETICS

The K-Cl cotransporter KCC3, encoded by the SLC12A6 gene, maps within
the ACCPN candidate region, prompting Howard et al. (2002) to screen
that gene for mutations in individuals with ACCPN. Four distinct
protein-truncated mutations (604878.0001-604878.0004) were found: 2 in
the French Canadian population and 2 in non-French Canadian families. A
1-bp deletion (2436delG; 604878.0001) was determined to be a founder
mutation in the French Canadian population.

In 3 unrelated patients with Andermann syndrome, Uyanik et al. (2006)
identified 4 different mutations in the SLC12A6 gene
(604878.0005-704878.0008). Two were of Turkish descent, and 1 was
German.

Salin-Cantegrel et al. (2007) identified 2 mutations in exon 22 of the
SLC12A6 gene (604878.0003; 604878.0009) in non-French Canadian patients
with ACCPN, including families from Turkey, South Africa, Sudan, and the
Netherlands.

POPULATION GENETICS

De Braekeleer et al. (1993) estimated that in the
Saguenay-Lac-Saint-Jean region of northeastern Quebec the incidence at
birth was 1 in 2,117 liveborns, and the carrier rate was 1 in 23
inhabitants. Remote consanguinity was found in several families, while
the mean kinship coefficient was 2.7 times higher in the polyneuropathic
group than in control groups. Genealogic reconstruction suggested that
the high incidence is probably the result of founder effect and that a
unique mutation accounts for most, if not all, of the cases known in
this region.

Howard et al. (2002) determined that a 1-bp deletion (2436delG) was a
founder mutation in the French Canadian population.

ANIMAL MODEL

Howard et al. (2002) found that mice with a targeted deletion of the
Slc12a6 gene had a locomotor deficit, peripheral neuropathy, and a
sensorimotor gating deficit, similar to the human disease. The findings
suggested a critical role for SLC12A6 in the development and maintenance
of the nervous system.

*FIELD* SA
Battistella et al. (1987)
*FIELD* RF
1. Andermann, E.; Andermann, F.; Carpenter, S.; Karpati, G.; Eisen,
A.; Melancon, D.; Bergeron, J.: Agenesis of the corpus callosum with
sensorimotor neuronopathy: a new autosomal recessive malformation
syndrome with high frequency in Charlevoix County, Quebec. (Abstract) Vth
Int. Conf. on Birth Defects, Montreal , 8/1977.

2. Andermann, F.; Andermann, E.; Joubert, M.; Karpati, G.; Carpenter,
S.; Melancon, D.: Familial agenesis of the corpus callosum with anterior
horn cell disease. A syndrome of mental retardation, areflexia, and
paraplegia. Trans. Am. Neurol. Assoc. 97: 242-244, 1972.

3. Battistella, P. A.; Drigo, P.; Laverda, A. M.; Casara, G. L.; De
Martin, P. G.; Condini, A.: La sindrome di Andermann: neuropatia
progressiva, ritardo mentale ed agenesia del corpo calloso. Riv.
Ital. Ped. 13: 200-202, 1987.

4. Cao, A.; Cianchetti, C.; Signorini, E.; Loi, M.; Sanna, G.; De
Virgiliis, S.: Agenesis of the corpus callosum, infantile spasms,
spastic quadriplegia, microcephaly and mental retardation in three
siblings. Clin. Genet. 12: 290-296, 1977.

5. Casaubon, L. K.; Melanson, M.; Lopes-Cendes, I.; Marineau, C.;
Andermann, E.; Andermann, F.; Weissenbach, J.; Prevost, C.; Bouchard,
J.-P.; Mathieu, J.; Rouleau, G. A.: The gene responsible for a severe
form of peripheral neuropathy and agenesis of the corpus callosum
maps to chromosome 15q. Am. J. Hum. Genet. 58: 28-34, 1996.

6. Castro Gago, M.; Rodriguez, E.; Ugarte, J.; Diaz Cardama, I.; Alonso,
A.; Pena, J.: Agenesia hereditaria del cuerpo calloso: una nueva
forma. Rev. Esp. Pediat. 38: 349-353, 1982.

