RBCC Red Blood Cell Collection

ATP6V0A4 (ATP6N1B, ATP6N2) [Confidence: low (only semi-automatic identification from reviews)]
V-type proton ATPase 116 kDa subunit a isoform 4; V-ATPase 116 kDa isoform a4 (Vacuolar proton translocating ATPase 116 kDa subunit a isoform 4; Vacuolar proton translocating ATPase 116 kDa subunit a kidney isoform)

UniProt Q9HBG4
ID VPP4_HUMAN Reviewed; 840 AA.
AC Q9HBG4; A4D1R4; A8KA80; Q32M47;
DT 14-NOV-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 05-OCT-2010, sequence version 2.
DT 22-JAN-2014, entry version 107.
DE RecName: Full=V-type proton ATPase 116 kDa subunit a isoform 4;
DE Short=V-ATPase 116 kDa isoform a4;
DE AltName: Full=Vacuolar proton translocating ATPase 116 kDa subunit a isoform 4;
DE AltName: Full=Vacuolar proton translocating ATPase 116 kDa subunit a kidney isoform;
GN Name=ATP6V0A4; Synonyms=ATP6N1B, ATP6N2;
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], VARIANTS RTADR LEU-524; THR-580 AND
RP ARG-820, AND VARIANT ALA-2.
RC TISSUE=Kidney;
RX PubMed=10973252; DOI=10.1038/79208;
RA Smith A.N., Skaug J., Choate K.A., Nayir A., Bakkaloglu A., Ozen S.,
RA Hulton S.A., Sanjad S.A., Al-Sabban E.A., Lifton R.P., Scherer S.W.,
RA Karet F.E.;
RT "Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116-
RT kD subunit, cause recessive distal renal tubular acidosis with
RT preserved hearing.";
RL Nat. Genet. 26:71-75(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ALA-2.
RC TISSUE=Trachea;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R.,
RA Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H.,
RA Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A.,
RA Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J.,
RA Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A.,
RA Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S.,
RA Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M.,
RA Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C.,
RA Latreille P., Miller N., Johnson D., Murray J., Woessner J.P.,
RA Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J.,
RA Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L.,
RA Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R.,
RA Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K.,
RA Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S.,
RA Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M.,
RA Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R.,
RA Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D.,
RA Waterston R.H., Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S.,
RA Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z.,
RA Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C.,
RA Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J.,
RA Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F.,
RA Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F.,
RA Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H.,
RA Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G.,
RA Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P.,
RA Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J.,
RA Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F.,
RA Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B.,
RA Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W.,
RA Mural R.J., Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP TISSUE SPECIFICITY, AND VARIANTS RTADR ASP-175; LYS-237 DEL; HIS-449
RP AND GLN-807.
RX PubMed=12414817; DOI=10.1136/jmg.39.11.796;
RA Stover E.H., Borthwick K.J., Bavalia C., Eady N., Fritz D.M.,
RA Rungroj N., Giersch A.B.S., Morton C.C., Axon P.R., Akil I.,
RA Al-Sabban E.A., Baguley D.M., Bianca S., Bakkaloglu A., Bircan Z.,
RA Chauveau D., Clermont M.-J., Guala A., Hulton S.A., Kroes H.,
RA Li Volti G., Mir S., Mocan H., Nayir A., Ozen S.,
RA Rodriguez Soriano J., Sanjad S.A., Tasic V., Taylor C.M.,
