RBCC Red Blood Cell Collection

WNK1 (HSN2, KDP, KIAA0344, PRKWNK1) [Confidence: high (present in two of the MS resources)]
Serine/threonine-protein kinase WNK1; 2.7.11.1 (Erythrocyte 65 kDa protein; p65; Kinase deficient protein; Protein kinase lysine-deficient 1; Protein kinase with no lysine 1; hWNK1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00004472
IPI00004472 Splice Isoform 1 Of Serine/threonine-protein kinase WNK1 ATP binding, protein serine/threonine kinase activity,ion transport, protein amino acid phosphorylation, protein kinase cascade, regulation of cellular process, Controls sodium and chloride ion transport soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic Isoform 1, 2 or 3 found at its expected molecular weight found at molecular weight

UniProt Q9H4A3
ID WNK1_HUMAN Reviewed; 2382 AA.
AC Q9H4A3; A1L4B0; C5HTZ5; C5HTZ6; C5HTZ7; O15052; P54963; Q4VBX9;
read moreAC Q6IFS5; Q86WL5; Q8N673; Q9P1S9;
DT 02-FEB-2004, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 2.
DT 22-JAN-2014, entry version 138.
DE RecName: Full=Serine/threonine-protein kinase WNK1;
DE EC=2.7.11.1;
DE AltName: Full=Erythrocyte 65 kDa protein;
DE Short=p65;
DE AltName: Full=Kinase deficient protein;
DE AltName: Full=Protein kinase lysine-deficient 1;
DE AltName: Full=Protein kinase with no lysine 1;
DE Short=hWNK1;
GN Name=WNK1; Synonyms=HSN2, KDP, KIAA0344, PRKWNK1;
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), TISSUE SPECIFICITY,
RP CHROMOSOMAL LOCATION, AND VARIANTS PRO-1056; SER-1506 AND ILE-1808.
RC TISSUE=Heart;
RX PubMed=11571656; DOI=10.1038/sj.onc.1204726;
RA Verissimo F., Jordan P.;
RT "WNK kinases, a novel protein kinase subfamily in multi-cellular
RT organisms.";
RL Oncogene 20:5562-5569(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS PRO-1056; SER-1506 AND
RP ILE-1808.
RG NHLBI resequencing and genotyping service (RS&G;);
RL Submitted (DEC-2008) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-668 (ISOFORMS 1/2), FUNCTION,
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RC TISSUE=Mammary carcinoma;
RX PubMed=10660600; DOI=10.1074/jbc.275.6.4311;
RA Moore T.M., Garg R., Johnson C., Coptcoat M.J., Ridley A.J.,
RA Morris J.D.H.;
RT "PSK, a novel STE20-like kinase derived from prostatic carcinoma that
RT activates the JNK MAPK pathway and regulates actin cytoskeletal
RT organisation.";
RL J. Biol. Chem. 275:4311-4322(2000).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 69-2382 (ISOFORM 2), AND
RP VARIANTS PRO-1056 AND SER-1506.
RC TISSUE=Brain;
RX PubMed=9205841; DOI=10.1093/dnares/4.2.141;
RA Nagase T., Ishikawa K., Nakajima D., Ohira M., Seki N., Miyajima N.,
RA Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. VII.
RT The complete sequences of 100 new cDNA clones from brain which can
RT code for large proteins in vitro.";
RL DNA Res. 4:141-150(1997).
RN [6]
RP SEQUENCE REVISION TO N-TERMINUS.
RX PubMed=12168954; DOI=10.1093/dnares/9.3.99;
RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.;
RT "Construction of expression-ready cDNA clones for KIAA genes: manual
RT curation of 330 KIAA cDNA clones.";
RL DNA Res. 9:99-106(2002).
RN [7]
RP PROTEIN SEQUENCE OF 163-175, AND GLYCOSYLATION.
RX PubMed=2507249;
RA Hart G.W., Haltiwanger R.S., Holt G.D., Kelly W.G.;
RT "Nucleoplasmic and cytoplasmic glycoproteins.";
RL Ciba Found. Symp. 145:102-118(1989).
RN [8]
RP PARTIAL NUCLEOTIDE SEQUENCE [MRNA] (N-TERMINUS OF ISOFORM 3),
RP ALTERNATIVE PROMOTER USAGE, ALTERNATIVE SPLICING, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Kidney;
RX PubMed=14645531; DOI=10.1128/MCB.23.24.9208-9221.2003;
RA Delaloy C., Lu J., Houot A.-M., Disse-Nicodeme S., Gasc J.-M.,
RA Corvol P., Jeunemaitre X.;
RT "Multiple promoters in the WNK1 gene: one controls expression of a
RT kidney-specific kinase-defective isoform.";
RL Mol. Cell. Biol. 23:9208-9221(2003).
RN [9]
RP PARTIAL NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 4/5).
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 IDENTIFICATION (ISOFORMS 4/5), FUNCTION, AND INVOLVEMENT IN HSAN2A.
RX PubMed=15060842; DOI=10.1086/420795;
RA Lafreniere R.G., MacDonald M.L.E., Dube M.-P., MacFarlane J.,
RA O'Driscoll M., Brais B., Meilleur S., Brinkman R.R., Dadivas O.,
RA Pape T., Platon C., Radomski C., Risler J., Thompson J.,
RA Guerra-Escobio A.-M., Davar G., Breakefield X.O., Pimstone S.N.,
RA Green R., Pryse-Phillips W., Goldberg Y.P., Younghusband H.B.,
RA Hayden M.R., Sherrington R., Rouleau G.A., Samuels M.E.;
RT "Identification of a novel gene (HSN2) causing hereditary sensory and
RT autonomic neuropathy type II through the study of Canadian genetic
RT isolates.";
RL Am. J. Hum. Genet. 74:1064-1073(2004).
RN [11]
RP INVOLVEMENT IN PHA2C.
RX PubMed=11498583; DOI=10.1126/science.1062844;
RA Wilson F.H., Disse-Nicodeme S., Choate K.A., Ishikawa K.,
RA Nelson-Williams C., Desitter I., Gunel M., Milford D.V., Lipkin G.W.,
RA Achard J.-M., Feely M.P., Dussol B., Berland Y., Unwin R.J., Mayan H.,
RA Simon D.B., Farfel Z., Jeunemaitre X., Lifton R.P.;
RT "Human hypertension caused by mutations in WNK kinases.";
RL Science 293:1107-1112(2001).
RN [12]
RP INVOLVEMENT IN HSAN2A.
RX PubMed=15911806; DOI=10.1212/01.WNL.0000161849.29944.43;
RA Roddier K., Thomas T., Marleau G., Gagnon A.M., Dicaire M.J.,
RA St Denis A., Gosselin I., Sarrazin A.M., Larbrisseau A., Lambert M.,
RA Vanasse M., Gaudet D., Rouleau G.A., Brais B.;
RT "Two mutations in the HSN2 gene explain the high prevalence of HSAN2
RT in French Canadians.";
RL Neurology 64:1762-1767(2005).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2002 AND SER-2032, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1261, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [15]
RP ALTERNATIVE SPLICING (ISOFORMS 4 AND 5), AND INVOLVEMENT IN HSAN2A.
RX PubMed=18521183; DOI=10.1172/JCI34088;
RA Shekarabi M., Girard N., Riviere J.B., Dion P., Houle M., Toulouse A.,
RA Lafreniere R.G., Vercauteren F., Hince P., Laganiere J., Rochefort D.,
RA Faivre L., Samuels M., Rouleau G.A.;
RT "Mutations in the nervous system--specific HSN2 exon of WNK1 cause
RT hereditary sensory neuropathy type II.";
RL J. Clin. Invest. 118:2496-2505(2008).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,
RA Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for
RT efficient phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-19; SER-1261; SER-2011;
RP SER-2012; SER-2027; SER-2029 AND SER-2032, AND MASS 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 [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1978, 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 [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-19; SER-1261; SER-1978;
RP SER-2032 AND SER-2121, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [21]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2027; SER-2029 AND
RP SER-2032, AND MASS 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).
RN [23]
RP INTERACTION WITH KLHL3.
RX PubMed=23387299; DOI=10.1042/BJ20121903;
RA Ohta A., Schumacher F.R., Mehellou Y., Johnson C., Knebel A.,
RA Macartney T.J., Wood N.T., Alessi D.R., Kurz T.;
RT "The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension
RT syndrome interacts with and ubiquitylates WNK isoforms: disease-
RT causing mutations in KLHL3 and WNK4 disrupt interaction.";
RL Biochem. J. 451:111-122(2013).
RN [24]
RP UBIQUITINATION, AND INTERACTION WITH KLHL3.
RX PubMed=23576762; DOI=10.1073/pnas.1304592110;
RA Shibata S., Zhang J., Puthumana J., Stone K.L., Lifton R.P.;
RT "Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via
RT ubiquitination and degradation of WNK4.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:7838-7843(2013).
RN [25]
RP VARIANTS [LARGE SCALE ANALYSIS] GLY-1199 AND GLU-1799.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [26]
RP VARIANTS [LARGE SCALE ANALYSIS] THR-141; VAL-149; GLN-419; THR-509;
RP GLY-527; ILE-665; ALA-674; ARG-823; VAL-1546; GLU-1799; ILE-1808;
RP LEU-1823; HIS-1957; CYS-2190; LEU-2362 AND TRP-2380.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Serine/threonine kinase which plays an important role in
CC the regulation of electrolyte homeostasis, cell signaling,
CC survival, and proliferation. Acts as an activator and inhibitor of
CC sodium-coupled chloride cotransporters and potassium-coupled
CC chloride cotransporters respectively. Activates SCNN1A, SCNN1B,
CC SCNN1D and SGK1. Controls sodium and chloride ion transport by
CC inhibiting the activity of WNK4, by either phosphorylating the
CC kinase or via an interaction between WNK4 and the autoinhibitory
CC domain of WNK1. WNK4 regulates the activity of the thiazide-
CC sensitive Na-Cl cotransporter, SLC12A3, by phosphorylation. WNK1
CC may also play a role in actin cytoskeletal reorganization.
CC Phosphorylates NEDD4L.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- COFACTOR: Magnesium.
CC -!- ENZYME REGULATION: By hypertonicity. Activation requires
CC autophosphorylation of Ser-382. Phosphorylation of Ser-378 also
CC promotes increased activity (By similarity).
CC -!- SUBUNIT: Interacts with SYT2 (By similarity). Interacts with WNK3
CC and WNK4 (By similarity). Interacts with KLHL3.
CC -!- INTERACTION:
CC O95747:OXSR1; NbExp=2; IntAct=EBI-457907, EBI-620853;
CC P62136:PPP1CA; NbExp=2; IntAct=EBI-457907, EBI-357253;
CC P29101:Syt2 (xeno); NbExp=2; IntAct=EBI-457907, EBI-458017;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative promoter usage, Alternative splicing; Named isoforms=5;
CC Name=1;
CC IsoId=Q9H4A3-1; Sequence=Displayed;
CC Note=Produced by alternative promoter usage;
CC Name=2;
CC IsoId=Q9H4A3-2; Sequence=VSP_040269, VSP_050638;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=Q9H4A3-4; Sequence=VSP_050634, VSP_050637;
CC Note=Kinase-defective isoform. Produced by alternative promoter
CC usage and alternative splicing;
CC Name=4; Synonyms=Brain and spinal cord variant;
CC IsoId=Q9H4A3-5; Sequence=VSP_040268;
CC Note=Contains the nervous system-specific exon HSN2. Produced by
CC alternative splicing;
CC Name=5; Synonyms=Dorsal root ganglia and sciatic nerve variant,
CC DRG and sciatic nerve variant;
CC IsoId=Q9H4A3-6; Sequence=VSP_040267, VSP_040270;
CC Note=Contains the nervous system-specific exon HSN2. Produced by
CC alternative splicing;
CC -!- TISSUE SPECIFICITY: Widely expressed, with highest levels observed
CC in the testis, heart, kidney and skeletal muscle. Isoform 3 is
CC kidney-specific.
CC -!- PTM: O-glycosylated.
CC -!- PTM: Ubiquitinated in vitro by the BCR(KLHL3) complex; additional
CC evidences are required in vivo.
CC -!- DISEASE: Pseudohypoaldosteronism 2C (PHA2C) [MIM:614492]: An
CC autosomal dominant disorder characterized by severe hypertension,
CC hyperkalemia, hyperchloremia, mild hyperchloremic metabolic
CC acidosis in some cases, and correction of physiologic
CC abnormalities by thiazide diuretics. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Hereditary sensory and autonomic neuropathy 2A (HSAN2A)
CC [MIM:201300]: A form of hereditary sensory and autonomic
CC neuropathy, a genetically and clinically heterogeneous group of
CC disorders characterized by degeneration of dorsal root and
CC autonomic ganglion cells, and by sensory and/or autonomic
CC abnormalities. HSAN2A is an autosomal recessive disorder
CC characterized by impairment of pain, temperature and touch
CC sensation, onset of symptoms in infancy or early childhood,
CC occurrence of distal extremity pathologies (paronychia, whitlows,
CC ulcers, and Charcot joints), frequent amputations, sensory loss
CC that affects all modalities of sensation (lower and upper limbs
CC and perhaps the trunk as well), absence or diminution of tendon
CC reflexes (usually in all limbs), minimal autonomic dysfunction,
CC absence of sensory nerve action potentials, and virtual absence of
CC myelinated fibers with decreased numbers of unmyelinated fibers in