7. De Braekeleer, M.; Dallaire, A.; Mathieu, J.: Genetic epidemiology
of sensorimotor polyneuropathy with or without agenesis of the corpus
callosum in northeastern Quebec. Hum. Genet. 91: 223-227, 1993.

8. Dobyns, W. B.: Absence makes the search grow longer. Am. J. Hum.
Genet. 58: 7-16, 1996.

9. Dupre, N.; Howard, H. C.; Mathieu, J.; Karpati, G.; Vanasse, M.;
Bouchard, J.-P.; Carpenter, S.; Rouleau, G. A.: Hereditary motor
and sensory neuropathy with agenesis of the corpus callosum. Ann.
Neurol. 54: 9-18, 2003.

10. Hauser, E.; Bittner, R.; Liegl, C.; Bernert, G.; Zeitlhofer, J.
: Occurrence of Andermann syndrome out of French Canada: agenesis
of the corpus callosum with neuronopathy. Neuropediatrics 24: 107-110,
1993. Note: Erratum: Neuropediatrics 24: 239 only, 1993.

11. Howard, H. C.; Dube, M.-P.; Prevost, C.; Bouchard, J.-P.; Mathieu,
J.; Rouleau, G. A.: Fine mapping the candidate region for peripheral
neuropathy with or without agenesis of the corpus callosum in the
French Canadian population. Europ. J. Hum. Genet. 10: 406-412, 2002.

12. Howard, H. C.; Mount, D. B.; Rochefort, D.; Byun, N.; Dupre, N.;
Lu, J.; Fan, X.; Song, L.; Riviere, J.-B.; Prevost, C.; Horst, J.;
Simonati, A.; and 12 others: The K-Cl cotransporter KCC3 is mutant
in a severe peripheral neuropathy associated with agenesis of the
corpus callosum. Nature Genet. 32: 384-392, 2002. Note: Erratum:
Nature Genet. 32: 681 only, 2002.

13. Larbrisseau, A.; Vanasse, M.; Brochu, P.; Jasmin, G.: The Andermann
syndrome: agenesis of the corpus callosum associated with mental retardation
and progressive sensorimotor neuronopathy. Canad. J. Neurol. Sci. 11:
257-261, 1984.

14. Naiman, J. L.; Fraser, F. C.: Agenesis of the corpus callosum.
A report of two cases in siblings. Arch. Neurol. Psychiat. 74: 182-185,
1955.

15. Salin-Cantegrel, A.; Riviere, J.-B.; Dupre, N.; Charron, F. M.;
Shekarabi, M.; Karemera, L.; Gaspar, C.; Horst, J.; Tekin, M.; Deda,
G.; Krause, A.; Lippert, M. M.; Willemsen, M. A. A. P.; Jarrer, R.;
Lapointe, J.-Y.; Rouleau, G. A.: Distal truncation of KCC3 in non-French
Canadian HMSN/ACC families. Neurology 69: 1350-1355, 2007.

16. Shapira, Y.; Cohen, T.: Agenesis of the corpus callosum in two
sisters. J. Med. Genet. 10: 266-269, 1973.

17. Uyanik, G.; Elcioglu, N.; Penzien, J.; Gross, C.; Yilmaz, Y.;
Olmez, A.; Demir, E.; Wahl, D.; Scheglmann, K.; Winner, B.; Bogdahn,
U.; Topaloglu, H.; Hehr, U.; Winkler, J.: Novel truncating and missense
mutations of the KCC3 gene associated with Andermann syndrome. Neurology 66:
1044-1048, 2006. Note: Erratum: Neurology 67: 1528 only, 2006.