RA Topaloglu R., Smith A.N., Karet F.E.;
RT "Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal
RT renal tubular acidosis with new evidence for hearing loss.";
RL J. Med. Genet. 39:796-803(2002).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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).
CC -!- FUNCTION: Part of the proton channel of the V-ATPase that is
CC involved in normal vectorial acid transport into the urine by the
CC kidney (By similarity).
CC -!- SUBUNIT: The V-ATPase is a heteromultimeric enzyme composed of at
CC least thirteen different subunits. It has a membrane peripheral V1
CC sector for ATP hydrolysis and an integral V0 for proton
CC translocation. The V1 sector comprises subunits A-H, whereas V0
CC includes subunits a, d, c, c', and c''.
CC -!- SUBCELLULAR LOCATION: Apical cell membrane; Multi-pass membrane
CC protein. Note=Present at high density almost exclusively on the
CC apical surface of alpha-intercalated cells in the cortical
CC collecting ducts of the distal nephron.
CC -!- TISSUE SPECIFICITY: Expressed in adult and fetal kidney. Found in
CC the inner ear.
CC -!- DISEASE: Renal tubular acidosis, distal, autosomal recessive
CC (RTADR) [MIM:602722]: An autosomal recessive disease characterized
CC by reduced ability to acidify urine, variable hyperchloremic
CC hypokalemic metabolic acidosis, nephrocalcinosis, and
CC nephrolithiasis. It is due to functional failure of alpha-
CC intercalated cells of the cortical collecting duct of the distal
CC nephron, where vectorial proton transport is required for urinary
CC acidification. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the V-ATPase 116 kDa subunit family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ATP6V0A4";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF245517; AAG11415.1; -; mRNA.
DR EMBL; AK292945; BAF85634.1; -; mRNA.
DR EMBL; AC018663; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC020983; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH236950; EAL24043.1; -; Genomic_DNA.
DR EMBL; CH471070; EAW83892.1; -; Genomic_DNA.
DR EMBL; BC109304; AAI09305.1; -; mRNA.
DR EMBL; BC109305; AAI09306.1; -; mRNA.
DR RefSeq; NP_065683.2; NM_020632.2.
DR RefSeq; NP_570855.2; NM_130840.2.
DR RefSeq; NP_570856.2; NM_130841.2.
DR RefSeq; XP_005250450.1; XM_005250393.1.
DR RefSeq; XP_005250451.1; XM_005250394.1.
DR UniGene; Hs.98967; -.
DR ProteinModelPortal; Q9HBG4; -.
DR STRING; 9606.ENSP00000253856; -.
DR TCDB; 3.A.2.2.4; the h(+)- or na(+)-translocating f-type, v-type and a-type atpase (f-atpase) superfamily.
DR PhosphoSite; Q9HBG4; -.
DR DMDM; 308153516; -.
DR PaxDb; Q9HBG4; -.
DR PRIDE; Q9HBG4; -.
DR Ensembl; ENST00000310018; ENSP00000308122; ENSG00000105929.
DR Ensembl; ENST00000353492; ENSP00000253856; ENSG00000105929.
DR Ensembl; ENST00000393054; ENSP00000376774; ENSG00000105929.
DR GeneID; 50617; -.
DR KEGG; hsa:50617; -.
DR UCSC; uc003vuf.3; human.
DR CTD; 50617; -.
DR GeneCards; GC07M138391; -.
DR H-InvDB; HIX0007123; -.
DR HGNC; HGNC:866; ATP6V0A4.
DR HPA; HPA018029; -.
DR MIM; 602722; phenotype.
DR MIM; 605239; gene.
DR neXtProt; NX_Q9HBG4; -.
DR Orphanet; 93609; Autosomal recessive distal renal tubular acidosis without deafness.
DR PharmGKB; PA25147; -.
DR eggNOG; COG1269; -.
DR HOGENOM; HOG000037059; -.
DR HOVERGEN; HBG014606; -.
DR InParanoid; Q9HBG4; -.
DR KO; K02154; -.
DR OMA; SWVIKVQ; -.
DR OrthoDB; EOG74FF04; -.
DR PhylomeDB; Q9HBG4; -.
DR BioCyc; MetaCyc:ENSG00000105929-MONOMER; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR GeneWiki; ATP6V0A4; -.
DR GenomeRNAi; 50617; -.
DR NextBio; 53132; -.
DR PRO; PR:Q9HBG4; -.
DR Bgee; Q9HBG4; -.
DR CleanEx; HS_ATP6V0A4; -.
DR Genevestigator; Q9HBG4; -.
DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB.
DR GO; GO:0031526; C:brush border membrane; IDA:HGNC.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0030670; C:phagocytic vesicle membrane; TAS:Reactome.