CC sural nerves. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr
CC protein kinase family. WNK subfamily.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- CAUTION: PubMed:2507249 describes a peptide sequence containing a
CC GlcNAc glycosylated Ser in position 164 while it is an Arg residue
CC according to others.
CC -!- CAUTION: Cys-250 is present instead of the conserved Lys which is
CC expected to be an active site residue. Lys-233 appears to fulfill
CC the required catalytic function.
CC -!- CAUTION: HSN2 was originally thought to be an intronless gene
CC lying within a WNK1 gene intron. It has been shown to be a nervous
CC system-specific exon of WNK1 included in isoform 4 and isoform 5
CC (PubMed:18521183).
CC -!- CAUTION: It is uncertain whether Met-1 or Met-214 is the initiator
CC in isoform 4 and isoform 5.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAF31483.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the C-terminal part;
CC Sequence=AAI30468.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact;
CC Sequence=AAI30470.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact;
CC Sequence=DAA04494.1; Type=Erroneous gene model prediction; Note=Includes 3' and 3' intronic sequences;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/WNK1";
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DR EMBL; AJ296290; CAC15059.1; -; mRNA.
DR EMBL; FJ515833; ACS13726.1; -; Genomic_DNA.
DR EMBL; FJ515833; ACS13727.1; -; Genomic_DNA.
DR EMBL; FJ515833; ACS13728.1; -; Genomic_DNA.
DR EMBL; AC004765; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC004803; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AF061944; AAF31483.1; ALT_SEQ; mRNA.
DR EMBL; AB002342; BAA20802.2; -; mRNA.
DR EMBL; AY231477; AAO46160.1; -; mRNA.
DR EMBL; BC130467; AAI30468.1; ALT_SEQ; mRNA.
DR EMBL; BC130469; AAI30470.1; ALT_SEQ; mRNA.
DR EMBL; BK004108; DAA04494.1; ALT_SEQ; Genomic_DNA.
DR RefSeq; NP_001171914.1; NM_001184985.1.
DR RefSeq; NP_055638.2; NM_014823.2.
DR RefSeq; NP_061852.3; NM_018979.3.
DR RefSeq; NP_998820.3; NM_213655.4.
DR UniGene; Hs.744906; -.
DR ProteinModelPortal; Q9H4A3; -.
DR SMR; Q9H4A3; 210-572.
DR DIP; DIP-32648N; -.
DR IntAct; Q9H4A3; 52.
DR MINT; MINT-2879524; -.
DR BindingDB; Q9H4A3; -.
DR ChEMBL; CHEMBL1075173; -.
DR PhosphoSite; Q9H4A3; -.
DR DMDM; 74709537; -.
DR PaxDb; Q9H4A3; -.
DR PRIDE; Q9H4A3; -.
DR DNASU; 65125; -.
DR Ensembl; ENST00000315939; ENSP00000313059; ENSG00000060237.
DR Ensembl; ENST00000340908; ENSP00000341292; ENSG00000060237.
DR Ensembl; ENST00000537687; ENSP00000444465; ENSG00000060237.
DR Ensembl; ENST00000574564; ENSP00000460651; ENSG00000060237.
DR GeneID; 65125; -.
DR KEGG; hsa:65125; -.
DR UCSC; uc001qio.4; human.
DR CTD; 65125; -.
DR GeneCards; GC12P000862; -.
DR H-InvDB; HIX0010312; -.
DR HGNC; HGNC:14540; WNK1.
DR MIM; 201300; phenotype.
DR MIM; 605232; gene.
DR MIM; 614492; phenotype.
DR neXtProt; NX_Q9H4A3; -.
DR Orphanet; 970; Hereditary sensory and autonomic neuropathy type 2.
DR Orphanet; 88940; Pseudohypoaldosteronism type 2C.
DR PharmGKB; PA134944932; -.
DR PharmGKB; PA33782; -.
DR eggNOG; COG0515; -.
DR HOVERGEN; HBG079897; -.
DR InParanoid; Q9H4A3; -.
DR KO; K08867; -.
DR OrthoDB; EOG7KDF8Z; -.
DR PhylomeDB; Q9H4A3; -.
DR SignaLink; Q9H4A3; -.
DR ChiTaRS; WNK1; human.
DR GeneWiki; WNK1; -.
DR GenomeRNAi; 65125; -.
DR NextBio; 67340; -.
DR PRO; PR:Q9H4A3; -.
DR ArrayExpress; Q9H4A3; -.
DR Bgee; Q9H4A3; -.
DR CleanEx; HS_WNK1; -.
DR Genevestigator; Q9H4A3; -.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0019902; F:phosphatase binding; IDA:UniProtKB.
DR GO; GO:0004860; F:protein kinase inhibitor activity; IEA:UniProtKB-KW.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0007243; P:intracellular protein kinase cascade; IDA:UniProtKB.
DR GO; GO:0006811; P:ion transport; ISS:UniProtKB.
DR GO; GO:0090188; P:negative regulation of pancreatic juice secretion; IEA:Ensembl.
DR GO; GO:0010923; P:negative regulation of phosphatase activity; IDA:UniProtKB.
DR GO; GO:0006469; P:negative regulation of protein kinase activity; IEA:GOC.
DR GO; GO:0048666; P:neuron development; NAS:UniProtKB.
DR GO; GO:0003084; P:positive regulation of systemic arterial blood pressure; IEA:Ensembl.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR024678; Kinase_OSR1/WNK_CCT.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF12202; OSR1_C; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SUPFAM; SSF56112; SSF56112; 2.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; FALSE_NEG.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW Alternative promoter usage; Alternative splicing; ATP-binding;
KW Complete proteome; Cytoplasm; Direct protein sequencing; Glycoprotein;
KW Kinase; Neuropathy; Nucleotide-binding; Phosphoprotein; Polymorphism;
KW Protein kinase inhibitor; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Ubl conjugation.
FT CHAIN 1 2382 Serine/threonine-protein kinase WNK1.
FT /FTId=PRO_0000086819.
FT DOMAIN 221 479 Protein kinase.
FT NP_BIND 227 235 ATP (By similarity).
FT ACT_SITE 349 349 Proton acceptor (By similarity).
FT BINDING 233 233 ATP (By similarity).
FT MOD_RES 19 19 Phosphoserine.
FT MOD_RES 378 378 Phosphoserine; by autocatalysis (By
FT similarity).
FT MOD_RES 382 382 Phosphoserine; by autocatalysis (By
FT similarity).
FT MOD_RES 1261 1261 Phosphoserine.
FT MOD_RES 1978 1978 Phosphoserine.
FT MOD_RES 2002 2002 Phosphoserine.
FT MOD_RES 2011 2011 Phosphoserine.
FT MOD_RES 2012 2012 Phosphoserine.
FT MOD_RES 2027 2027 Phosphoserine.
FT MOD_RES 2029 2029 Phosphoserine.
FT MOD_RES 2032 2032 Phosphoserine.
FT MOD_RES 2121 2121 Phosphoserine.
FT VAR_SEQ 1 407 Missing (in isoform 3).
FT /FTId=VSP_050634.
FT VAR_SEQ 408 437 FGMCMLEMATSEYPYSECQNAAQIYRRVTS -> MDIKKKD
FT FCSVFVIINSHCCCCPQKDCINE (in isoform 3).
FT /FTId=VSP_050637.
FT VAR_SEQ 713 713 V -> VPQSMAHPCGGTPTYPESQIFFPTIHERPVSFSPPP
FT TCPPKVAISQRRKSTSFLEAQTHHFQPLLRTVGQSLLPPGG
FT SPTNWTPEAVVMLGTTASRVTGESCEIQVHPMFEPSQVYSD
FT YRPGLVLPEEAHYFIPQEAVYVAGVHYQARVAEQYEGIPYN
FT SSVLSSPMKQIPEQKPVQGGPTSSSVFEFPSGQAFLVGHLQ
FT NLRLDSGLGPGSPLSSISAPISTDATRLKFHPVFVPHSAPA
FT VLTHNNESRSNCVFEFHVHTPSSSSGEGGGILPQRVYRNRQ
FT VAVDLNQEELPPQSVGLHGYLQPVTEEKHNYHAPELTVSVV
FT EPIGQNWPIGSPEYSSDSSQITSSDPSDFQSPPPTGGAAAP
FT FGSDVSMPFIHLPQTVLQESPLFFCFPQGTTSQQVLTASFS
FT SGGSALHPQ (in isoform 5).
FT /FTId=VSP_040267.
FT VAR_SEQ 714 1037 AQGQSQGQPSSSSLTGVSSSQPIQHPQQQQGIQQTAPPQQT
FT VQYSLSQTSTSSEATTAQPVSQPQAPQVLPQVSAGKQLPVS
FT QPVPTIQGEPQIPVATQPSVVPVHSGAHFLPVGQPLPTPLL
FT PQYPVSQIPISTPHVSTAQTGFSSLPITMAAGITQPLLTLA
FT SSATTAAIPGVSTVVPSQLPTLLQPVTQLPSQVHPQLLQPA
FT VQSMGIPANLGQAAEVPLSSGDVLYQGFPPRLPPQYPGDSN
FT IAPSSNVASVCIHSTVLSPPMPTEVLATPGYFPTVVQPYVE
FT SNLLVPMGGVGGQVQVSQPGGSLAQAPTTSSQQAVLE ->
FT PRRGRSMSVCVPIFLLLPLCPASLPVLFHPTASTVCTSFSF
FT PPPDCPEETFAEKLSKALESVLPMHSASQRKHRRSSLPSLF
FT VSTPQSMAHPCGGTPTYPESQIFFPTIHERPVSFSPPPTCP
FT PKVAISQRRKSTSFLEAQTHHFQPLLRTVGQSLLPPGGSPT
FT NWTPEAVVMLGTTASRVTGESCEIQVHPMFEPSQVYSDYRP
FT GLVLPEEAHYFIPQEAVYVAGVHYQARVAEQYEGIPYNSSV
FT LSSPMKQIPEQKPVQGGPTSSSVFEFPSGQAFLVGHLQNLR
FT LDSGLGPGSPLSSISAPISTDATRLKFHPVFVPHSAPAVLT
FT HNNESRSNCVFEFHVHTPSSSSGEGGGILPQRVYRNRQVAV
FT DLNQEELPPQSVGLHGYLQPVTEEKHNYHAPELTVSVVEPI
FT GQNWPIGSPEYSSDSSQITSSDPSDFQSPPPTGGAAAPFGS
FT DVSMPFIHLPQTVLQESPLFFCFPQGTTSQQVLTASFSSGG
FT SALHPQAQGQSQGQPSSSSLTGVSSSQPIQHPQQQQGIQQT
FT APPQQTVQYSLSQTSTSSEATTAQPVSQPQAPQVLPQVSAG
FT KQ (in isoform 4).
FT /FTId=VSP_040268.
FT VAR_SEQ 740 740 Missing (in isoform 2).
FT /FTId=VSP_040269.
FT VAR_SEQ 792 1037 Missing (in isoform 2).
FT /FTId=VSP_050638.
FT VAR_SEQ 792 944 Missing (in isoform 5).
FT /FTId=VSP_040270.
FT VARIANT 141 141 A -> T (in dbSNP:rs11554421).
FT /FTId=VAR_041309.
FT VARIANT 149 149 A -> V (in dbSNP:rs34880640).
FT /FTId=VAR_041310.
FT VARIANT 419 419 E -> Q (in a breast pleomorphic lobular
FT carcinoma sample; somatic mutation).
FT /FTId=VAR_041311.
FT VARIANT 509 509 I -> T (in dbSNP:rs34728563).
FT /FTId=VAR_041312.
FT VARIANT 527 527 D -> G (in dbSNP:rs34408667).
FT /FTId=VAR_041313.
FT VARIANT 665 665 T -> I (in dbSNP:rs2286007).
FT /FTId=VAR_019992.
FT VARIANT 674 674 T -> A (in dbSNP:rs11833299).
FT /FTId=VAR_041314.
FT VARIANT 823 823 H -> R (in dbSNP:rs56015776).
FT /FTId=VAR_041315.
FT VARIANT 1056 1056 T -> P (in dbSNP:rs956868).
FT /FTId=VAR_059033.
FT VARIANT 1199 1199 E -> G (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035640.
FT VARIANT 1506 1506 C -> S (in dbSNP:rs7955371).
FT /FTId=VAR_059034.
FT VARIANT 1546 1546 A -> V (in dbSNP:rs56351358).
FT /FTId=VAR_041316.
FT VARIANT 1799 1799 Q -> E (in breast cancer samples;
FT infiltrating ductal carcinoma; somatic
FT mutation).
FT /FTId=VAR_035641.
FT VARIANT 1808 1808 M -> I (in dbSNP:rs12828016).
FT /FTId=VAR_041317.
FT VARIANT 1823 1823 P -> L (in dbSNP:rs17755373).
FT /FTId=VAR_041318.
FT VARIANT 1957 1957 R -> H (in dbSNP:rs36083875).
FT /FTId=VAR_041319.
FT VARIANT 2190 2190 S -> C (in a breast pleomorphic lobular
FT carcinoma sample; somatic mutation).
FT /FTId=VAR_041320.
FT VARIANT 2362 2362 F -> L (in a lung adenocarcinoma sample;
FT somatic mutation).
FT /FTId=VAR_041321.
FT VARIANT 2380 2380 R -> W (in dbSNP:rs56262445).
FT /FTId=VAR_041322.
FT CONFLICT 164 164 R -> S (in Ref. 7; AA sequence).
FT CONFLICT 1836 1836 Missing (in Ref. 5; BAA20802).
SQ SEQUENCE 2382 AA; 250794 MW; 426785F98A452A0A CRC64;
MSGGAAEKQS STPGSLFLSP PAPAPKNGSS SDSSVGEKLG AAAADAVTGR TEEYRRRRHT
MDKDSRGAAA TTTTTEHRFF RRSVICDSNA TALELPGLPL SLPQPSIPAA VPQSAPPEPH
REETVTATAT SQVAQQPPAA AAPGEQAVAG PAPSTVPSST SKDRPVSQPS LVGSKEEPPP
ARSGSGGGSA KEPQEERSQQ QDDIEELETK AVGMSNDGRF LKFDIEIGRG SFKTVYKGLD
TETTVEVAWC ELQDRKLTKS ERQRFKEEAE MLKGLQHPNI VRFYDSWEST VKGKKCIVLV
TELMTSGTLK TYLKRFKVMK IKVLRSWCRQ ILKGLQFLHT RTPPIIHRDL KCDNIFITGP
TGSVKIGDLG LATLKRASFA KSVIGTPEFM APEMYEEKYD ESVDVYAFGM CMLEMATSEY
PYSECQNAAQ IYRRVTSGVK PASFDKVAIP EVKEIIEGCI RQNKDERYSI KDLLNHAFFQ
EETGVRVELA EEDDGEKIAI KLWLRIEDIK KLKGKYKDNE AIEFSFDLER DVPEDVAQEM
VESGYVCEGD HKTMAKAIKD RVSLIKRKRE QRQLVREEQE KKKQEESSLK QQVEQSSASQ
TGIKQLPSAS TGIPTASTTS ASVSTQVEPE EPEADQHQQL QYQQPSISVL SDGTVDSGQG
SSVFTESRVS SQQTVSYGSQ HEQAHSTGTV PGHIPSTVQA QSQPHGVYPP SSVAQGQSQG
QPSSSSLTGV SSSQPIQHPQ QQQGIQQTAP PQQTVQYSLS QTSTSSEATT AQPVSQPQAP
QVLPQVSAGK QLPVSQPVPT IQGEPQIPVA TQPSVVPVHS GAHFLPVGQP LPTPLLPQYP
VSQIPISTPH VSTAQTGFSS LPITMAAGIT QPLLTLASSA TTAAIPGVST VVPSQLPTLL
QPVTQLPSQV HPQLLQPAVQ SMGIPANLGQ AAEVPLSSGD VLYQGFPPRL PPQYPGDSNI
APSSNVASVC IHSTVLSPPM PTEVLATPGY FPTVVQPYVE SNLLVPMGGV GGQVQVSQPG
GSLAQAPTTS SQQAVLESTQ GVSQVAPAEP VAVAQTQATQ PTTLASSVDS AHSDVASGMS
DGNENVPSSS GRHEGRTTKR HYRKSVRSRS RHEKTSRPKL RILNVSNKGD RVVECQLETH
NRKMVTFKFD LDGDNPEEIA TIMVNNDFIL AIERESFVDQ VREIIEKADE MLSEDVSVEP
EGDQGLESLQ GKDDYGFSGS QKLEGEFKQP IPASSMPQQI GIPTSSLTQV VHSAGRRFIV
SPVPESRLRE SKVFPSEITD TVAASTAQSP GMNLSHSASS LSLQQAFSEL RRAQMTEGPN
TAPPNFSHTG PTFPVVPPFL SSIAGVPTTA AATAPVPATS SPPNDISTSV IQSEVTVPTE
EGIAGVATST GVVTSGGLPI PPVSESPVLS SVVSSITIPA VVSISTTSPS LQVPTSTSEI
VVSSTALYPS VTVSATSASA GGSTATPGPK PPAVVSQQAA GSTTVGATLT SVSTTTSFPS
TASQLCIQLS SSTSTPTLAE TVVVSAHSLD KTSHSSTTGL AFSLSAPSSS SSPGAGVSSY
ISQPGGLHPL VIPSVIASTP ILPQAAGPTS TPLLPQVPSI PPLVQPVANV PAVQQTLIHS
QPQPALLPNQ PHTHCPEVDS DTQPKAPGID DIKTLEEKLR SLFSEHSSSG AQHASVSLET
SLVIESTVTP GIPTTAVAPS KLLTSTTSTC LPPTNLPLGT VALPVTPVVT PGQVSTPVST
TTSGVKPGTA PSKPPLTKAP VLPVGTELPA GTLPSEQLPP FPGPSLTQSQ QPLEDLDAQL
RRTLSPEMIT VTSAVGPVSM AAPTAITEAG TQPQKGVSQV KEGPVLATSS GAGVFKMGRF
QVSVAADGAQ KEGKNKSEDA KSVHFESSTS ESSVLSSSSP ESTLVKPEPN GITIPGISSD
VPESAHKTTA SEAKSDTGQP TKVGRFQVTT TANKVGRFSV SKTEDKITDT KKEGPVASPP
FMDLEQAVLP AVIPKKEKPE LSEPSHLNGP SSDPEAAFLS RDVDDGSGSP HSPHQLSSKS
LPSQNLSQSL SNSFNSSYMS SDNESDIEDE DLKLELRRLR DKHLKEIQDL QSRQKHEIES
LYTKLGKVPP AVIIPPAAPL SGRRRRPTKS KGSKSSRSSS LGNKSPQLSG NLSGQSAASV
LHPQQTLHPP GNIPESGQNQ LLQPLKPSPS SDNLYSAFTS DGAISVPSLS APGQGTSSTN
TVGATVNSQA AQAQPPAMTS SRKGTFTDDL HKLVDNWARD AMNLSGRRGS KGHMNYEGPG
MARKFSAPGQ LCISMTSNLG GSAPISAASA TSLGHFTKSM CPPQQYGFPA TPFGAQWSGT
GGPAPQPLGQ FQPVGTASLQ NFNISNLQKS ISNPPGSNLR TT
//