18. Ziegler, E.: Boesartige familiaere fruehinfantile Krampfkrankheit,
teilweise verbunden mit familiaerer Balkenaplasie. Helv. Paediat.
Acta 13: 169-184, 1958.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Head];
Brachycephaly;
[Face];
Narrow forehead;
Hypoplastic maxilla;
Facial asymmetry;
Facial diplegia;
Long face;
[Ears];
Large ears;
[Eyes];
Hypertelorism;
Ptosis;
Gaze palsies;
[Nose];
Broad nasal root;
Short nose;
[Mouth];
High-arched palate;
Protruding, fissured tongue

RESPIRATORY:
Restrictive respiratory disease

SKELETAL:
Joint contractures;
[Spine];
Scoliosis;
[Hands];
Long tapered fingers;
[Feet];
Syndactyly of the second and third toes;
Overriding of the first toe

SKIN, NAILS, HAIR:
[Hair];
Low hairline

MUSCLE, SOFT TISSUE:
Progressive distal and proximal symmetric limb weakness;
Neonatal hypotonia;
Amyotrophy;
EMG shows denervation

NEUROLOGIC:
[Central nervous system];
Delayed motor milestones;
Developmental delay;
Hypotonia, generalized;
Mental retardation, mild to severe;
Individuals can stand or walk with support by 4 to 6 years of age;
Seizures;
Agenesis of the corpus callosum;
Enlarged ventricles;
Axonal swelling of spinal nerve roots and cranial nerves;
[Peripheral nervous system];
Peripheral motor neuropathy, severe;
Peripheral sensory neuropathy, severe;
Areflexia;
Limb tremor;
Sural nerve biopsy shows absence of large myelinated fibers;
Axonal neuropathy;
Axonal degeneration/regeneration;
Demyelinating neuropathy;
'Onion bulb' formations;
Hypomyelinated fibers;
Decreased motor and sensory nerve conduction velocities;
[Behavioral/psychiatric manifestations];
Hallucinatory psychosis develops during adolescence

LABORATORY ABNORMALITIES:
Increased CSF protein

MISCELLANEOUS:
Onset within the first year of life;
Progressive disorder;
Most individuals are wheelchair-bound or bedridden by adolescence;
Death in third or fourth decades, usually due to respiratory infection;
Increased frequency in the Charlevoix and Saguenat-Lac-St-Jean regions
of Quebec, Canada (1 in 2,117 live births, carrier rate 1 in 23)

MOLECULAR BASIS:
Caused by mutation in the solute carrier family 12 (sodium/chloride
transporter), member 6 gene (SLC12A6, 604878.0001)

*FIELD* CN
Cassandra L. Kniffin - revised: 7/25/2007

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 12/05/2008
joanna: 8/29/2007
ckniffin: 7/25/2007

*FIELD* CN
Cassandra L. Kniffin - updated: 3/31/2008
Cassandra L. Kniffin - updated: 7/25/2007
Cassandra L. Kniffin - updated: 8/14/2003
Michael B. Petersen - updated: 2/12/2003
Victor A. McKusick - updated: 10/4/2002

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
terry: 06/06/2012
terry: 10/26/2011
wwang: 4/7/2008
ckniffin: 3/31/2008
ckniffin: 9/12/2007
carol: 8/7/2007
wwang: 8/2/2007
ckniffin: 7/25/2007
ckniffin: 8/14/2003
cwells: 2/25/2003
cwells: 2/12/2003
alopez: 1/16/2003
alopez: 11/4/2002
cwells: 10/7/2002
terry: 10/4/2002
carol: 6/22/2001
alopez: 2/9/1998
alopez: 7/31/1997
mark: 1/25/1996
terry: 1/22/1996
mimadm: 4/18/1994
warfield: 3/8/1994
terry: 1/28/1994
carol: 11/3/1993
carol: 7/19/1993
carol: 6/25/1993

MIM 604878
*RECORD*
*FIELD* NO
604878
*FIELD* TI
*604878 SOLUTE CARRIER FAMILY 12 (SODIUM/CHLORIDE TRANSPORTER), MEMBER 6;
SLC12A6
;;POTASSIUM-CHLORIDE COTRANSPORTER 3; KCC3
read morePOTASSIUM-CHLORIDE COTRANSPORTER 3, ISOFORM A, INCLUDED; KCC3A, INCLUDED;;
POTASSIUM-CHLORIDE COTRANSPORTER 3, ISOFORM B, INCLUDED; KCC3B, INCLUDED
*FIELD* TX

DESCRIPTION

Cation chloride cotransporters, including the potassium-chloride
cotransporters (KCCs), are involved in the electroneutral movement of
ions across the plasma membrane. Under most physiologic conditions, KCCs
function as efflux pathways (Hiki et al., 1999; Mount et al., 1999).