DR GO; GO:0000220; C:vacuolar proton-transporting V-type ATPase, V0 domain; IEA:InterPro.
DR GO; GO:0015078; F:hydrogen ion transmembrane transporter activity; IEA:InterPro.
DR GO; GO:0015991; P:ATP hydrolysis coupled proton transport; IEA:Ensembl.
DR GO; GO:0006879; P:cellular iron ion homeostasis; TAS:Reactome.
DR GO; GO:0007588; P:excretion; IMP:HGNC.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0051701; P:interaction with host; TAS:Reactome.
DR GO; GO:0001503; P:ossification; IMP:HGNC.
DR GO; GO:0090382; P:phagosome maturation; TAS:Reactome.
DR GO; GO:0015992; P:proton transport; IMP:HGNC.
DR GO; GO:0006885; P:regulation of pH; IMP:HGNC.
DR GO; GO:0007605; P:sensory perception of sound; IMP:HGNC.
DR GO; GO:0033572; P:transferrin transport; TAS:Reactome.
DR GO; GO:0055085; P:transmembrane transport; TAS:Reactome.
DR InterPro; IPR002490; V-ATPase_116kDa_su.
DR InterPro; IPR026028; V-type_ATPase_116kDa_su_euka.
DR PANTHER; PTHR11629; PTHR11629; 1.
DR Pfam; PF01496; V_ATPase_I; 1.
DR PIRSF; PIRSF001293; ATP6V0A1; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Complete proteome; Disease mutation;
KW Hydrogen ion transport; Ion transport; Membrane; Polymorphism;
KW Reference proteome; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1 840 V-type proton ATPase 116 kDa subunit a
FT isoform 4.
FT /FTId=PRO_0000119219.
FT TOPO_DOM 1 390 Cytoplasmic (Potential).
FT TRANSMEM 391 409 Helical; (Potential).
FT TOPO_DOM 410 411 Vacuolar (Potential).
FT TRANSMEM 412 428 Helical; (Potential).
FT TOPO_DOM 429 443 Cytoplasmic (Potential).
FT TRANSMEM 444 473 Helical; (Potential).
FT TOPO_DOM 474 538 Vacuolar (Potential).
FT TRANSMEM 539 558 Helical; (Potential).
FT TOPO_DOM 559 576 Cytoplasmic (Potential).
FT TRANSMEM 577 597 Helical; (Potential).
FT TOPO_DOM 598 642 Vacuolar (Potential).
FT TRANSMEM 643 662 Helical; (Potential).
FT TOPO_DOM 663 727 Cytoplasmic (Potential).
FT TRANSMEM 728 752 Helical; (Potential).
FT TOPO_DOM 753 773 Vacuolar (Potential).
FT TRANSMEM 774 812 Helical; (Potential).
FT TOPO_DOM 813 840 Cytoplasmic (Potential).
FT VARIANT 2 2 V -> A (in dbSNP:rs10258719).
FT /FTId=VAR_020992.
FT VARIANT 175 175 G -> D (in RTADR).
FT /FTId=VAR_020993.
FT VARIANT 237 237 Missing (in RTADR).
FT /FTId=VAR_020994.
FT VARIANT 449 449 R -> H (in RTADR).
FT /FTId=VAR_020995.
FT VARIANT 524 524 P -> L (in RTADR).
FT /FTId=VAR_017255.
FT VARIANT 554 554 F -> L (in dbSNP:rs1026435).
FT /FTId=VAR_066612.
FT VARIANT 580 580 M -> T (in RTADR; dbSNP:rs3807153).
FT /FTId=VAR_017256.
FT VARIANT 604 604 H -> Q (in dbSNP:rs3807154).
FT /FTId=VAR_066613.
FT VARIANT 807 807 R -> Q (in RTADR; dbSNP:rs28939081).
FT /FTId=VAR_020996.
FT VARIANT 820 820 G -> R (in RTADR).
FT /FTId=VAR_017257.
FT CONFLICT 252 252 P -> R (in Ref. 6; AAI09305/AAI09306).
SQ SEQUENCE 840 AA; 96386 MW; 449964EBC01D4649 CRC64;
MVSVFRSEEM CLSQLFLQVE AAYCCVAELG ELGLVQFKDL NMNVNSFQRK FVNEVRRCES
LERILRFLED EMQNEIVVQL LEKSPLTPLP REMITLETVL EKLEGELQEA NQNQQALKQS
FLELTELKYL LKKTQDFFET ETNLADDFFT EDTSGLLELK AVPAYMTGKL GFIAGVINRE
RMASFERLLW RICRGNVYLK FSEMDAPLED PVTKEEIQKN IFIIFYQGEQ LRQKIKKICD
GFRATVYPCP EPAVERREML ESVNVRLEDL ITVITQTESH RQRLLQEAAA NWHSWLIKVQ
KMKAVYHILN MCNIDVTQQC VIAEIWFPVA DATRIKRALE QGMELSGSSM APIMTTVQSK
TAPPTFNRTN KFTAGFQNIV DAYGVGSYRE INPAPYTIIT FPFLFAVMFG DCGHGTVMLL
AALWMILNER RLLSQKTDNE IWNTFFHGRY LILLMGIFSI YTGLIYNDCF SKSLNIFGSS
WSVQPMFRNG TWNTHVMEES LYLQLDPAIP GVYFGNPYPF GIDPIWNLAS NKLTFLNSYK
MKMSVILGIV QMVFGVILSL FNHIYFRRTL NIILQFIPEM IFILCLFGYL VFMIIFKWCC
FDVHVSQHAP SILIHFINMF LFNYSDSSNA PLYKHQQEVQ SFFVVMALIS VPWMLLIKPF
ILRASHRKSQ LQASRIQEDA TENIEGDSSS PSSRSGQRTS ADTHGALDDH GEEFNFGDVF
VHQAIHTIEY CLGCISNTAS YLRLWALSLA HAQLSEVLWT MVMNSGLQTR GWGGIVGVFI
IFAVFAVLTV AILLIMEGLS AFLHALRLHW VEFQNKFYVG DGYKFSPFSF KHILDGTAEE
//