MIM 201300
*RECORD*
*FIELD* NO
201300
*FIELD* TI
#201300 NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IIA; HSAN2A
;;HSAN IIA;;
read moreNEUROPATHY, HEREDITARY SENSORY, TYPE IIA; HSN2A;;
HSN IIA;;
ACROOSTEOLYSIS, NEUROGENIC;;
ACROOSTEOLYSIS, GIACCAI TYPE;;
NEUROPATHY, HEREDITARY SENSORY RADICULAR, AUTOSOMAL RECESSIVE;;
MORVAN DISEASE;;
NEUROPATHY, PROGRESSIVE SENSORY, OF CHILDREN;;
NEUROPATHY, CONGENITAL SENSORY
*FIELD* TX
A number sign (#) is used with this entry because hereditary sensory and
autonomic neuropathy type IIA (HSAN2A) can be caused by mutation in the
HSN2 isoform of the WNK1 gene (WNK1/HSN2; see 605232).

HSAN2B (613115) is caused by mutation in the FAM134B gene (613114). For
a discussion of genetic heterogeneity of HSAN, see HSAN1 (162400).

CLINICAL FEATURES

Giaccai (1952) reported 'neurogenic acroosteolysis' in 4 children born
of an Arab man who married 2 first cousins. By the first wife, 1 of the
children was affected, and by the second wife, 3 of 5 children were
affected. Since the spinal cord was normal at autopsy, Giaccai (1952)
concluded that the abnormality resided in peripheral sensory nerves.
Heller and Robb (1955) described a French Canadian family in which 5
members had the full form of hereditary sensory neuropathy and 3 had an
incomplete form, suggesting autosomal dominant inheritance. No amyloid
was found on dorsal root ganglion biopsy. Heller and Robb (1955)
suggested that the disease was the same as Morvan disease. The patient
reported by Ogden et al. (1959) as having progressive sensory radicular
neuropathy of Denny-Brown (HSAN1) may have had neurogenic acroosteolysis
because symptoms began as early as 1 year and the parents were first
cousins.

Biemond (1955) described 11-year-old fraternal twins (male and female)
with loss of pain sensation, diminished touch and temperature sense, and
absent tendon reflexes. Postmortem examination showed deficient
development in the posterior root ganglia, gasserian ganglion, posterior
roots, posterior horns of the spinal gray matter, and posterior columns.
The spinothalamic tracts could not be demonstrated. In a child with
sensory and autonomic dysfunction, Freytag and Lindenberg (1967) found
decreased posterior ascending tracts, severe reduction in the number of
neurons in peripheral sensory and autonomic ganglia, and hypoplasia of
the pyramidal tracts.

Johnson and Spalding (1964) described a slowly progressive sensory
neuropathy in 2 unrelated boys, aged 10 and 15 years, each of whom had
consanguineous parents. The disorder began in early childhood and
involved all modalities of sensation with no disturbance of motor or
autonomic function. Involvement was predominantly distal with late
involvement of the trunk, and resulted in loss of digits and Charcot
joints at the ankles. Johnson and Spalding (1964) differentiated the
disorder from congenital indifference to pain (147430, 243000) by the
involvement of all sensory modalities, preservation of proximal
sensation, including pain, loss of tendon reflexes, gradual progression,
and peripheral nerve degeneration, and from autosomal dominant HSN1 by
the recessive mode of inheritance, early age of onset, and ultimate
involvement of the trunk.

Haddow et al. (1970) described a brother and sister, offspring of
nonconsanguineous parents, with a nonprogressive sensory defect leading
to extensive damage of the fingers. The patients had low spinal fluid
protein and had suffered from unexplained chronic diarrhea in early
life. The mother was Irish and the father was French-Canadian. Haddow et
al. (1970) suggested that the disorder in the French-Canadian family
described by Hould and Verret (1967) was the same, although onset in
that family was not until the middle of the first decade. Ohta et al.
(1973) reported further on the family described by Hould and Verret
(1967). They suggested that the families of Schoene et al. (1970),
Ogryzlo (1946), and Parks and Staples (1945) had the same condition.
Ohta et al. (1973) suggested the designation 'hereditary sensory
neuropathy type II,' giving the name of type I to the dominant disorder.

Murray (1973) reported 2 daughters of first cousins with a recessive
form of congenital sensory neuropathy. Impairment of pain, temperature,
and touch sensations in varying degrees affected the limbs and trunk.
The disorder was thought to be nonprogressive and perhaps caused by a
failure of sensory nerve formation rather than by sensory nerve
degeneration. Murray (1973) noted that those affected with the disorder
often developed painless finger and toe ulcerations which consequently
led to damage to the underlying bone. Some patients also developed
neuropathic joint degeneration. Murray (1973) compiled 33 cases of
congenital sensory neuropathy from the literature, 20 of whom were from
6 families.

Jedrzejowska and Milczarek (1976) reported light and electron
microscopic findings in the sural nerve from a patient with HSAN2. There
was a marked reduction in the number of myelinated fibers due to
Wallerian-like axonal degeneration, as well as segmental demyelination,
most likely secondary to axonal changes. The authors suggested a
progressive nature of the pathologic process.

