Full text data of PRKCSH
PRKCSH
(G19P1)
[Confidence: high (present in two of the MS resources)]
Glucosidase 2 subunit beta (80K-H protein; Glucosidase II subunit beta; Protein kinase C substrate 60.1 kDa protein heavy chain; PKCSH; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Glucosidase 2 subunit beta (80K-H protein; Glucosidase II subunit beta; Protein kinase C substrate 60.1 kDa protein heavy chain; PKCSH; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00026154
IPI00026154 Glucosidase II beta subunit precursor Glucosidase II beta subunit precursor membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 2 n/a n/a 1 n/a n/a 1 n/a 1 n/a intracellular n/a found at its expected molecular weight found at molecular weight
IPI00026154 Glucosidase II beta subunit precursor Glucosidase II beta subunit precursor membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 2 n/a n/a 1 n/a n/a 1 n/a 1 n/a intracellular n/a found at its expected molecular weight found at molecular weight
UniProt
P14314
ID GLU2B_HUMAN Reviewed; 528 AA.
AC P14314; A8K318; Q96BU9; Q96D06; Q9P0W9;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 17-OCT-2006, sequence version 2.
DT 22-JAN-2014, entry version 153.
DE RecName: Full=Glucosidase 2 subunit beta;
DE AltName: Full=80K-H protein;
DE AltName: Full=Glucosidase II subunit beta;
DE AltName: Full=Protein kinase C substrate 60.1 kDa protein heavy chain;
DE Short=PKCSH;
DE Flags: Precursor;
GN Name=PRKCSH; Synonyms=G19P1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=2793184; DOI=10.1016/0888-7543(89)90063-3;
RA Sakai K., Masamichi H., Minoshima S., Kudoh J., Fukuyama R.,
RA Shimizu N.;
RT "Isolation of cDNAs encoding a substrate for protein kinase C:
RT nucleotide sequence and chromosomal mapping of the gene for a human
RT 80K protein.";
RL Genomics 5:309-315(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9043864;
RA Ophoff R.A., Terwindt G.M., Vergouwe M.N., van Eijk R.,
RA Mohrenweiser H., Litt M., Hofker M.H., Haan J., Ferrari M.D.,
RA Frants R.R.;
RT "A 3-Mb region for the familial hemiplegic migraine locus on 19p13.1-
RT p13.2: exclusion of PRKCSH as a candidate gene.";
RL Eur. J. Hum. Genet. 4:321-328(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, INTERACTION WITH
RP GANAB, AND SUBCELLULAR LOCATION.
RC TISSUE=Lymphocyte;
RX PubMed=10929008; DOI=10.1093/glycob/10.8.815;
RA Pelletier M.F., Marcil A., Sevigny G., Jakob C.A., Tessier D.C.,
RA Chevet E., Menard R., Bergeron J.J.M., Thomas D.Y.;
RT "The heterodimeric structure of glucosidase II is required for its
RT activity, solubility, and localization in vivo.";
RL Glycobiology 10:815-827(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 130-528 (ISOFORM 1), AND
RP VARIANT THR-291.
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 22-528 (ISOFORM 2), AND
RP VARIANT THR-291.
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP PROTEIN SEQUENCE OF 15-21.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [9]
RP INVOLVEMENT IN PCLD.
RX PubMed=12529853; DOI=10.1086/368295;
RA Li A., Davila S., Furu L., Qian Q., Tian X., Kamath P.S., King B.F.,
RA Torres V.E., Somlo S.;
RT "Mutations in PRKCSH cause isolated autosomal dominant polycystic
RT liver disease.";
RL Am. J. Hum. Genet. 72:691-703(2003).
RN [10]
RP INVOLVEMENT IN PCLD.
RX PubMed=12577059; DOI=10.1038/ng1104;
RA Drenth J.P.H., te Morsche R.H.M., Smink R., Bonifacino J.S.,
RA Jansen J.B.M.J.;
RT "Germline mutations in PRKCSH are associated with autosomal dominant
RT polycystic liver disease.";
RL Nat. Genet. 33:345-347(2003).
RN [11]
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).
CC -!- FUNCTION: Regulatory subunit of glucosidase II.
CC -!- PATHWAY: Glycan metabolism; N-glycan metabolism.
CC -!- SUBUNIT: Heterodimer of a catalytic alpha subunit (GANAB) and a
CC beta subunit (PRKCSH). Binds glycosylated PTPRC (By similarity).