MIM 602722
*RECORD*
*FIELD* NO
602722
*FIELD* TI
#602722 RENAL TUBULAR ACIDOSIS, DISTAL, AUTOSOMAL RECESSIVE; RTADR
;;RTA, DISTAL, AUTOSOMAL RECESSIVE;;
read moreRENAL TUBULAR ACIDOSIS, AUTOSOMAL RECESSIVE, WITH PRESERVED HEARING
RENAL TUBULAR ACIDOSIS, DISTAL, AUTOSOMAL RECESSIVE, WITH LATE-ONSET
SENSORINEURAL HEARING LOSS, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because autosomal recessive
distal renal tubular acidosis (dRTA) with preserved hearing or
late-onset sensorineural hearing loss can be caused by mutation in the
ATP6V0A4 (ATP6N1B) gene (605239).

CLINICAL FEATURES

The maintenance of body fluid pH within a narrow range is critical for a
wide variety of essential biochemical and metabolic functions. The
kidney plays a key role in this homeostasis under normal circumstances,
owing to its ability to vary bicarbonate reclamation and net acid
excretion over a wide range. In the renal tubular acidoses (RTAs),
however, acid-base balance becomes deranged either because of inability
to secrete acid in the distal nephron or because of proximal bicarbonate
loss (267200). Primary distal RTA is characterized by the failure of the
kidney to produce an appropriately acid urine in the presence of
systemic metabolic acidosis or after acid loading, due to failure of
hydrogen ion secretion or bicarbonate reabsorption in the distal
nephron. This results in hyperchloremic metabolic acidosis of varying
severity. The condition is usually accompanied by nephrocalcinosis or
nephrolithiasis. Other findings include hypokalemia and normal serum
calcium and phosphate levels, although osteomalacia or rickets may
supervene in untreated cases. Alkali replacement serves to reverse most
of the biochemical abnormalities. Both autosomal dominant (179800) and
autosomal recessive patterns have been observed in kindreds with primary
distal RTA, and the spectrum of clinical severity is wide. Some patients
with autosomal dominant distal RTA remain asymptomatic until adolescence
or adulthood, whereas others, and those with recessive disease, may be
severely affected in infancy, with impaired growth and early
nephrocalcinosis causing eventual renal insufficiency.