CLONING

Using differential display PCR on vascular endothelial cells treated
with vascular endothelial growth factor (VEGF; 192240), Hiki et al.
(1999) identified a cDNA encoding SLC12A6, which they called KCC3. The
predicted 1,099-amino acid SLC12A6 protein contains 12 membrane-spanning
segments and 5 N-glycosylation sites. SLC12A6 shares 77% amino acid
identity with the ubiquitously expressed KCC1 (SLC12A4; 604119) and 73%
identity with the brain-restricted KCC2 (SLC12A5; 606726). Northern blot
analysis detected strong expression of 9-, 7.5-, and 4.5-kb SLC12A6
transcripts in brain, heart, skeletal muscle, and kidney. Western blot
analysis showed expression of a 150-kD SLC12A6 protein that was reduced
to 120 kD by glycosidase treatment. Functional analyses confirmed that
SLC12A6 is a KCC.

By searching EST databases, Mount et al. (1999) identified a full-length
cDNA encoding SLC12A6, which they initially termed KCC4 but later
renamed KCC3. This cDNA encodes a deduced 1,150-amino acid protein.
Northern blot analysis detected 2 SLC12A6 transcripts of 6- to 7-kb,
consistent with alternative splicing, in muscle, brain, lung, heart, and
kidney. Mount (2000) designated the longer SLC12A6 isoform KCC3A (Mount
et al., 1999) and the shorter SLC12A6 isoform KCC3B (Hiki et al., 1999).
KCC3A is transcribed from a promoter approximately 23 kb 5-prime of
KCC3B, and the additional N-terminal sequence contains a cluster of
potential protein kinase C phosphorylation sites.

MAPPING

Hiki et al. (1999) mapped the SLC12A6 gene to chromosome 15q13 using
FISH. By radiation hybrid and somatic cell hybrid analyses, Mount et al.
(1999) mapped the SLC12A6 gene to 15q14.

Jiao et al. (2008) mapped the mouse Slc12a6 gene to chromosome 2.

GENE FUNCTION

Using a yeast 2-hybrid approach, Salin-Cantegrel et al. (2008) found
that the last 18 amino acids of the C-terminal domain of KCC3 directly
interacted with brain-specific creatine kinase (CKB; 123280), an
ATP-generating enzyme that is also a partner of KCC2. The interaction of
KCC3 with CKB was confirmed by GST pull-down assay, followed by
sequencing of the pulled-down complexes. Studies in transfected cultured
cells indicated that CKB colocalized with wildtype KCC3 in vitro.
However, mutant KCC3 lacking the C terminus was unable to interact with
CKB. Functional studies in Xenopus oocytes showed that an inhibitor of
CKB reduced KCC3 transport activity, indicating the proper KCC3 function
is dependent on interaction with functional CKB. Salin-Cantegrel et al.
(2008) hypothesized that disruption of ATP trafficking in patients with
KCC3 mutations may influence the osmotic integrity of neurons, resulting
in neurologic disease.

MOLECULAR GENETICS

The SLC12A6 gene maps to the same region of 15q as agenesis of the
corpus callosum associated with peripheral neuropathy (ACCPN; 218000).
ACCPN is transmitted in autosomal recessive fashion and is found at a
high frequency in the province of Quebec in Canada. In patients with
ACCPN, Howard et al. (2002) identified 4 distinct protein-truncating
mutations in the SLC12A6 gene: 2 in the French Canadian population
(604878.0001-604878.0002) and 2 in non-French Canadian families
(604878.0003-604878.0004).

In 3 unrelated patients with Andermann syndrome, Uyanik et al. (2006)
identified 4 different mutations in the SLC12A6 gene
(604878.0005-604878.0008). Two were of Turkish descent and 1 was German.