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum (Potential).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P14314-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P14314-2; Sequence=VSP_043749;
CC -!- DISEASE: Polycystic liver disease (PCLD) [MIM:174050]: A
CC hepatobiliary disease characterized by overgrowth of biliary
CC epithelium and supportive connective tissue, resulting in multiple
CC liver cysts. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Contains 2 EF-hand domains.
CC -!- SIMILARITY: Contains 1 PRKCSH domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH15154.1; Type=Erroneous initiation;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PRKCSH";
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DR EMBL; J03075; AAA52493.1; -; mRNA.
DR EMBL; U50326; AAA98668.1; -; Genomic_DNA.
DR EMBL; U50317; AAA98668.1; JOINED; Genomic_DNA.
DR EMBL; U50318; AAA98668.1; JOINED; Genomic_DNA.
DR EMBL; U50319; AAA98668.1; JOINED; Genomic_DNA.
DR EMBL; U50320; AAA98668.1; JOINED; Genomic_DNA.
DR EMBL; U50321; AAA98668.1; JOINED; Genomic_DNA.
DR EMBL; U50322; AAA98668.1; JOINED; Genomic_DNA.
DR EMBL; U50323; AAA98668.1; JOINED; Genomic_DNA.
DR EMBL; U50324; AAA98668.1; JOINED; Genomic_DNA.
DR EMBL; U50325; AAA98668.1; JOINED; Genomic_DNA.
DR EMBL; AF144075; AAF66686.1; -; mRNA.
DR EMBL; BT009858; AAP88860.1; -; mRNA.
DR EMBL; AK290433; BAF83122.1; -; mRNA.
DR EMBL; AC008481; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC024575; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC013586; AAH13586.2; -; mRNA.
DR EMBL; BC015154; AAH15154.1; ALT_INIT; mRNA.
DR PIR; A32469; A32469.
DR RefSeq; NP_001001329.1; NM_001001329.1.
DR RefSeq; NP_002734.2; NM_002743.2.
DR UniGene; Hs.610830; -.
DR ProteinModelPortal; P14314; -.
DR SMR; P14314; 423-512.
DR IntAct; P14314; 13.
DR MINT; MINT-1380114; -.
DR STRING; 9606.ENSP00000252455; -.
DR PhosphoSite; P14314; -.
DR DMDM; 116242499; -.
DR PaxDb; P14314; -.
DR PRIDE; P14314; -.
DR DNASU; 5589; -.
DR Ensembl; ENST00000252455; ENSP00000252455; ENSG00000130175.
DR Ensembl; ENST00000412601; ENSP00000395616; ENSG00000130175.
DR Ensembl; ENST00000586486; ENSP00000465948; ENSG00000130175.
DR Ensembl; ENST00000587327; ENSP00000466012; ENSG00000130175.
DR Ensembl; ENST00000589838; ENSP00000465461; ENSG00000130175.
DR Ensembl; ENST00000591462; ENSP00000465489; ENSG00000130175.
DR GeneID; 5589; -.
DR KEGG; hsa:5589; -.
DR UCSC; uc002mrt.3; human.
DR CTD; 5589; -.
DR GeneCards; GC19P011546; -.
DR HGNC; HGNC:9411; PRKCSH.
DR HPA; CAB004465; -.
DR MIM; 174050; phenotype.
DR MIM; 177060; gene.
DR neXtProt; NX_P14314; -.
DR Orphanet; 2924; Isolated polycystic liver disease.
DR PharmGKB; PA33774; -.
DR eggNOG; NOG289998; -.
DR HOGENOM; HOG000007805; -.
DR HOVERGEN; HBG051738; -.
DR InParanoid; P14314; -.
DR KO; K08288; -.
DR OrthoDB; EOG7DZ8JX; -.
DR PhylomeDB; P14314; -.
DR BRENDA; 3.2.1.84; 2681.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P14314; -.
DR UniPathway; UPA00957; -.
DR ChiTaRS; PRKCSH; human.
DR GeneWiki; PRKCSH; -.
DR GenomeRNAi; 5589; -.
DR NextBio; 21678; -.
DR PMAP-CutDB; P14314; -.
DR PRO; PR:P14314; -.
DR ArrayExpress; P14314; -.
DR Bgee; P14314; -.
DR CleanEx; HS_PRKCSH; -.
DR Genevestigator; P14314; -.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0003723; F:RNA binding; IEA:Ensembl.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0007243; P:intracellular protein kinase cascade; NAS:UniProtKB.