Seedat (1964) reported a family with 8 affected members in 4
generations. The proband was born of first-cousin parents. In another
first-cousin marriage, 4 of his half sibs were affected. Kuhlencordt et
al. (1967) observed affected monozygotic twins whose parents were first
cousins.

Karet et al. (1998) assembled information on 26 kindreds with primary
distal RTA. Autosomal recessive inheritance was found in at least 17
kindreds; affected individuals were offspring of consanguineous unions
in 14 of these families and there were 2 or more affected sibs of
unaffected parents in the other 3. Among the recessive kindreds, 19 of
the 25 patients were diagnosed at 1 year of age or less, and the
remainder presented at 6 years or younger. All index cases presented
either acutely with vomiting and dehydration, or with failure to thrive,
or delayed growth. Younger affected sibs were often diagnosed
prospectively. All patients with recessive disease were found to have
nephrocalcinosis, nephrolithiasis, or both, and several had rickets.
Nine of these patients from 6 families also had bilateral sensorineural
deafness confirmed by audiometry.

MAPPING

Karet et al. (1999) performed genomewide linkage analysis in 13 kindreds
with recessive dRTA and found evidence for linkage with locus
heterogeneity to a segment of 7q33-q34; a maximum multipoint lod score
of 8.84 with this region was obtained with 68% of kindreds linked. That
4 of these 13 kindreds did not support linkage to 7q33-q34 or to
chromosome 2 (see dRTA with progressive nerve deafness, 267300) implied
the existence of at least 1 additional distal RTA locus.

MOLECULAR GENETICS

Karet et al. (1998) analyzed the SLC4A1 gene (109270) in 17 families
with autosomal recessive distal RTA but found no mutations.

In 8 of 9 renal tubular acidosis kindreds with normal audiometry linked
to the ATP6N1B locus, Smith et al. (2000) identified homozygous
mutations in the ATP6N1B gene (ATP6V0A4; 605239). These included
nonsense, deletion, and splice site changes, all of which were predicted
to truncate the protein. The findings identified a new kidney-specific
proton pump 116-kD accessory subunit that is highly expressed in
proton-secreting cells in the distal nephron, and illustrated its
essential role in normal vectorial acid transport into the urine by the
kidney.

In 12 new kindreds with autosomal recessive dRTA and 11 sporadic cases,
Stover et al. (2002) identified 19 ATP6V0A4 mutations in 23 patients.
Several of these patients, including 1 with a previously identified
splice site mutation (605239.0003) and 2 with missense mutations
(605239.0009-605239.0010), were found to have developed later onset of
hearing loss than occurs in dRTA families with progressive sensorineural
hearing loss and mutation in the ATP6V1B1 gene. Review of a previously
studied ATP6V0A4 cohort revealed 1 patient who had developed mild
sensorineural hearing loss at the age of 22 years. Stover et al. (2002)
also found ATP6V0A4 expression within the cochlea of both fetal and
adult tissue specimens. Another 4 dRTA families (2 with normal
audiometry, 1 with sensorineural hearing loss, and 1 of unknown hearing
status) were not linked to ATP6V0A4 or ATP6V1B1, providing further
evidence for additional genetic heterogeneity in dRTA. The discovery of
late-onset sensorineural hearing loss in some cases of autosomal
recessive dRTA, as well as the demonstration that ATP6V0A4 is expressed
within the cochlea, suggested that RTA with or without sensorineural
hearing loss is the same disorder.

*FIELD* RF
1. Karet, F. E.; Finberg, K. E.; Nayir, A.; Bakkaloglu, A.; Ozen,
S.; Hulton, S. A.; Sanjad, S. A.; Al-Sabban, E. A.; Medina, J. F.;
Lifton, R. P.: Localization of a gene for autosomal recessive distal
renal tubular acidosis with normal hearing (rdRTA2) to 7q33-34. Am.
J. Hum. Genet. 65: 1656-1665, 1999.