Sirinavin et al. (1982) reported a 12-year-old Cambodian girl with
digital clubbing and joint and leg pain with swelling. Acroosteolysis of
the distal phalanges was accompanied by profuse hyperhidrosis of the
hands and feet and thickening of soft tissues around the knees and
ankles, giving a cylindrical appearance to the legs; these associated
features suggested pachydermoperiostosis (167100) to the authors.
However, the periosteum showed no radiologic changes and the 'clubbing,'
was more suggestive of foreshortening due to collapse of the distal
phalanges, similar to that seen in chronic uremia. There was generalized
osteoporosis and the bones of the calvaria were thin with a single small
wormian bone in the lambdoidal suture; these features suggested Cheney
syndrome (102500), but the fact that the parents were first cousins
favored recessive inheritance for the disorder in this patient.

Sugiura and Sengoku (1986) reported 2 kindreds with 4 affected persons.
In the first family, the parents were consanguineous and had 2 affected
children; in the second family, second cousins were affected. The
authors suggested that the disorder referred to as the recessive form of
hereditary sensory radicular neuropathy is the same as the Giaccai type
of acroosteolysis. Bockers et al. (1989) observed 3 sibs in a Turkish
family who developed progressive footdrop between ages 7 and 12 years
and ulcers on the lateral edge of the feet. Hyperkeratotic plaques,
erosions, and ulcers of the fingers developed in 1 patient at the age of
11 years. The fingers showed ainhum-like constriction bands and
spontaneous amputations. Osteomyelitis and osteolysis led to
amputations. A high urinary excretion of sphingomyelin and lecithin
suggested that the pathogenetic mechanism might be a disorder of
phospholipid metabolism. Two of the patients showed the rare blood group
O (Bombay); see 211100.

Lafreniere et al. (2004) reported 5 families with HSAN2, including the
large family from Newfoundland originally reported by Ogryzlo (1946).
Beginning in early childhood, affected individuals experienced numbness
in the hands and feet, aggravated by cold, together with reduced
sensation to pain. They experienced loss of touch, pain, and
temperature, with touch most severely affected. The loss was
predominantly distal, extending from the elbows to the fingertips and
from just above the knees down to the toes, a pattern of distribution
often described as 'glove and stocking.' The lower limbs were typically
more severely affected than the upper limbs, and the trunk was involved
in some patients. Ulceration and infections caused spontaneous
amputation of digits and surgical amputation of lower limbs. There was
no overt autonomic dysfunction; sweating and tearing were within normal
range, and postural hypotension was not present. As in the other
hereditary sensory neuropathies, there was absence of axon flare after
intradermal histamine, indicating defective nociceptive fibers. Biopsy
showed a severe loss of myelinated axons, some loss of nonmyelinated
fibers in the sural nerve, and the absence of cutaneous sensory
receptors and nerve fibers.

MAPPING

By linkage analysis of 8 affected members from the consanguineous
multigenerational Newfoundland pedigree reported by Ogryzlo (1946), and
an additional family with 2 affected members, Lafreniere et al. (2004)
mapped the HSAN2 disease locus to 12p13.33 (maximum lod score of 8.4).

MOLECULAR GENETICS

Among 5 families with HSAN2, including those from Newfoundland reported
by Ogryzlo (1946) and patients from rural Quebec and Nova Scotia,
Lafreniere et al. (2004) identified 3 different truncating mutations in
the HSN2 isoform of the WNK1 gene (605232.0003-605232.0005)

In 4 affected members of a large consanguineous Lebanese family with
HSAN2, Riviere et al. (2004) identified a homozygous 1-bp deletion in
the HSN2 isoform of the WNK1 gene (605232.0006).

In 16 patients from 13 HSAN2 families originating from southern Quebec,
Roddier et al. (2005) identified 2 HSN2 founder mutations: 56% of
patients were homozygous for a nonsense mutation (Q315X; 605232.0005),
6% were homozygous for a 1-bp insertion (918insA; 605232.0004), and 38%
were compound heterozygous for the 2 mutations.

In a Korean man with HSAN2, Cho et al. (2006) identified compound
heterozygosity for 2 mutations in the HSN2 isoform of the WNK1 gene
(605232.0008 and 605232.0009).

Coen et al. (2006) reported 3 unrelated patients with HSAN2 from Italy,
Austria, and Belgium, respectively. All had compound heterozygous or
homozygous truncating mutations in the HSAN2 gene resulting in complete
loss of protein function. All patients had early onset of a severe
sensory neuropathy with mutilating acropathy but without autonomic
dysfunction. Muscle strength was preserved.

In a girl with HSAN2, Shekarabi et al. (2008) identified compound
heterozygosity for 2 mutations in the WNK1 gene: 1 in the WNK1/HSN2
isoform (605232.0010) and 1 in the WNK1 isoform (605232.0011). She did
not have hypertension. The authors noted that all recessive mutations
associated with the HSAN2 phenotype resulted in truncations of the
WNK1/HSN2 nervous system-specific protein. Disease-causing mutations in
WNK1 resulting in pseudohyperaldosteronism type 2 (PHA2C; 614492) were
large, heterozygous intronic deletions that increase the gene
expression. This impact on the expression level in PHA2C patients may
explain the absence of hypertension in individuals affected with HSAN2,
as the expression of the WNK1 isoform in which the HSN2 exon is not
incorporated should not be affected. The findings in their patient
suggested that 1 mutation in the HSN2 exon is sufficient to cause the
HSAN2 phenotype when combined with a mutation in WNK1 on the other
allele. Moreover, homozygous mutations disrupting WNK1 isoforms without
HSN2 may be lethal, which would explain why all loss-of-function
mutations reported to date have been located in the HSN2 exon.

POPULATION GENETICS

Clustering of cases of HSAN II in eastern Canada was reported by Murray
(1973) and had first been noted in Newfoundland in the early 1900s. The
original family members came from Dorset, United Kingdom, approximately
100 years earlier, as part of a mass migration of Protestant settlers
from southwestern England and Roman Catholic settlers from southern
Ireland (Lafreniere et al., 2004).

Roddier et al. (2005) reported that 12 of 16 patients with HSAN2
originated from the Lanaudiere region of Quebec, along the Saint
Lawrence River, that was first settled by the French during the second
half of the 17th century. Several of the families were consanguineous,
and several of the families were distantly related. The affected family
reported by Heller and Robb (1955) also originated from the Lanaudiere
region. The regional carrier frequency for the identified Q315X and
918insA mutations was estimated at 1 in 116 and 1 in 260, respectively.

*FIELD* SA
Barry et al. (1974); Hozay (1953); Van Bogaert (1957)
*FIELD* RF
1. Barry, J. E.; Hopkins, I. J.; Neal, B. W.: Congenital sensory
neuropathy. Arch. Dis. Child. 49: 128-132, 1974.

2. Biemond, A.: Investigation of the brain in a case of congenital
and familial analgesia. (Abstract) Proc. 11th Int. Cong. Neuropath.,
London , 9/1955.

3. Bockers, M.; Benes, P.; Bork, K.: Persistent skin ulcers, mutilations,
and acro-osteolysis in hereditary sensory and autonomic neuropathy
with phospholipid excretion: report of a family. J. Am. Acad. Derm. 21:
736-739, 1989.

4. Cho, H.-J.; Kim, B. J.; Suh, Y.-L.; An, J.-Y.; Ki, C.-S.: Novel
mutation in the HSN2 gene in a Korean patient with hereditary sensory
and autonomic neuropathy type 2. J. Hum. Genet. 51: 905-908, 2006.

5. Coen, K.; Pareyson, D.; Auer-Grumbach, M.; Buyse, G.; Goemans,
N.; Claeys, K. G.; Verpoorten, N.; Laura, M.; Scaioli, V.; Salmhofer,
W.; Pieber, T. R.; Nelis, E.; De Jonghe, P.; Timmerman, V.: Novel
mutations in the HSN2 gene causing hereditary sensory and autonomic
neuropathy type II. Neurology 66: 748-751, 2006.

6. Freytag, E.; Lindenberg, R.: Neuropathologic findings in patients
of a hospital for the mentally deficient: a survey of 359 cases. Johns
Hopkins Med. J. 121: 379-392, 1967.

7. Giaccai, L.: Familial and sporadic neurogenic acro-osteolysis. Acta
Radiol. 38: 17-29, 1952.

8. Haddow, J. E.; Shapiro, S. R.; Gall, D. G.: Congenital sensory
neuropathy in siblings. Pediatrics 45: 651-655, 1970.

9. Heller, I. H.; Robb, P.: Hereditary sensory neuropathy. Neurology 5:
15-29, 1955.

10. Hould, F.; Verret, S.: Neuropathie radiculaire hereditaire avec
pertes de sensibilite: etude d'une famille Canadienne-Francaise. Laval
Med. 38: 454-459, 1967.

11. Hozay, J.: Sur une dystrophie familiale particuliere (inhibition
precoce de la croissance et osteolyse non-mutilante acrales avec dysmorphie
faciale). Rev. Neurol. 89: 245-258, 1953.

12. Jedrzejowska, H.; Milczarek, H.: Recessive hereditary sensory
neuropathy. J. Neurol. Sci. 29: 371-387, 1976.

13. Johnson, R. H.; Spalding, J. M. K.: Progressive sensory neuropathy
in children. J. Neurol. Neurosurg. Psychiat. 27: 125-130, 1964.

14. Lafreniere, R. G.; MacDonald, M. L. E.; Dube, M.-P.; MacFarlane,
J.; O'Driscoll, M.; Brais, B.; Meilleur, S.; Brinkman, R. R.; Dadivas,
O.; Pape, T.; Platon, C.; Radomski, C.; and 14 others: Identification
of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy
type II through the study of Canadian genetic isolates. Am. J. Hum.
Genet. 74: 1064-1073, 2004.

15. Murray, T. J.: Congenital sensory neuropathy. Brain 96: 387-394,
1973.

16. Ogden, T. E.; Robert, F.; Carmichael, E. A.: Some sensory syndromes
in children: indifference to pain and sensory neuropathy. J. Neurol.
Neurosurg. Psychiat. 22: 267-276, 1959.

17. Ogryzlo, M. A.: A familial peripheral neuropathy of unknown etiology
resembling Morvan's disease. Canad. Med. Assoc. J. 54: 547-553,
1946.

18. Ohta, M.; Ellefson, R. D.; Lambert, E. H.; Dyck, P. J.: Hereditary
sensory neuropathy, type II: Clinical, electrophysiologic, histologic,
and biochemical studies of a Quebec kinship. Arch. Neurol. 29: 23-37,
1973.

19. Parks, H.; Staples, O. S.: Two cases of Morvan's syndrome of
uncertain cause. Arch. Intern. Med. 75: 75-81, 1945.

20. Riviere, J.-B.; Verlaan, D. J.; Shekarabi, M.; Lafreniere, R.
G.; Benard, M.; Der Kaloustian, V. M.; Shbaklo, Z.; Rouleau, G. A.
: A mutation in the HSN2 gene causes sensory neuropathy type II in
a Lebanese family. Ann. Neurol. 56: 572-575, 2004.

21. Roddier, K.; Thomas, T.; Marleau, G.; Gagnon, A. M.; Dicaire,
M. J.; St-Denis, A.; Gosselin, I.; Sarrazin, A. M.; Larbrisseau, A.;
Lambert, M.; Vanasse, M.; Gaudet, D.; Rouleau, G. A.; Brais, B.:
Two mutations in the HSN2 gene explain the high prevalence of HSAN2
in French Canadians. Neurology 64: 1762-1767, 2005.

22. Schoene, W. C.; Asbury, A. K.; Astrom, K. E.; Masters, R.: Hereditary
sensory neuropathy: a clinical and ultrastructural study. J. Neurol.
Sci. 11: 463-487, 1970.

23. Shekarabi, M.; Girard, N.; Riviere, J.-B.; Dion, P.; Houle, M.;
Toulouse, A.; Lafreniere, R. G.; Vercauteren, F.; Hince, P.; Laganiere,
J.; Rochefort, D.; Faivre, L.; Samuels, M.; Rouleau, G. A.: Mutations
in the nervous system-specific HSN2 exon of WNK1 cause hereditary
sensory neuropathy type II. J. Clin. Invest. 118: 2496-2505, 2008.

24. Sirinavin, C.; Buist, N. R. M.; Mokkhaves, P.: Digital clubbing,
hyperhidrosis, acroosteolysis and osteoporosis: a case resembling
pachydermoperiostosis. Clin. Genet. 22: 83-89, 1982.

25. Sugiura, Y.; Sengoku, H.: Familial neurogenic acro-osteolysis,
type Giaccai--report of two families. Jpn. J. Hum. Genet. 31: 49-56,
1986.