Salin-Cantegrel et al. (2011) showed in in vitro studies that mutant
SLC12A6 mutations (see, e.g., 604878.0001; 604878.0008; 604878.0010)
caused a loss of function by 2 mechanisms, either defective interaction
with brain-type creatine kinase or defective trafficking to the plasma
membrane. One missense mutation (R207C; 604878.0008) was retained in the
endoplasmic reticulum, and cell treatment with curcumin partially
corrected the mislocalization.

ANIMAL MODEL

Howard et al. (2002) found that mice with a targeted deletion of the
Slc12a6 gene had a locomotor deficit, peripheral neuropathy, and a
sensorimotor gating deficit, similar to the human disease. The findings
suggested a critical role for SLC12A6 in the development and maintenance
of the nervous system.

Giant axonopathy (gaxp) is an autosomal recessive mutation in mice.
Homozygous mutants exhibit ataxia, characteristically lifting their hind
legs too high and wobbling side-to-side as they walk. The swollen axons
observed in gaxp/gaxp mice have lightly packed organelles, suggesting
that swelling is due in part to increased water uptake. Jiao et al.
(2008) identified the gaxp mutation as a 17-base deletion within exon 4
of the Slc12a6 gene. Western blot analysis showed no mutant protein in
brain or kidney of gaxp/gaxp mice.

*FIELD* AV
.0001
AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY
SLC12A6, 1-BP DEL, 2436G

In 20 French Canadians with ACCPN (218000) from the Charlevoix and
Saguenay-Lac-Saint-Jean regions of the province of Quebec in Canada,
Howard et al. (2002) found homozygosity for a guanine deletion in exon
18 at nucleotide 2436 (2436delG) of the KCC3A open reading frame. The
deletion converted GT at the splice donor site of exon 18 to TA,
suggesting an effect on RNA splicing. Furthermore, this splice site
mutation was predicted to cause a premature stop codon at amino acid
813, removing the last 338 amino acids from the KCC3 protein (2436delG,
thr813fsX813). Functional expression studies in Xenopus oocytes showed
that the truncated mutant protein was appropriately glycosylated and
expressed at the cellular membrane, but was nonfunctional.

Salin-Cantegrel et al. (2011) found that the mutant T813X protein had
abnormal intracellular localization around the nucleus in brain tissue
from a patient with the mutation. The mutant protein was not found in
swollen axons. The findings suggested a transit defect of the mutant
protein.

.0002
AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY
SLC12A6, 2-BP DEL, 1584CT AND 1-BP INS, 1584G

In a French Canadian patient with ACCPN (218000), Howard et al. (2002)
found that 1 chromosome 15 allele carried the predominant French
Canadian mutation 2436delG (604878.0001) in exon 18, as well as the
deletion of adjacent cytosine and thymine nucleotides, along with the
insertion of 1 guanine, at positions 1584 and 1585 in exon 11 of the
SLC12A6 gene. This mutation caused a frameshift and a premature stop
codon, predicted to truncate 619 amino acids from the KCC3 protein
(phe529fsX532). Sequencing both parents indicated that 1 carried the
2436delG mutation and the other carried the deletion/insertion mutation.

.0003
AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY
SLC12A6, ARG1011TER

In 2 sibs of Turkish origin with ACCPN (218000), Howard et al. (2002)
found a 3031C-T transition in exon 22 of the SLC12A6 gene, resulting in
an arg1011-to-ter (R1011X) substitution.

Salin-Cantegrel et al. (2007) identified homozygosity for the R1011X
mutation in affected members of 5 unrelated non-French Canadian families
with ACCPN. Two families were Afrikaner from South Africa, 2 were from
Turkey, and 1 from the Netherlands. Haplotype analysis showed 2
different haplotypes, 1 of which was shared by the Afrikaner and Dutch
patients. In vitro functional expression studies showed that the R1011X
mutation completely abolished transporter activity, although the mutant
protein was weakly expressed at the cell membrane.

.0004
AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY
SLC12A6, ARG675TER

In 2 sibs of Italian origin with ACCPN (218000), Howard et al. (2002)
found a homozygous 2023C-T transition in exon 15 of the SLC12A6 gene,
predicted to result in an arg675-to-ter (R675X) substitution.