2. Karet, F. E.; Gainza, F. J.; Gyory, A. Z.; Unwin, R. J.; Wrong,
O.; Tanner, M. J. A.; Nayir, A.; Alpay, H.; Santos, F.; Hulton, S.
A.; Bakkaloglu, A.; Ozen, S.; Cunningham, M. J.; di Pietro, A.; Walker,
W. G.; Lifton, R. P.: Mutations in the chloride-bicarbonate exchanger
gene AE1 cause autosomal dominant but not autosomal recessive distal
renal tubular acidosis. Proc. Nat. Acad. Sci. 95: 6337-6342, 1998.

3. Kuhlencordt, F.; Lenz, W.; Seeman, N.; Zukschwerdt, L.: Renal
tubular acidosis and bilateral nephrocalcinosis in uniovular twins. German
Med. Monthly 12: 565-570, 1967.

4. Seedat, Y. K.: Some observations of renal tubular acidosis--a
family study. S. Afr. Med. J. 38: 606-610, 1964.

5. Smith, A. N.; Skaug, J.; Choate, K. A.; Nayir, A.; Bakkaloglu,
A.; Ozen, S.; Hulton, S. A.; Sanjad, S. A.; Al-Sabban, E. A.; Lifton,
R. P.; Scherer, S. W.; Karet, F. E.: Mutations in ATP6N1B, encoding
a new kidney vacuolar proton pump 116-kD subunit, cause recessive
distal renal tubular acidosis with preserved hearing. Nature Genet. 26:
71-75, 2000.

6. Stover, E. H.; Borthwick, K. J.; Bavalia, C.; Eady, N.; Fritz,
D. M.; Rungroj, N.; Giersch, A. B. S.; Morton, C. C.; Axon, P. R.;
Akil, I.; Al-Sabban, E. A.; Baguley, D. M.; and 20 others: Novel
ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal
tubular acidosis with new evidence for hearing loss. J. Med. Genet. 39:
796-803, 2002.

*FIELD* CN
Marla J. F. O'Neill - updated: 11/08/2007
Marla J. F. O'Neill - updated: 2/9/2005
Marla J. F. O'Neill - updated: 2/5/2004
Victor A. McKusick - updated: 8/28/2000
Victor A. McKusick - updated: 12/17/1999

*FIELD* CD
Victor A. McKusick: 6/16/1998

*FIELD* ED
carol: 11/08/2007
carol: 7/26/2005
terry: 2/9/2005
carol: 5/25/2004
tkritzer: 5/25/2004
carol: 2/5/2004
carol: 2/2/2004
alopez: 5/11/2001
alopez: 8/29/2000
terry: 8/28/2000
mgross: 12/29/1999
mgross: 12/28/1999
terry: 12/17/1999
carol: 6/16/1998

MIM 605239
*RECORD*
*FIELD* NO
605239
*FIELD* TI
*605239 ATPase, H+ TRANSPORTING, LYSOSOMAL, V0 SUBUNIT A, ISOFORM 4; ATP6V0A4
;;ATPase, H+ TRANSPORTING, LYSOSOMAL, NONCATALYTIC ACCESSORY PROTEIN
read more1B; ATP6N1B;;
ATP6N2;;
VACUOLAR PROTEIN PUMP, SUBUNIT 2; VPP2
*FIELD* TX
The multisubunit H(+)-ATPase pump is present at particularly high
density on the apical (luminal) surface of alpha-intercalated cells of
the cortical collecting duct of the distal nephron, where vectorial
proton transport is required for urinary acidification. Functional
failure of alpha-intercalated cells results in a group of disorders, the
distal renal tubular acidoses, whose features include metabolic acidosis
accompanied by disturbances of potassium balance, urinary calcium
solubility, bone physiology, and growth. Karet et al. (1999) localized a
gene for distal renal tubular acidosis with preserved hearing (RTADR;
602722) to 7q33-q34. Smith et al. (2000) identified and cloned the gene,
ATP6N1B, which encodes an 840-amino acid kidney-specific isoform of
ATP6N1A (ATP6V0A1; 192130), the 116-kD noncatalytic accessory subunit of
the proton pump. The ATP6N1B protein shares 61% and 47% amino acid
identity, respectively, with the other human 116-kD subunits ATP6N1A and
OC116 (see 604592). Northern blot analysis demonstrated ATP6N1B
expression in kidney but not other main organs. Immunofluorescence
studies in human kidney cortex showed that ATP6N1B localizes almost
exclusively to the apical surface of alpha-intercalated cells.