26. Van Bogaert, L.: Familial ulcers, mutilating lesions of the extremities
and acro-osteolysis. Brit. Med. J. 2: 367-371, 1957.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Eyes];
Impaired corneal reflex;
[Mouth];
Decreased taste sensation

ABDOMEN:
[Gastrointestinal];
Poor feeding;
Gastroesophageal reflux

SKELETAL:
Painless fractures due to injury;
Neurogenic joint degeneration;
[Hands];
Acroosteolysis;
Acral ulceration leading to autoamputation of digits;
[Feet];
Acroosteolysis;
Acral ulceration leading to autoamputation of digits

SKIN, NAILS, HAIR:
[Skin];
Hyperhidrosis, episodic;
Anhidrosis, patchy;
Ulcerations of distal extremities;
[Nails];
Paronychia

MUSCLE, SOFT TISSUE:
Muscle strength and bulk is preserved

NEUROLOGIC:
[Peripheral nervous system];
Impaired sensation in distal extremities (pain, temperature, position,
touch);
Lower limbs more affected than upper limbs;
Trunk may be involved later;
Decreased taste sensation;
Impaired corneal reflex;
Impaired gag reflex;
Hyporeflexia;
Areflexia;
Hypotonia;
Decreased sensory nerve conduction velocities (NCV);
Sural nerve biopsy shows severe loss of myelinated fibers;
Some loss of unmyelinated fibers;
Absence of cutaneous sensory receptors and fibers;
Autonomic involvement does not always occur

LABORATORY ABNORMALITIES:
Decreased axonal flare response after intradermal histamine injection

MISCELLANEOUS:
Onset in infancy or early childhood;
Slow progression;
High disease prevalence among French-Canadians

MOLECULAR BASIS:
Caused by mutation in the HSN2 isoform of the protein kinase, lysine-deficient
1 gene (WNK1, 605232.0003)

*FIELD* CN
Cassandra L. Kniffin - revised: 5/18/2004

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

*FIELD* ED
joanna: 07/02/2013
ckniffin: 2/6/2009
ckniffin: 6/25/2007
ckniffin: 8/17/2005
ckniffin: 9/13/2004
ckniffin: 9/9/2004
joanna: 9/8/2004
ckniffin: 5/18/2004

*FIELD* CN
Cassandra L. Kniffin - updated: 1/23/2009
Cassandra L. Kniffin - updated: 6/25/2007
Cassandra L. Kniffin - updated: 12/27/2006
Cassandra L. Kniffin - updated: 8/17/2005
Cassandra L. Kniffin - updated: 12/20/2004
Cassandra L. Kniffin - reorganized: 5/21/2004
Victor A. McKusick - updated: 4/23/2004

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
carol: 02/12/2014
alopez: 2/27/2012
alopez: 11/10/2009
ckniffin: 11/10/2009
wwang: 2/6/2009
ckniffin: 1/23/2009
wwang: 6/28/2007
ckniffin: 6/25/2007
wwang: 1/2/2007
ckniffin: 12/27/2006
wwang: 10/23/2006
wwang: 8/22/2005
ckniffin: 8/17/2005
terry: 6/9/2005
tkritzer: 12/28/2004
ckniffin: 12/20/2004
carol: 5/21/2004
ckniffin: 5/18/2004
tkritzer: 4/30/2004
tkritzer: 4/28/2004
terry: 4/23/2004
alopez: 3/17/2004
carol: 4/29/2003
mimadm: 11/12/1995
carol: 3/10/1994
carol: 4/17/1992
supermim: 3/16/1992
carol: 3/8/1992
carol: 3/7/1992

MIM 605232
*RECORD*
*FIELD* NO
605232
*FIELD* TI
*605232 PROTEIN KINASE, LYSINE-DEFICIENT 1; WNK1
;;PROSTATE-DERIVED STERILE 20-LIKE KINASE; PSK;;
read morePRKWNK1;;
KDP;;
KIAA0344
WNK1/HSN2 ISOFORM, INCLUDED
*FIELD* TX

CLONING

Nagase et al. (1997) cloned a WNK1 cDNA, which they called KIAA0344. The
deduced protein contains 1,246 amino acids. RT-PCR detected highest
expression in kidney.

Using degenerate PCR against conserved kinase catalytic subdomains,
Moore et al. (2000) cloned human WNK1, which they called PSK. PSK
belongs to the STE20 family of serine-threonine kinases. The PSK protein
contains 1,235 amino acids and has an N-terminal kinase domain. PSK was
ubiquitously expressed in all tissues examined by Northern blot
analysis, with strongest expression in testis.

Xu et al. (2000) isolated a full-length rat cDNA encoding Wnk1 and
identified homologs in various species, including partial human
sequences. The N-terminal half of the deduced 2,126-amino acid rat
protein has a proline-rich region, followed by a serine/threonine kinase
domain and coiled-coil region, and the C-terminal half has a
proline-rich region and coiled-coil region. Wnk1 contains a cysteine
instead of the usual lysine at a key position in its active site.
Immunoblot analysis detected an endogenous 230-kD protein in rat brain
and several mammalian cell lines, including human embryonic kidney
(HEK293) cells. Most endogenous WNK1 protein was found in the
particulate fraction of HEK293 cells, suggesting that WNK1 is associated
with membranes or the cytoskeleton. Immunofluorescence analysis of
HEK293 cells transfected with rat Wnk1 revealed cytoplasmic staining.

Wilson et al. (2001) noted that the deduced human and rat WNK1 proteins
share 86% identity. By Northern blot analysis, they observed expression
of human WNK1 in most tissues, with 2 predominant isoforms: a 10-kb
transcript expressed at high levels in the kidney, and a 12-kb
transcript predominant in heart and skeletal muscle. By
immunofluorescence microscopy, Wilson et al. (2001) demonstrated that
WNK1 localizes to the distal convoluted tubule and the cortical
collecting duct, and is also abundant in the medullary collecting duct.

Choate et al. (2003) examined the distribution of WNK1 in extrarenal
tissues. Immunostaining using WNK1-specific antibodies demonstrated that
WNK1 was not present in all cell types; rather, it was predominantly
localized in polarized epithelia, including those lining the lumen of
the hepatic biliary ducts, pancreatic ducts, epididymis, sweat ducts,
colonic crypts, and gallbladder. WNK1 was also found in the basal layers
of epidermis and throughout the esophageal epithelium. Subcellular
localization of WNK1 varied among these epithelia. WNK1 was cytoplasmic
in kidney, colon, gallbladder, sweat duct, skin, and esophagus. In
contrast, it localized to the lateral membrane in bile ducts, pancreatic
ducts, and epididymis. These epithelia are all notable for their
prominent role in chloride-iron flux.

Using primer extension with human leukocyte and kidney RNA, 5-prime RACE
of human heart and kidney cDNA libraries, and RT-PCR of human heart,
skeletal muscle, and kidney RNA, Delaloy et al. (2003) characterized
several WNK1 variants resulting from tissue-specific splicing and the
use of multiple transcriptional start sites and polyadenylation sites.
Two promoters in exon 1 generate 2 ubiquitously expressed WNK1 isoforms
with complete kinase domains. A third promoter in exon 4A generates a
kidney-specific transcript that encodes an N-terminally truncated
protein that is kinase defective. Exon 4A is highly conserved between
human and rodents and encodes a cysteine-rich region. Northern blot
analysis detected a 9-kb transcript expressed predominantly in human
kidney and a 10.5-kb transcript expressed predominantly in skeletal
muscle, heart, and brain. Qualitative RT-PCR detected 10 times more
kinase-defective transcript than kinase domain-containing transcript in
human kidney mRNA. In situ hybridization of adult mouse kidney using an
exon 4A-specific probe revealed expression in kidney cortex,
predominantly in distal convoluted tubules.

- WNK1/HSN2 Isoform

Lafreniere et al. (2004) identified a novel gene, which they designated
HSN2, within the hereditary sensory neuropathy type II (HSAN2; 201300)
critical region on 12p13.33. The HSN2 gene encodes a deduced 434-amino
acid protein. Northern blot analysis of adult human tissues failed to
detect HSN2 transcripts, suggesting that the gene might be expressed at
very low levels. Lafreniere et al. (2004) suggested that the HSN2
protein may play a role in the development and/or maintenance of
peripheral sensory neurons or their supporting Schwann cells.

By Northern blot and RT-PCR analysis using mouse Wnk1, Shekarabi et al.
(2008) concluded that HSN2 is an alternatively spliced exon of WNK1 and
is part of a nervous system-specific isoform of WNK1, which they called
WNK1/HSN2. Northern blot analysis of mouse tissues showed a 10-kb
transcript exclusively expressed in nervous system tissues, including
the spinal cord, brain, and dorsal root ganglia. RT-PCR analysis
demonstrated that the Wnk1/Hsn2 isoform includes either the Hsn2 exon
alone or Hsn2 along with a novel exon 8B and lacks exons 11 and 12.
Immunohistochemical studies confirmed localization of the Wnk1/Hsn2
isoform to mouse nervous system tissues.

GENE STRUCTURE

Wilson et al. (2001) determined that the WNK1 gene contains 28 exons
that span 156 kb of genomic DNA.

Delaloy et al. (2003) identified 2 promoters in exon 1 of the WNK1 gene,
including 1 within the coding region, that generate ubiquitously
expressed WNK1 transcripts. A third promoter, located in the alternative
exon 4A within intron 4, generates a kidney-specific transcript. The
promoters lack TATA boxes, are GC-rich, and contain several
transcription factor-binding sites. A repressor element is present in
the most 5-prime promoter in exon 1. In addition, WNK1 has multiple
transcription start sites in exon 1 and 2 polyadenylation sites at its
3-prime end.

- WNK1/HSN2 Isoform

Lafreniere et al. (2004) determined that the HSN2 gene consists of a
single exon that is located within intron 8 of the WNK1 gene and
transcribed from the same strand. The authors initially concluded that
the WNK1 and HSN2 genes were differentially regulated. Subsequently,
Shekarabi et al. (2008) determined that HSN2 is a nervous-system
specific exon of the WNK1 gene, and they identified a novel exon 8B.

MAPPING

By analysis of a radiation hybrid panel, Nagase et al. (1997) mapped the
WNK1 gene to chromosome 12.

GENE FUNCTION

Moore et al. (2000) found that immunoprecipitated PSK phosphorylated
myelin basic protein (159430) and transfected PSK-stimulated MKK4
(601335) and MKK7 (603014), and activated the c-Jun N-terminal kinase
(JNK) mitogen-activated protein kinase (MAPK) pathway (see 603014).
Microinjection of PSK into cells resulted in localization of PSK to a
vesicular compartment and caused a marked reduction in actin stress
fibers. In contrast, C-terminally truncated PSK did not localize to this
compartment or induce a decrease in stress fibers, demonstrating a
requirement for the C terminus. Kinase-defective PSK, carrying a
lys57-to-ala (K57A) mutation, was unable to reduce stress fibers.

Xu et al. (2002) expressed fragments of rat Wnk1 in bacteria and
identified an autoinhibitory region just C-terminal to the kinase
domain. The isolated autoinhibitory domain, which is conserved in all 4
human WNKs, suppressed the activity of the Wnk1 kinase domain. Mutation
of 2 conserved phenylalanines in the autoinhibitory domain (phe524 and
phe526 in rat Wnk1) attenuated its ability to inhibit Wnk1 kinase
activity, and the same mutations in a Wnk1 fragment containing the
autoinhibitory domain increased its kinase activity. Wnk1 expressed in
bacteria was autophosphorylated, and autophosphorylation of ser382 in
the activation loop was required for its activity.

Yang et al. (2003) found that mouse Wnk4 (601844) reduced the plasma
membrane association of the thiazide-sensitive sodium-chloride
cotransporter (NCC, or SLC12A3; 600968) in injected Xenopus oocytes.
They further demonstrated that Wnk1 did not affect Slc12a3-mediated
sodium uptake in oocytes, but coexpression of Wnk1 with both Wnk4 and
Slc12a3 restored sodium uptake to levels observed in oocytes expressing
Slc12a3 alone.

To investigate the mechanisms by which WNK1 and WNK4 interact to
regulate ion transport, Yang et al. (2005) performed experiments in
HEK293 cells and Xenopus oocytes which showed that the WNK4 C terminus
mediates SLC12A3 suppression, that the WNK1 kinase domain interacts with
the WNK4 kinase domain, and that WNK1 inhibition of WNK4 is dependent on
WNK1 catalytic activity and an intact WNK1 protein.