.0005
AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY
SLC12A6, 1-BP INS, 2031T

In a 3.5-year-old German girl with ACCPN (218000), Uyanik et al. (2006)
identified compound heterozygosity for 2 mutations in the SLC12A6 gene:
a 1-bp insertion (2031insT) and an 8-bp deletion (604878.0006). Both
mutations were predicted to result in a frameshift and premature
termination of the protein. Each unaffected parent was heterozygous for
1 of the mutations.

.0006
AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY
SLC12A6, 8-BP DEL, NT1478

In a 3.5-year-old German girl with ACCPN (218000), Uyanik et al. (2006)
identified compound heterozygosity for 2 mutations in the SLC12A6 gene:
an 8-bp deletion (1478delTTCCCTCT) and a 1-bp insertion (604878.0005).
Both mutations were predicted to result in a frameshift and premature
termination of the protein. Each unaffected parent was heterozygous for
1 of the mutations.

.0007
AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY
SLC12A6, 1-BP DEL, 901A

In a Turkish girl with ACCPN (218000), born of consanguineous parents,
Uyanik et al. (2006) identified a homozygous 1-bp deletion (901delA) in
the SLC12A6 gene, resulting in premature termination of the protein at
codon 315.

.0008
AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY
SLC12A6, ARG207CYS

In a 10.5-year-old Turkish boy with ACCPN (218000), born of
consanguineous parents, Uyanik et al. (2006) identified a homozygous
619C-T transition in the SLC12A6 gene, resulting in an arg207-to-cys
(R207C) substitution. This patient had slightly less severe neuropathy
and also had white matter abnormalities not previously reported in this
disorder. The authors noted that this was the first SLC12A6 missense
mutation associated with ACCPN and postulated that a dysfunctional
SLC12A6 protein may lead to a different phenotype.

By in vitro studies in mammalian cells, Salin-Cantegrel et al. (2011)
demonstrated that the R207C mutant protein interacted with brain-type
creatine kinase (CKB; 123280), but had decreased transport activity when
expressed in Xenopus oocytes. The mutant protein showed strong
localization to the perinuclear region and endoplasmic reticulum, as
well as poor membrane localization when expressed in HeLa cells,
suggesting a trafficking defect. Western blot analysis showed that the
mutant R207C protein also formed stable homodimers, which may have
affected transit to the plasma membrane. Treatment with curcumin
partially corrected the mislocalization.

.0009
AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY
SLC12A6, 10-BP DEL, NT2994

In 2 brothers, born of consanguineous Sudanese parents, with ACCPN
(218000), Salin-Cantegrel et al. (2007) identified a homozygous 10-bp
deletion (nucleotides 2995 to 3003) in exon 22 of the SLC12A6 gene,
resulting in a frameshift and premature termination.

.0010
AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY
SLC12A6, ARG1134TER

In affected members of a consanguineous Algerian family with ACCPN
(218000), Salin-Cantegrel et al. (2011) identified a homozygous 3402C-T
transition in exon 25 of the SCL12A6 gene, resulting in an
arg1134-to-ter (R1134X) substitution and a truncated protein missing
only the last 17 residues. In vitro immunofluorescence studies in HeLa
cells showed that the mutant truncated protein did not interact properly
with brain-type creatine kinase (CKB; 123280) and did not have transport
activity when expressed in Xenopus oocytes, consistent with a loss of
function. The mutant protein also showed abnormal localization within
the cytoplasm, not at the cell membrane, suggesting a defect in
trafficking.

*FIELD* RF
1. Hiki, K.; D'Andrea, R. J.; Furze, J.; Crawford, J.; Woollatt, E.;
Sutherland, G. R.; Vadas, M. A.; Gamble, J. R.: Cloning, characterization,
and chromosomal location of a novel human K(+)-Cl(-) cotransporter. J.
Biol. Chem. 274: 10661-10667, 1999.

2. Howard, H. C.; Mount, D. B.; Rochefort, D.; Byun, N.; Dupre, N.;
Lu, J.; Fan, X.; Song, L.; Riviere, J.-B.; Prevost, C.; Horst, J.;
Simonati, A.; and 12 others: The K-Cl cotransporter KCC3 is mutant
in a severe peripheral neuropathy associated with agenesis of the
corpus callosum. Nature Genet. 32: 384-392, 2002. Note: Erratum:
Nature Genet. 32: 681 only, 2002.