Stover et al. (2002) found ATP6V0A4 expression within the cochlea of
both fetal and adult tissue specimens.

GENE STRUCTURE

The ATP6N1B gene consists of 23 exons and encodes 3 alternatively
spliced isoforms.

MOLECULAR GENETICS

In 8 of 9 renal tubular acidosis kindreds with normal audiometry linked
to the ATP6V0A4 locus (602722), Smith et al. (2000) identified
homozygous mutations in the ATP6V0A4 gene. These included nonsense,
deletion, and splice site changes, all of which were predicted to
truncate the protein. The findings identified a new kidney-specific
proton pump 116-kD accessory subunit that is highly expressed in
proton-secreting cells in the distal nephron, and illustrated its
essential role in normal vectorial acid transport into the urine by the
kidney.

In 12 kindreds with autosomal recessive distal renal tubular acidosis
and 11 sporadic cases of dRTA, Stover et al. (2002) identified 19
ATP6V0A4 mutations in 23 patients. Several of these patients, including
1 with a previously identified splice site mutation (605239.0003), were
found to have developed later onset of hearing loss than occurs in dRTA
families with progressive sensorineural hearing loss (267000) and
mutations in the ATP6V1B1 gene (192132). Review of a previously studied
ATP6V0A4 cohort revealed 1 patient who had developed mild sensorineural
hearing loss at the age of 22.

*FIELD* AV
.0001
RENAL TUBULAR ACIDOSIS, DISTAL, AUTOSOMAL RECESSIVE
ATP6V0A4, GLU753TER

In a 6.5-year-old Turkish child in whom the diagnosis of distal renal
tubular acidosis (602722) had been made at the age of 3 weeks, Smith et
al. (2000) found a glu753-to-ter (Q753X) nonsense mutation in the
ATP6N1B gene. Audiometry at the age of 4.5 years was normal. A C-to-T
transition introduced the premature termination codon.

.0002
RENAL TUBULAR ACIDOSIS, DISTAL, AUTOSOMAL RECESSIVE
ATP6V0A4, GLY820ARG1

In a 10-year-old child with distal renal tubular acidosis with normal
hearing (602722), Smith et al. (2000) identified a gly820-to-arg (G820R)
missense mutation in the ATP6N1B gene. Renal tubular acidosis had been
diagnosed at the age of 1 year.

.0003
RENAL TUBULAR ACIDOSIS, DISTAL, AUTOSOMAL RECESSIVE
ATP6V0A4, IVS17, G-A, +1

In a 22-year-old Pakistani female with distal renal tubular acidosis
with normal hearing (602722), Smith et al. (2000) identified a mutation
in the consensus donor splice site of intron 17 of the ATP6N1B gene.
Renal tubular acidosis had been diagnosed at the age of 1 week.

.0004
RENAL TUBULAR ACIDOSIS, DISTAL, AUTOSOMAL RECESSIVE
ATP6V0A4, 1-BP DEL, VAL35

In a 14-year-old Turkish female with distal renal acidosis (602722),
Smith et al. (2000) found a 1-bp deletion in codon 35 (valine) of the
ATP6N1B gene causing a frameshift, altering the following protein
sequence and ending in premature termination at codon 40. Renal acidosis
was diagnosed at the age of 3 months; audiometry was normal at 12 years.

.0005
RENAL TUBULAR ACIDOSIS, DISTAL, AUTOSOMAL RECESSIVE
ATP6V0A4, MET580THR

In a 4-year-old Turkish boy with distal renal tubular acidosis and
normal hearing (602722), Smith et al. (2000) found an met580-to-thr
missense mutation in the ATP6N1B gene.

.0006
RENAL TUBULAR ACIDOSIS, DISTAL, AUTOSOMAL RECESSIVE
ATP6V0A4, IVS6, G-A, -1

In an 11-year-old Turkish girl with distal renal tubular acidosis and
normal hearing (602722), Smith et al. (2000) identified a change in the
canonical acceptor splice sequence in intron 6 of the ATP6N1B gene from
AG to AA.