DR GO; GO:0001889; P:liver development; IEA:Ensembl.
DR GO; GO:0006491; P:N-glycan processing; IEA:InterPro.
DR GO; GO:0010977; P:negative regulation of neuron projection development; IEA:Ensembl.
DR GO; GO:0006807; P:nitrogen compound metabolic process; IEA:Ensembl.
DR GO; GO:0043687; P:post-translational protein modification; TAS:Reactome.
DR GO; GO:0006457; P:protein folding; TAS:Reactome.
DR GO; GO:0051291; P:protein heterooligomerization; IEA:Ensembl.
DR GO; GO:0018279; P:protein N-linked glycosylation via asparagine; TAS:Reactome.
DR GO; GO:0072001; P:renal system development; IEA:Ensembl.
DR Gene3D; 4.10.400.10; -; 2.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR026874; Glucosidase_2_bsu.
DR InterPro; IPR002172; LDrepeatLR_classA_rpt.
DR InterPro; IPR009011; Man6P_isomerase_rcpt-bd_dom.
DR InterPro; IPR028146; PRKCSH_N.
DR PANTHER; PTHR12630:SF1; PTHR12630:SF1; 1.
DR Pfam; PF13202; EF-hand_5; 2.
DR Pfam; PF12999; PRKCSH-like; 1.
DR SMART; SM00192; LDLa; 1.
DR SUPFAM; SSF50911; SSF50911; 1.
DR SUPFAM; SSF57424; SSF57424; 1.
DR PROSITE; PS00018; EF_HAND_1; 1.
DR PROSITE; PS50222; EF_HAND_2; 1.
DR PROSITE; PS00014; ER_TARGET; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Calcium; Complete proteome;
KW Direct protein sequencing; Endoplasmic reticulum; Glycoprotein;
KW Metal-binding; Phosphoprotein; Polymorphism; Reference proteome;
KW Repeat; Signal.
FT SIGNAL 1 14
FT CHAIN 15 528 Glucosidase 2 subunit beta.
FT /FTId=PRO_0000004143.
FT DOMAIN 209 244 EF-hand 1.
FT DOMAIN 245 290 EF-hand 2.
FT DOMAIN 413 468 PRKCSH.
FT CA_BIND 213 236 1 (Potential).
FT MOTIF 525 528 Prevents secretion from ER (Potential).
FT COMPBIAS 313 336 Glu-rich (acidic).
FT MOD_RES 89 89 Phosphoserine; by PKC (Potential).
FT MOD_RES 383 383 Phosphoserine; by PKC (Potential).
FT MOD_RES 390 390 Phosphoserine; by PKC (Potential).
FT MOD_RES 434 434 Phosphoserine; by PKC (Potential).
FT CARBOHYD 72 72 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 476 476 N-linked (GlcNAc...) (Potential).
FT VAR_SEQ 337 346 EAPPPLSPPQ -> VQGEQPK (in isoform 2).
FT /FTId=VSP_043749.
FT VARIANT 74 74 S -> N (in dbSNP:rs10406672).
FT /FTId=VAR_028761.
FT VARIANT 291 291 A -> T (in dbSNP:rs11557488).
FT /FTId=VAR_028762.
FT VARIANT 338 338 A -> G (in dbSNP:rs35847588).
FT /FTId=VAR_048658.
FT CONFLICT 325 325 Missing (in Ref. 1; AAA52493, 2;
FT AAA98668, 4; AAP88860 and 6; AAH13586).
SQ SEQUENCE 528 AA; 59425 MW; 8DAD9776037E878E CRC64;
MLLPLLLLLP MCWAVEVKRP RGVSLTNHHF YDESKPFTCL DGSATIPFDQ VNDDYCDCKD
GSDEPGTAAC PNGSFHCTNT GYKPLYIPSN RVNDGVCDCC DGTDEYNSGV ICENTCKEKG
RKERESLQQM AEVTREGFRL KKILIEDWKK AREEKQKKLI ELQAGKKSLE DQVEMLRTVK
EEAEKPEREA KEQHQKLWEE QLAAAKAQQE QELAADAFKE LDDDMDGTVS VTELQTHPEL
DTDGDGALSE AEAQALLSGD TQTDATSFYD RVWAAIRDKY RSEALPTDLP APSAPDLTEP
KEEQPPVPSS PTEEEEEEEE EEEEEAEEEE EEEDSEEAPP PLSPPQPASP AEEDKMPPYD
EQTQAFIDAA QEARNKFEEA ERSLKDMEES IRNLEQEISF DFGPNGEFAY LYSQCYELTT
NEYVYRLCPF KLVSQKPKLG GSPTSLGTWG SWIGPDHDKF SAMKYEQGTG CWQGPNRSTT
VRLLCGKETM VTSTTEPSRC EYLMELMTPA ACPEPPPEAP TEDDHDEL
//
ID GLU2B_HUMAN Reviewed; 528 AA.