3. Jiao, Y.; Jin, X.; Yan, J.; Zhang, C.; Jiao, F.; Li, X.; Roe, B.
A.; Mount, D. B.; Gu, W.: A deletion mutation in Slc12a6 is associated
with neuromuscular disease in gaxp mice. Genomics 91: 407-414, 2008.

4. Mount, D. B.: Personal Communication. Nashville, Tenn. 3/28/2000.

5. Mount, D. B.; Mercado, A.; Song, L.; Xu, J.; George, A. L., Jr.;
Delpire, E.; Gamba, G.: Cloning and characterization of KCC3 and
KCC4, new members of the cation-chloride cotransporter gene family. J.
Biol. Chem. 274: 16355-16362, 1999.

6. Salin-Cantegrel, A.; Riviere, J.-B.; Dupre, N.; Charron, F. M.;
Shekarabi, M.; Karemera, L.; Gaspar, C.; Horst, J.; Tekin, M.; Deda,
G.; Krause, A.; Lippert, M. M.; Willemsen, M. A. A. P.; Jarrer, R.;
Lapointe, J.-Y.; Rouleau, G. A.: Distal truncation of KCC3 in non-French
Canadian HMSN/ACC families. Neurology 69: 1350-1355, 2007.

7. Salin-Cantegrel, A.; Riviere, J.-B.; Shekarabi, M.; Rasheed, S.;
DaCal, S.; Laganiere, J.; Gaudet, R.; Rochefort, D.; Lesca, G.; Gaspar,
C.; Dion, P. A.; Lapointe, J.-Y.; Rouleau, G. A.: Transit defect
of potassium-chloride co-transporter 3 is a major pathogenic mechanism
in hereditary motor and sensory neuropathy with agenesis of the corpus
callosum. J. Biol. Chem. 286: 28456-28465, 2011.

8. Salin-Cantegrel, A.; Shekarabi, M.; Holbert, S.; Dion, P.; Rochefort,
D.; Laganiere, J.; Dacal, S.; Hince, P.; Karemera, L.; Gaspar, C.;
Lapointe, J.-Y.; Rouleau, G. A.: HMSN/ACC truncation mutations disrupt
brain-type creatine kinase-dependant activation of K(+)/Cl(-) co-transporter
3. Hum. Molec. Genet. 17: 2703-2711, 2008.

9. Uyanik, G.; Elcioglu, N.; Penzien, J.; Gross, C.; Yilmaz, Y.; Olmez,
A.; Demir, E.; Wahl, D.; Scheglmann, K.; Winner, B.; Bogdahn, U.;
Topaloglu, H.; Hehr, U.; Winkler, J.: Novel truncating and missense
mutations of the KCC3 gene associated with Andermann syndrome. Neurology 66:
1044-1048, 2006. Note: Erratum: Neurology 67: 1528 only, 2006.

*FIELD* CN
Cassandra L. Kniffin - updated: 10/11/2011
Cassandra L. Kniffin - updated: 7/29/2010
Patricia A. Hartz - updated: 6/6/2008
Cassandra L. Kniffin - updated: 3/31/2008
Cassandra L. Kniffin - updated: 7/25/2007
Victor A. McKusick - updated: 10/4/2002

*FIELD* CD
Paul J. Converse: 4/26/2000

*FIELD* ED
carol: 09/16/2013
terry: 6/6/2012
terry: 10/26/2011
carol: 10/14/2011
terry: 10/12/2011
ckniffin: 10/11/2011
wwang: 8/5/2010
ckniffin: 7/29/2010
mgross: 6/11/2008
terry: 6/6/2008
wwang: 4/7/2008
ckniffin: 3/31/2008
wwang: 8/2/2007
ckniffin: 7/25/2007
cwells: 11/12/2003
alopez: 1/16/2003
alopez: 11/7/2002
cwells: 10/7/2002
terry: 10/4/2002
mgross: 4/26/2000