.0007
RENAL TUBULAR ACIDOSIS, DISTAL, AUTOSOMAL RECESSIVE
ATP6V0A4, 1-BP DEL, GLN276

In a 13-year-old Saudi Arabian male with distal renal tubular acidosis
and presumably normal hearing (602722), Smith et al. (2000) identified
deletion of 1 bp in codon 376 of the ATP6N1B gene (glutamine) resulting
in frameshift and premature termination.

.0008
RENAL TUBULAR ACIDOSIS, DISTAL, AUTOSOMAL RECESSIVE
ATP6V0A4, PRO524LEU

In a 3-year-old Turkish male with distal renal tubular acidosis and
normal hearing (602722), Smith et al. (2000) identified a pro524-to-leu
missense mutation in the ATP6N1B gene.

.0009
RENAL TUBULAR ACIDOSIS, DISTAL, AUTOSOMAL RECESSIVE, WITH LATE-ONSET
SENSORINEURAL HEARING LOSS
ATP6V0A4, TYR502TER

In a 34-year-old Spanish patient with distal renal tubular acidosis
(602722), Stover et al. (2002) identified a 1506T-A transversion in the
ATP6V0A4 gene, resulting in a tyr502-to-stop (Y502X) mutation. This
mutation was found to be frequent in patients from northern Spain,
suggesting founder effect. The patient was found to have sensorineural
hearing loss for the first time at the age of 33 years. He had had
previous audiograms within normal limits.

.0010
RENAL TUBULAR ACIDOSIS, DISTAL, AUTOSOMAL RECESSIVE, WITH LATE-ONSET
SENSORINEURAL HEARING LOSS
ATP6V0A4, ARG807GLN

In a 26-year-old Spanish male with distal renal tubular acidosis
(602722), Stover et al. (2002) identified a 2420G-A transition in the
ATP6V0A4 gene, resulting in an arg807-to-gln (R807Q) mutation. The
diagnosis of renal tubular acidosis had been made at the age of 2
months. The patient had severe hearing loss requiring the use of hearing
aids.

*FIELD* RF
1. Karet, F. E.; Finberg, K. E.; Nayir, A.; Bakkaloglu, A.; Ozen,
S.; Hulton, S. A.; Sanjad, S. A.; Al-Sabban, E. A.; Medina, J. F.;
Lifton, R. P.: Localization of a gene for autosomal recessive distal
renal tubular acidosis with normal hearing (rdRTA2) to 7q33-34. Am.
J. Hum. Genet. 65: 1656-1665, 1999.

2. Smith, A. N.; Skaug, J.; Choate, K. A.; Nayir, A.; Bakkaloglu,
A.; Ozen, S.; Hulton, S. A.; Sanjad, S. A.; Al-Sabban, E. A.; Lifton,
R. P.; Scherer, S. W.; Karet, F. E.: Mutations in ATP6N1B, encoding
a new kidney vacuolar proton pump 116-kD subunit, cause recessive
distal renal tubular acidosis with preserved hearing. Nature Genet. 26:
71-75, 2000.

3. Stover, E. H.; Borthwick, K. J.; Bavalia, C.; Eady, N.; Fritz,
D. M.; Rungroj, N.; Giersch, A. B. S.; Morton, C. C.; Axon, P. R.;
Akil, I.; Al-Sabban, E. A.; Baguley, D. M.; and 20 others: Novel
ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal
tubular acidosis with new evidence for hearing loss. J. Med. Genet. 39:
796-803, 2002.

*FIELD* CN
Victor A. McKusick - updated: 5/4/2004
Marla J. F. O'Neill - updated: 2/5/2004

*FIELD* CD
Victor A. McKusick: 8/29/2000

*FIELD* ED
wwang: 01/07/2008
carol: 1/4/2005
tkritzer: 5/25/2004
terry: 5/4/2004
carol: 2/5/2004
carol: 2/2/2004
alopez: 7/30/2002
alopez: 8/29/2000