Yang et al. (2007) noted that WNK1, WNK4, and the kidney-specific WNK1
isoform interact to regulate SLC12A3 activity, suggesting that WNKs form
a signaling complex. They found that human WNK3 (300358), which is
expressed by distal tubule cells, interacted with rodent Wnk1 and Wnk4
to regulate SLC12A3 in cultured kidney cells and Xenopus oocytes.
Regulation of SLC12A3 in oocytes resulted from antagonism between WNK3
and Wnk4.

Lee et al. (2004) found that rat Wnk1 selectively bound to and
phosphorylated synaptotagmin-2 (SYT2; 600104) calcium-binding C2
domains. Endogenous Wnk1 and Syt2 coimmunoprecipitated and colocalized
on a subset of secretory granules in a rat insulinoma cell line.
Phosphorylation by Wnk1 increased the amount of Ca(2+) required for Syt2
binding to phospholipid vesicles. Lee et al. (2004) concluded that
phosphorylation of SYT2 by WNK1 can regulate Ca(2+) sensing and the
subsequent Ca(2+)-dependent interactions mediated by synaptotagmin C2
domains.

Lenertz et al. (2005) found that hypertonic stress activated rat Wnk1
when it was expressed in kidney epithelial cells and breast and colon
cancer cell lines. Hypotonic stress led to a modest increase in Wnk1
activity. Gel filtration suggested that Wnk1 exists as a tetramer, and
yeast 2-hybrid analysis revealed interaction between residues 1 to 222
of the Wnk1 N terminus and Wnk1 residues 481 to 660, which contain the
autoinhibitory domain and a coiled-coil region. Lenertz et al. (2005)
found no direct interaction between Wnk1 and Wnk4, but Wnk1
phosphorylated both Wnk2 (606249) and Wnk4, and the Wnk1 autoinhibitory
domain inhibited the catalytic activities of Wnk2 and Wnk4.

Using Xenopus oocytes and Chinese hamster ovary cells, Xu et al. (2005)
showed that WNK1 controls ion permeability by activating SGK1 (602958),
leading to activation of the epithelial sodium channel (see SCNN1A;
600228). Increased WNK1-induced channel activity depended on SGK1 and
the E3 ubiquitin ligase, NEDD4-2 (NEDD4L; 606384).

Alternative splicing of WNK1 produces a kidney-specific short form that
lacks a kinase domain, KS-WNK1, and a more ubiquitous long form, L-WNK1.
Using reconstitution studies in Xenopus oocytes, Wade et al. (2006)
found that rat L-Wnk1 inhibited the K+ channel Kir1.1 (KCNJ1; 600359) by
reducing its cell surface localization, and this inhibition required an
intact kinase domain. Ks-Wnk1 did not directly alter Kir1.1 channel
activity, but it acted as a dominant-negative inhibitor of L-Wnk1 and
released Kir1.1 from inhibition. Acute dietary potassium loading in rats
increased the relative abundance of Ks-Wnk1 to L-Wnk1 transcript and
protein in kidney, indicating that physiologic upregulation of Kir1.1
activity involves a WNK1 isoform switch.

By yeast 2-hybrid analysis of Jurkat human T cells and
immunoprecipitation analysis of human embryonic kidney cells and HeLa
cells, Anselmo et al. (2006) showed that OSR1 (OXSR1; 604046) and WNK1
interacted through conserved C-terminal motifs. OSR1 was phosphorylated
in a WNK1-dependent manner, and depletion of WNK1 from HeLa cells with
small interfering RNA reduced OSR1 kinase activity. Depletion of either
WNK1 or OSR1 reduced Na-K-Cl cotransporter (NKCC; see 600839) activity,
suggesting that WNK1 and OSR1 are required for NKCC function.

He et al. (2007) showed that mammalian Wnk1 and Wnk4 interacted with the
endocytic scaffold protein intersectin-1 (ITSN1; 602442) and that these
interactions were crucial for stimulation of Romk1 (KCNJ1) endocytosis.
Stimulation of Romk1 endocytosis by Wnk1 and Wnk4 required their
proline-rich motifs, but it did not require their kinase activities.
Pseudohypoaldosteronism II (145260)-causing mutations in Wnk4 enhanced
the interactions of Wnk4 with Itsn1 and Romk1, leading to increased
endocytosis of Romk1.

Yang et al. (2007) showed that coexpression of rodent Wnk1 and Wnk4 with
human CFTR (602421) suppressed CFTR-dependent chloride channel activity
in Xenopus oocytes. The effect of Wnk4 was dose dependent, independent
of Wnk4 kinase activity, and occurred, at least in part, by reducing
CFTR protein abundance at the plasma membrane. In contrast, the effect
of Wnk1 on CFTR activity required Wnk1 kinase activity. Moreover, Wnk1
and Wnk4 exhibited additive CFTR inhibition.

MOLECULAR GENETICS

- Pseudohypoaldosteronism Type IIC

Wilson et al. (2001) identified WNK1 as the gene mutant in one form of
pseudohypoaldosteronism type II (PHA2C; 614492), an autosomal dominant
disorder characterized by hypertension, hyperkalemia, and renal tubular
acidosis. In a 10-member kindred segregating PHAII, they identified a
41-kb deletion in intron 1 of WNK1 (605232.0001). In the family
previously described by Disse-Nicodeme et al. (2000), they identified a
22-kb deletion within intron 1 of WNK1 (605232.0002). Wilson et al.
(2001) found that affected individuals carrying the 22-kb deletion had a
5-fold increase in the level of WNK1 transcripts in leukocytes relative
to those of their unaffected relatives, thus demonstrating that the
deletion alters WNK1 expression.

- Hereditary Sensory and Autonomic Neuropathy II

Among from 5 families with HSAN2, including 2 from Newfoundland, 2 from
rural Quebec, and 2 from Nova Scotia, Lafreniere et al. (2004)
identified 3 different truncating mutations in the WNK1 gene (594delA,
605232.0003; 918insA, 605232.0004; Q315X, 605232.0005).

Roddier et al. (2005) identified 2 founder mutations in the WNK1 gene
(918insA and Q315X) that were responsible for HSAN2 in the southern part
of Quebec.

Coen et al. (2006) reported 3 unrelated patients with HSAN2 from Italy,
Austria, and Belgium, respectively. All had compound heterozygous or
homozygous truncating mutations in the WNK1 gene, resulting in complete
loss of protein function. All patients had early onset of a severe
sensory neuropathy with mutilating acropathy but without autonomic
dysfunction. Muscle strength was preserved.

- Hypokalemic Salt-Losing Renal Tubulopathy

Zhang et al. (2013) studied 44 Chinese patients with hypokalemia of
unknown cause, metabolic alkalosis, and normal to low blood pressure. In
33 patients, they identified homozygosity or compound heterozygosity for
known mutations in the CLCNKB (602023) or SLC12A3 (600968) genes,
associated with forms of Bartter syndrome (see 607364) and Gitelman
syndrome (263800), respectively. Of the 11 remaining patients, 8 were
heterozygous for a mutation in the SLC12A3 gene, whereas in 3, no
mutation was detected in either gene. Screening for mutations in the
candidate genes WNK1 and WNK4 (601844) revealed heterozygosity for 2
missense mutations in WNK1 (605232.0012 and 605232.0013, respectively)
in 2 of the 11 patients, both of whom were also heterozygous for a known
mutation in SLC12A3, each of which had previously been reported in a
patient diagnosed with Gitelman syndrome (Simon et al., 1996 and Shao et
al., 2008, respectively). No mutations were detected in WNK4. Zhang et
al. (2013) suggested that inactivating mutations in WNK1 may cause
salt-losing renal tubulopathy, which represents a phenotype that is the
converse of PHAII, caused by WNK1 gain-of-function mutations.

GENOTYPE/PHENOTYPE CORRELATIONS

In a girl with HSAN2, Shekarabi et al. (2008) identified compound
heterozygosity for 2 mutations in the WNK1 gene: 1 in the WNK1/HSN2
isoform (605232.0010) and 1 in the WNK1 isoform (605232.0011). She did
not have hypertension. The authors noted that all recessive mutations
associated with the HSAN2 phenotype resulted in truncations of the
WNK1/HSN2 nervous system-specific protein. Disease-causing mutations in
WNK1 resulting in PHA2C were large, heterozygous intronic deletions that
increase the gene expression. This impact on the expression level in
PHA2C patients may explain the absence of hypertension in individuals
affected with HSAN2, as the expression of the WNK1 isoform in which the
HSN2 exon is not incorporated should not be affected. The findings in
their patient suggested that 1 mutation in the HSN2 exon is sufficient
to cause the HSAN2 phenotype when combined with a mutation in WNK1 on
the other allele. Moreover, homozygous mutations disrupting WNK1
isoforms without HSN2 may be lethal, which would explain why all
loss-of-function mutations reported to date have been located in the
HSN2 exon.

ANIMAL MODEL

To accelerate the genetic determination of gene function, Zambrowicz et
al. (2003) developed a sequence-tagged gene-trap library of more than
270,000 mouse embryonic stem cell clones representing mutations in
approximately 60% of mammalian genes. Through the generation and
phenotypic analysis of knockout mice from this resource, they undertook
a functional screen to identify genes regulating physiologic parameters
such as blood pressure. As part of this screen, mice deficient for the
Wnk1 gene were generated and analyzed. Genetic studies in humans had
shown that large intronic deletions in WNK1 lead to its overexpression
and are responsible for pseudohypoaldosteronism type II (Wilson et al.,
2001), an autosomal dominant disorder characterized by hypertension,
increased renal salt reabsorption, and impaired potassium and hydrogen
excretion. Consistent with the human genetic studies, Wnk1 heterozygous
mice displayed a significant decrease in blood pressure. Mice homozygous
for the Wnk1 mutation died during embryonic development before day 13 of
gestation. Zambrowicz et al. (2003) concluded that WNK1 is a regulator
of blood pressure critical for development and illustrated the utility
of a functional screen driven by a sequence-based mutagenesis approach.

*FIELD* AV
.0001
PSEUDOHYPOALDOSTERONISM, TYPE IIC
WNK1, 41-KB DEL, IVS1

In a family with pseudohypoaldosteronism type II (PHA2C; 614492), Wilson
et al. (2001) identified a 41-kb deletion in intron 1 of the WNK1 gene.

.0002
PSEUDOHYPOALDOSTERONISM, TYPE IIC
WNK1, 22-KB DEL, IVS1

In a family with pseudohypoaldosteronism type II (PHA2C; 614492)
reported by Disse-Nicodeme et al. (2000), Wilson et al. (2001)
identified a 21,761-bp deletion in intron 1 of the WNK1 gene. Affected
individuals had a 5-fold increase in the level of WNK1 transcripts in
leukocytes compared to those of unaffected family members.

.0003
NEUROPATHY, HEREDITARY SENSORY, TYPE II
WNK1, 1-BP DEL, 594A

In affected members of 2 Newfoundland families with hereditary sensory
neuropathy type II (201300), 1 of which was consanguineous, Lafreniere
et al. (2004) identified a homozygous 1-bp deletion in the HSN2 exon of
the WNK1 gene, 594delA, resulting in a frameshift at codon 198 with a
premature termination and a truncated 206-amino acid peptide. Numbering
of this mutation is based on the HSN exon ORF only.

.0004
NEUROPATHY, HEREDITARY SENSORY, TYPE II
WNK1, 1-BP INS, 918A

In 2 sisters from Nova Scotia, born to consanguineous parents, with
hereditary sensory neuropathy type II (201300), Lafreniere et al. (2004)
found homozygosity for a 1-bp insertion in the HSN2 exon of the WNK1
gene, 918insA, resulting in a frameshift at codon 307 with a premature
termination and a truncated 318-amino acid peptide. In 2 French Canadian
sisters with HSAN2, the 918insA mutation was in compound heterozygous
state with the Q315X mutation (605232.0005). Numbering of this mutation
is based on the HSN exon ORF only.

Roddier et al. (2005) identified the 918insA mutation in 7 (58%) of 12
HSAN2 patients from the Lanaudiere region of southern Quebec, suggesting
a founder effect. One patient was homozygous, and 6 were compound
heterozygous with the Q315X mutation. Regional carrier frequency of the
918insA mutation was estimated to range from 1 in 260 to 1 in 28.

.0005
NEUROPATHY, HEREDITARY SENSORY, TYPE II
WNK1, GLN315TER

In a French Canadian patient with hereditary sensory neuropathy type II
(201300), Lafreniere et al. (2004) found homozygosity for a 943C-T
transition in the HSN2 exon of the WNK1 gene, resulting in a
gln315-to-ter substitution (Q315X) predicted to truncate the protein to
314 amino acids. In 2 French Canadian sisters with HSAN2, the Q315X
mutation was found in compound heterozygous state with the 918insA
mutation (605343.0004) in the HSN2 exon. Numbering of this mutation is
based on the HSN exon ORF only.

In affected members of families with HSAN2 (201300) from the the
southern part of Quebec, Roddier et al. (2005) identified the Q315X
mutation. Nine (56%) of 16 patients were homozygous for the mutation,
and 6 (38%) of 16 patients were compound heterozygous with the 918insA
mutation. Most of the patients were from the Lanaudiere region. Regional
carrier frequency of the Q315X mutation was estimated to range from 1 in
116 to 1 in 18.

.0006
NEUROPATHY, HEREDITARY SENSORY, TYPE II
WNK1, 1-BP DEL, 947C

In 4 affected members of a large consanguineous Lebanese family with
hereditary sensory neuropathy type II (201300), Riviere et al. (2004)
identified a homozygous 1-bp deletion (947delC) in the HSN2 exon of the
WNK1 gene, resulting in the loss of 117 amino acids from the protein.
Numbering of this mutation is based on the HSN exon ORF only.

.0007
NEUROPATHY, HEREDITARY SENSORY, TYPE II
WNK1, ARG290TER

In a 13-year-old Canadian child of Lebanese origin with HSAN2 (201300),
Roddier et al. (2005) identified a homozygous 868C-T transition in the
HSN2 exon of the WNK1 gene, resulting in an arg290-to-ter (R290X)
substitution. The authors noted that this mutation differed from that
reported in another Lebanese family (605232.0006).

.0008
NEUROPATHY, HEREDITARY SENSORY, TYPE II
WNK1, 1-BP INS, 1134T

In a 28-year-old Korean man with HSAN2 (201300), Cho et al. (2006)
identified compound heterozygosity for 2 mutations in the HSN2 exon of
the WNK1 gene: a 1-bp insertion (1134insT) and a 217C-T transition,
resulting in a gln73-to-ter (Q73X; 605232.0009) substitution. The
patient had childhood onset of the disorder and amputation of both lower
limbs and several fingers due to ulceration and infection. The patient's
unaffected mother was heterozygous for the 1-bp insertion, and 3
unaffected sibs were heterozygous for the Q73X mutation. The father was
deceased. Numbering of this mutation is based on the HSN exon ORF only.

Takagi et al. (2006) identified homozygosity for the 1134insT mutation
in a Japanese patient with HSAN2, born of consanguineous parents. The
insertion results in frameshift and premature termination of the protein
at residue 378. The patient noted that he felt no pain in his
extremities during his teenage years. He had recurrent skin ulcers on
his fingers and toes resulting in spontaneous or surgical amputation of
several digit tips. Physical examination at age 39 years showed no
autonomic involvement.

.0009
NEUROPATHY, HEREDITARY SENSORY, TYPE II
WNK1, GLN73TER

See Cho et al. (2006) and 605232.0008.

.0010
NEUROPATHY, HEREDITARY SENSORY, TYPE II
WNK1, 1-BP DEL, 639A

In an 18-year-old French girl with HSAN2 (201300), Shekarabi et al.
(2008) identified a heterozygous 1-bp deletion (639delA) in the HSN2
exon of the WNK1 gene, resulting in a frameshift and premature
termination. Numbering of this mutation is based on the HSN exon ORF
only. Her unaffected father and brother also carried the heterozygous
mutation. Screening of the rest of the WNK1/HSN2 isoform did not reveal
any mutations. However, subsequent screening of the girl in other exons
in the WNK1 gene revealed a heterozygous 2-bp deletion (1584_1585delAG;
605232.0011) in exon 6 of the WNK1 gene, which resulted in frameshift at
codon 531 and premature termination at codon 547 (asp531fsX547). This
mutation was inherited from the unaffected mother. Neither the girl nor
the mother showed signs of hypertension. The findings prompted Shekarabi
et al. (2008) to concluded that HSN2 is an alternative exon within WNK1,
rather than an independent gene.

.0011
NEUROPATHY, HEREDITARY SENSORY, TYPE II
WNK1, 2-BP DEL, 1584AG

See 605232.0010 and Shekarabi et al. (2008).

.0012
VARIANT OF UNKNOWN SIGNIFICANCE
WNK1, ILE1172MET

This variant is classified as a variant of unknown significance because
its contribution to hypokalemic salt-losing renal tubulopathy (see
241150) has not been confirmed due to the presence of an additional
heterozygous mutation in the SLC12A3 gene (600968).

In a Chinese patient who presented at 10 years of age with fatigue,
numbness, enuresis, and nocturia and was found to have hypokalemia,
metabolic alkalosis, and low to normal blood pressure and to be
heterozygous for a known splice site mutation (7426del13ins12; Shao et
al., 2008) in the SLC12A3 gene, Zhang et al. (2013) identified
heterozygosity for an A-G transition in exon 16 of the WNK1 gene,
resulting in an ile1172-to-met (I1172M) substitution at an
evolutionarily conserved residue within a coiled-coil domain in the C
terminus. The I1172M mutation arose de novo, as neither parent carried
the WNK1 variant, and it was not found in 400 control alleles or
reported in dbSNP or HGMD databases. However, his unaffected mother was
heterozygous for the SLC12A3 indel splice site mutation. Functional
analysis in HEK293 cells using the corresponding rat WNK1 mutation,
I918M, showed reduced SLC12A3 protein membrane expression in vitro when
cotransfected with WNK4, due to complete abolishment of the suppressive
effect of WNK4-mediated inhibition.

.0013
VARIANT OF UNKNOWN SIGNIFICANCE
WNK1, SER2047ASN

This variant is classified as a variant of unknown significance because
its contribution to hypokalemic salt-losing renal tubulopathy (see
241150) has not been confirmed due to the presence of an additional
heterozygous mutation in the SLC12A3 gene (600968).

In a Chinese man who presented at age 26 years with fatigue and
hypotonia and was found to have hypokalemia, metabolic alkalosis, and
low to normal blood pressure and to be heterozygous for a known missense
mutation (D486N; Simon et al., 1996) in the SLC12A3 gene, Zhang et al.
(2013) identified heterozygosity for a G-A transition in exon 24 of the
WNK1 gene, resulting in a ser2047-to-asn (S2047N) substitution at a
highly conserved residue within a coiled-coil domain in the C terminus.
The S2047N WNK1 mutation was inherited from his father, who also
displayed hypokalemia, alkalosis, and hypotension; the WNK1 variant was
not found in 400 control alleles or reported in dbSNP or HGMD databases.
The affected father and the patient's asymptomatic 2-year-old daughter
also carried the SLC12A3 mutation, which was not found in other
asymptomatic family members.

*FIELD* RF
1. Anselmo, A. N.; Earnest, S.; Chen, W.; Juang, Y.-C.; Kim, S. C.;
Zhao, Y.; Cobb, M. H.: WNK1 and OSR1 regulate the Na+, K+, 2Cl- cotransporter
in HeLa cells. Proc. Nat. Acad. Sci. 103: 10883-10888, 2006.

2. Cho, H.-J.; Kim, B. J.; Suh, Y.-L.; An, J.-Y.; Ki, C.-S.: Novel
mutation in the HSN2 gene in a Korean patient with hereditary sensory
and autonomic neuropathy type 2. J. Hum. Genet. 51: 905-908, 2006.

3. Choate, K. A.; Kahle, K. T.; Wilson, F. H.; Nelson-Williams, C.;
Lifton, R. P.: WNK1, a kinase mutated in inherited hypertension with
hyperkalemia, localizes to diverse Cl(-)-transporting epithelia. Proc.
Nat. Acad. Sci. 100: 663-668, 2003.

4. Coen, K.; Pareyson, D.; Auer-Grumbach, M.; Buyse, G.; Goemans,
N.; Claeys, K. G.; Verpoorten, N.; Laura, M.; Scaioli, V.; Salmhofer,
W.; Pieber, T. R.; Nelis, E.; De Jonghe, P.; Timmerman, V.: Novel
mutations in the HSN2 gene causing hereditary sensory and autonomic
neuropathy type II. Neurology 66: 748-751, 2006.

5. Delaloy, C.; Lu, J.; Houot, A.-M.; Disse-Nicodeme, S.; Gasc, J.-M.;
Corvol, P.; Jeunemaitre, X.: Multiple promoters in the WNK1 gene:
one controls expression of a kidney-specific kinase-defective isoform. Molec.
Cell. Biol. 23: 9208-9221, 2003.

6. Disse-Nicodeme, S.; Achard, J.-M.; Desitter, I.; Houot, A.-M.;
Fournier, A.; Corvol, P.; Jeunemaitre, X.: A new locus on chromosome
12p13.3 for pseudohypoaldosteronism type II, an autosomal dominant
form of hypertension. Am. J. Hum. Genet. 67: 302-310, 2000.

7. 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.

8. Lafreniere, R. G.; MacDonald, M. L. E.; Dube, M.-P.; MacFarlane,
J.; O'Driscoll, M.; Brais, B.; Meilleur, S.; Brinkman, R. R.; Dadivas,
O.; Pape, T.; Platon, C.; Radomski, C.; and 14 others: Identification
of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy
type II through the study of Canadian genetic isolates. Am. J. Hum.
Genet. 74: 1064-1073, 2004.

9. Lafreniere, R. G.; MacDonald, M. L. E.; Dube, M.-P.; MacFarlane,
J.; O'Driscoll, M.; Brais, B.; Meilleur, S.; Brinkman, R. R.; Dadivas,
O.; Pape, T.; Platon, C.; Radomski, C.; and 14 others: Identification
of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy
type II through the study of Canadian genetic isolates. Am. J. Hum.
Genet. 74: 1064-1073, 2004.

10. Lee, B.-H.; Min, X.; Heise, C. J.; Xu, B.; Chen, S.; Shu, H.;
Luby-Phelps, K.; Goldsmith, E. J.; Cobb, M. H.: WNK1 phosphorylates
synaptotagmin 2 and modulates its membrane binding. Molec. Cell 15:
741-751, 2004.

11. Lenertz, L. Y.; Lee, B.-H.; Min, X.; Xu, B.; Wedin, K.; Earnest,
S.; Goldsmith, E. J.; Cobb, M. H.: Properties of WNK1 and implications
for other family members. J. Biol. Chem. 280: 26653-26658, 2005.

12. Moore, T. M.; Garg, R.; Johnson, C.; Coptcoat, M. J.; Ridley,
A. J.; Morris, J. D. H.: PSK, a novel STE20-like kinase derived from
prostatic carcinoma that activates the c-Jun N-terminal kinase mitogen-activated
protein kinase pathway and regulates actin cytoskeletal organization. J.
Biol. Chem. 275: 4311-4322, 2000.

13. Nagase, T.; Ishikawa, I.; Nakajima, D.; Ohira, M.; Seki, N.; Miyajima,
N.; Tanaka, A.; Kotani, H.; Nomura, N.; O'Hara, O.: Prediction of
the coding sequences of unidentified human genes. VII. The complete
sequences of 100 new cDNA clones from brain which can code for large
proteins in vitro. DNA Res. 4: 141-150, 1997.

14. Riviere, J.-B.; Verlaan, D. J.; Shekarabi, M.; Lafreniere, R.
G.; Benard, M.; Der Kaloustian, V. M.; Shbaklo, Z.; Rouleau, G. A.
: A mutation in the HSN2 gene causes sensory neuropathy type II in
a Lebanese family. Ann. Neurol. 56: 572-575, 2004.

15. Roddier, K.; Thomas, T.; Marleau, G.; Gagnon, A. M.; Dicaire,
M. J.; St-Denis, A.; Gosselin, I.; Sarrazin, A. M.; Larbrisseau, A.;
Lambert, M.; Vanasse, M.; Gaudet, D.; Rouleau, G. A.; Brais, B.:
Two mutations in the HSN2 gene explain the high prevalence of HSAN2
in French Canadians. Neurology 64: 1762-1767, 2005.

16. Shao, L.; Liu, L.; Miao, Z.; Ren, H.; Wang, W.; Lang, Y.; Yue,
S.; Chen, N.: A novel SLC12A3 splicing mutation skipping of two exons
and preliminary screening for alternative splice variants in human
kidney. Am. J. Nephrol. 28: 900-907, 2008.

17. Shekarabi, M.; Girard, N.; Riviere, J.-B.; Dion, P.; Houle, M.;
Toulouse, A.; Lafreniere, R. G.; Vercauteren, F.; Hince, P.; Laganiere,
J.; Rochefort, D.; Faivre, L.; Samuels, M.; Rouleau, G. A.: Mutations
in the nervous system-specific HSN2 exon of WNK1 cause hereditary
sensory neuropathy type II. J. Clin. Invest. 118: 2496-2505, 2008.

18. Simon, D. B.; Nelson-Williams, C.; Bia, M. J.; Ellison, D.; Karet,
F. E.; Molina, A. M.; Vaara, I.; Iwata, F.; Cushner, H. M.; Koolen,
M.; Gainza, F. J.; Gitelman, H. J.; Lifton, R. P.: Gitelman's variant
of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused
by mutations in the thiazide-sensitive Na-Cl cotransporter. Nature
Genet. 12: 24-30, 1996.

19. Takagi, M.; Ozawa, T.; Hara, K.; Naruse, S.; Ishihara, T.; Shimbo,
J.; Igarashi, S.; Tanaka, K.; Onodera, O.; Nishizawa, M.: New HSN2
mutation in Japanese patient with hereditary sensory and autonomic
neuropathy type 2. Neurology 66: 1251-1252, 2006.

20. Wade, J. B.; Fang, L.; Liu, J.; Li, D.; Yang, C.-L.; Subramanya,
A. R.; Maouyo, D.; Mason, A.; Ellison, D. H.; Welling, P. A.: WNK1
kinase isoform switch regulates renal potassium excretion. Proc.
Nat. Acad. Sci. 103: 8558-8563, 2006.

21. Wilson, F. H.; Disse-Nicodeme, S.; Choate, K. A.; Ishikawa, K.;
Nelson-Williams, C.; Desitter, I.; Gunel, M.; Milford, D. V.; Lipkin,
G. W.; Achard, J.-M.; Feely, M. P.; Dussol, B.; Berland, Y.; Unwin,
R. J.; Mayan, H.; Simon, D. B.; Farfel, Z.; Jeunemaitre, X.; Lifton,
R. P.: Human hypertension caused by mutations in WNK kinases. Science 293:
1107-1112, 2001.

22. Xu, B.; English, J. M.; Wilsbacher, J. L.; Stippec, S.; Goldsmith,
E. J.; Cobb, M. H.: WNK1, a novel mammalian serine/threonine protein
kinase lacking the catalytic lysine in subdomain II. J. Biol. Chem. 275:
16795-16801, 2000.

23. Xu, B.; Stippec, S.; Chu, P.-Y.; Lazrak, A.; Li, X.-J.; Lee, B.-H.;
English, J. M.; Ortega, B.; Huang, C.-L.; Cobb, M. H.: WNK1 activates
SGK1 to regulate the epithelial sodium channel. Proc. Nat. Acad.
Sci. 102: 10315-10320, 2005.

24. Xu, B. E.; Min, X.; Stippec, S.; Lee, B. H.; Goldsmith, E. J.;
Cobb, M. H.: Regulation of WNK1 by an autoinhibitory domain and autophosphorylation. J.
Biol. Chem. 277: 48456-48462, 2002.

25. Yang, C.-L.; Angell, J.; Mitchell, R.; Ellison, D. H.: WNK kinases
regulate thiazide-sensitive Na-Cl cotransport. J. Clin. Invest. 111:
1039-1045, 2003.

26. Yang, C.-L.; Liu, X.; Paliege, A.; Zhu, X.; Bachmann, S.; Dawson,
D. C.; Ellison, D. H.: WNK1 and WNK4 modulate CFTR activity. Biochem.
Biophys. Res. Commun. 353: 535-540, 2007.

27. Yang, C.-L.; Zhu, X.; Ellison, D. H.: The thiazide-sensitive
Na-Cl cotransporter is regulated by a WNK kinase signaling complex. J.
Clin. Invest. 117: 3403-3411, 2007.

28. Yang, C.-L.; Zhu, X.; Wang, Z.; Subramanya, A. R.; Ellison, D.
H.: Mechanisms of WNK1 and WNK4 interaction in the regulation of
thiazide-sensitive NaCl cotransport. J. Clin. Invest. 115: 1379-1387,
2005.

29. Zambrowicz, B. P.; Abuin, A.; Ramirez-Solis, R.; Richter, L. J.;
Piggott, J.; BeltrandelRio, H.; Buxton, E. C.; Edwards, J.; Finch,
R. A.; Friddle, C. J.; Gupta, A.; Hansen, G.; and 22 others: Wnk1
kinase deficiency lowers blood pressure in mice: a gene-trap screen
to identify potential targets for therapeutic intervention. Proc.
Nat. Acad. Sci. 100: 14109-14114, 2003.

30. Zhang, C.; Zhu, Y.; Huang, F.; Jiang, G.; Chang, J.; Li, R.:
Novel missense mutations of WNK1 in patients with hypokalemic salt-losing
tubulopathies. Clin. Genet. 83: 545-552, 2013.

*FIELD* CN
Marla J. F. O'Neill - updated: 7/3/2013
Cassandra L. Kniffin - updated: 1/23/2009
Matthew B. Gross - updated: 2/5/2008
Patricia A. Hartz - updated: 1/17/2008
Patricia A. Hartz - updated: 10/18/2007
Patricia A. Hartz - updated: 10/5/2006
Patricia A. Hartz - updated: 9/1/2006
Patricia A. Hartz - updated: 7/11/2006
Patricia A. Hartz - updated: 5/11/2006
Marla J. F. O'Neill - updated: 5/20/2005
Victor A. McKusick - updated: 12/3/2004
Victor A. McKusick - updated: 4/23/2004
Victor A. McKusick - updated: 2/12/2003
Ada Hamosh - updated: 8/28/2001
Ada Hamosh - updated: 8/14/2001

*FIELD* CD
Victor A. McKusick: 8/28/2000

*FIELD* ED
carol: 09/16/2013
carol: 7/3/2013
joanna: 4/25/2013
alopez: 2/27/2012
wwang: 2/6/2009
ckniffin: 1/23/2009
mgross: 2/5/2008
terry: 1/17/2008
mgross: 10/18/2007
terry: 10/18/2007
mgross: 10/5/2006
mgross: 9/6/2006
mgross: 9/1/2006
mgross: 7/11/2006
terry: 7/11/2006
wwang: 6/16/2006
wwang: 6/15/2006
terry: 5/11/2006
carol: 5/26/2005
terry: 5/20/2005
tkritzer: 12/8/2004
tkritzer: 12/7/2004
terry: 12/3/2004
tkritzer: 4/28/2004
terry: 4/23/2004
carol: 3/17/2004
mgross: 2/21/2003
terry: 2/12/2003
alopez: 8/31/2001
terry: 8/28/2001
alopez: 8/14/2001
terry: 8/14/2001
carol: 8/28/2000

MIM 614492
*RECORD*
*FIELD* NO
614492
*FIELD* TI
#614492 PSEUDOHYPOALDOSTERONISM, TYPE IIC; PHA2C
*FIELD* TX
A number sign (#) is used with this entry because
read morepseudohypoaldosteronism type IIC (PHA2C) is caused by heterozygous
mutation in the WNK1 gene (605232) on chromosome 12p13.

For a phenotypic description and a discussion of genetic heterogeneity
of PHAII, see PHA2A (145260).

CLINICAL FEATURES

Disse-Nicodeme et al. (2000) analyzed a large French pedigree in which
12 affected members over 3 generations confirmed autosomal dominant
inheritance. Affected subjects had hypertension together with long-term
hyperkalemia (range, 5.2-6.2 mmol/liter), hyperchloremia (range, 100-109
mmol/liter), normal plasma creatinine, and low renin (179820) levels.

Wilson et al. (2001) studied a new PHAII kindred that included 10 living
members with typical features of PHAII, including hypertension,
hyperkalemia (mean serum potassium, 6.2 mM), normal glomerular
filtration rate, suppressed plasma renin activity, normal or elevated
aldosterone levels, hyperchloremia (mean serum chloride, 112 mM), and
reduced bicarbonate (mean serum bicarbonate, 17.5 mM). These features
were absent in unaffected kindred members, and inheritance of the trait
was consistent with autosomal dominant transmission with high
penetrance.

MAPPING

In a 3-generation French pedigree with 12 affected members with PHAII,
Disse-Nicodeme et al. (2000) excluded genetic linkage for the 2
previously mapped PHAII loci as well as for the thiazide-sensitive
sodium-chloride cotransporter gene (SLC12A3; 600968) on chromosome 16q.
A genomewide screen using 383 microsatellite markers showed strong
linkage to 12p13 (PHA2C). Haplotype analysis using 10 additional
polymorphic markers led to a minimal 13-cM interval. Analysis of 2
obvious candidate genes, SCNN1A (139130) and GNB3 (600228), located
within the interval showed no deleterious mutation.

Wilson et al. (2001) performed genomic sequence analysis of linkage in a
3-generation PHAII kindred, which demonstrated complete linkage of the
phenotype to the most telomeric 2-cM segment of chromosome 12p, with a
multipoint lod score of 5.07.

MOLECULAR GENETICS

Wilson et al. (2001) found that members of a family with PHAII carried a
deletion in the interval between D12S341 and D12S91. Further evaluation
indicated that affected family members had a heterozygous 41-kb deletion
within intron 1 of the WNK1 gene (605232.0001). Both deletion endpoints
occur within Alu repetitive elements. Wilson et al. (2001) also
identified a deletion in the WNK1 gene (605232.0002) in the family
reported by Disse-Nicodeme et al. (2000).

Boyden et al. (2012) studied a cohort of 52 PHAII kindreds including 126
affected subjects with renal hyperkalemia and otherwise normal renal
function; hypertension and acidosis were present in 71% and 82%,
respectively. The authors identified 2 kindreds with PHAII caused by
WNK1 mutation. There were 23 affected individuals in those 2 kindreds.
Mean age at diagnosis was 36 +/- 20 years with a mean potassium of 5.8
+/- 0.8 and a mean bicarbonate 22.4 +/- 4.6, and only 13% developed
hypertension by 18 years of age.

GENOTYPE/PHENOTYPE CORRELATIONS

Boyden et al. (2012) observed that families with PHAII due to mutation
in the WNK1 gene (PHA2C) are significantly less severely affected than
those with mutation in WNK4 (PHA2B; 614491) or dominant or recessive
mutation in the KLHL3 gene (605775; PHA2D, 614495), and all are less
severely affected than those with dominant mutation in the CUL3 gene
(603136; PHA2E, 614496).

*FIELD* RF
1. Boyden, L. M.; Choi, M.; Choate, K. A.; Nelson-Williams, C. J.;
Farhi, A.; Toka, H. R.; Tikhonova, I. R.; Bjornson, R.; Mane, S. M.;
Colussi, G.; Lebel, M.; Gordon, R. D.; and 34 others: Mutations
in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature 482:
98-102, 2012.

2. Disse-Nicodeme, S.; Achard, J.-M.; Desitter, I.; Houot, A.-M.;
Fournier, A.; Corvol, P.; Jeunemaitre, X.: A new locus on chromosome
12p13.3 for pseudohypoaldosteronism type II, an autosomal dominant
form of hypertension. Am. J. Hum. Genet. 67: 302-310, 2000.

3. Wilson, F. H.; Disse-Nicodeme, S.; Choate, K. A.; Ishikawa, K.;
Nelson-Williams, C.; Desitter, I.; Gunel, M.; Milford, D. V.; Lipkin,
G. W.; Achard, J.-M.; Feely, M. P.; Dussol, B.; Berland, Y.; Unwin,
R. J.; Mayan, H.; Simon, D. B.; Farfel, Z.; Jeunemaitre, X.; Lifton,
R. P.: Human hypertension caused by mutations in WNK kinases. Science 293:
1107-1112, 2001.

*FIELD* CS
INHERITANCE:
Autosomal dominant

CARDIOVASCULAR:
[Vascular];
Hypertension

METABOLIC FEATURES:
Hyperchloremic metabolic acidosis, mild, in some cases (HCO3 22.4
+/- 4.6 mM)

LABORATORY ABNORMALITIES:
Hyperkalemia (5.8 +/- 0.8 mM);
Hyperchloremia (mean 109 mM)

MISCELLANEOUS:
23 patients from 2 kindreds reported (as of February 2012);
Age at diagnosis 36 +/- 20 years;
Only 13% develop hypertension at 18 years of age or less;
Responsive to thiazide diuretics

MOLECULAR BASIS:
Caused by mutation in the WNK lysine deficient protein kinase 1 gene
(WNK1, 605232.0001)

*FIELD* CD
Ada Hamosh: 2/27/2012

*FIELD* ED
joanna: 02/27/2012

*FIELD* CN
Marla J. F. O'Neill - updated: 05/14/2012

*FIELD* CD
Anne M. Stumpf: 2/23/2012

*FIELD* ED
carol: 05/14/2012
alopez: 2/27/2012