AC P14314; A8K318; Q96BU9; Q96D06; Q9P0W9;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 17-OCT-2006, sequence version 2.
DT 22-JAN-2014, entry version 153.
DE RecName: Full=Glucosidase 2 subunit beta;
DE AltName: Full=80K-H protein;
DE AltName: Full=Glucosidase II subunit beta;
DE AltName: Full=Protein kinase C substrate 60.1 kDa protein heavy chain;
DE Short=PKCSH;
DE Flags: Precursor;
GN Name=PRKCSH; Synonyms=G19P1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=2793184; DOI=10.1016/0888-7543(89)90063-3;
RA Sakai K., Masamichi H., Minoshima S., Kudoh J., Fukuyama R.,
RA Shimizu N.;
RT "Isolation of cDNAs encoding a substrate for protein kinase C:
RT nucleotide sequence and chromosomal mapping of the gene for a human
RT 80K protein.";
RL Genomics 5:309-315(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9043864;
RA Ophoff R.A., Terwindt G.M., Vergouwe M.N., van Eijk R.,
RA Mohrenweiser H., Litt M., Hofker M.H., Haan J., Ferrari M.D.,
RA Frants R.R.;
RT "A 3-Mb region for the familial hemiplegic migraine locus on 19p13.1-
RT p13.2: exclusion of PRKCSH as a candidate gene.";
RL Eur. J. Hum. Genet. 4:321-328(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, INTERACTION WITH
RP GANAB, AND SUBCELLULAR LOCATION.
RC TISSUE=Lymphocyte;
RX PubMed=10929008; DOI=10.1093/glycob/10.8.815;
RA Pelletier M.F., Marcil A., Sevigny G., Jakob C.A., Tessier D.C.,
RA Chevet E., Menard R., Bergeron J.J.M., Thomas D.Y.;
RT "The heterodimeric structure of glucosidase II is required for its
RT activity, solubility, and localization in vivo.";
RL Glycobiology 10:815-827(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 130-528 (ISOFORM 1), AND
RP VARIANT THR-291.
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 22-528 (ISOFORM 2), AND
RP VARIANT THR-291.
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP PROTEIN SEQUENCE OF 15-21.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [9]
RP INVOLVEMENT IN PCLD.
RX PubMed=12529853; DOI=10.1086/368295;
RA Li A., Davila S., Furu L., Qian Q., Tian X., Kamath P.S., King B.F.,
RA Torres V.E., Somlo S.;
RT "Mutations in PRKCSH cause isolated autosomal dominant polycystic
RT liver disease.";
RL Am. J. Hum. Genet. 72:691-703(2003).
RN [10]
RP INVOLVEMENT IN PCLD.
RX PubMed=12577059; DOI=10.1038/ng1104;
RA Drenth J.P.H., te Morsche R.H.M., Smink R., Bonifacino J.S.,
RA Jansen J.B.M.J.;
RT "Germline mutations in PRKCSH are associated with autosomal dominant
RT polycystic liver disease.";
RL Nat. Genet. 33:345-347(2003).
RN [11]
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).
CC -!- FUNCTION: Regulatory subunit of glucosidase II.
CC -!- PATHWAY: Glycan metabolism; N-glycan metabolism.
CC -!- SUBUNIT: Heterodimer of a catalytic alpha subunit (GANAB) and a
CC beta subunit (PRKCSH). Binds glycosylated PTPRC (By similarity).
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum (Potential).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P14314-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P14314-2; Sequence=VSP_043749;
CC -!- DISEASE: Polycystic liver disease (PCLD) [MIM:174050]: A
CC hepatobiliary disease characterized by overgrowth of biliary
CC epithelium and supportive connective tissue, resulting in multiple
CC liver cysts. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Contains 2 EF-hand domains.
CC -!- SIMILARITY: Contains 1 PRKCSH domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH15154.1; Type=Erroneous initiation;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PRKCSH";
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; J03075; AAA52493.1; -; mRNA.
DR EMBL; U50326; AAA98668.1; -; Genomic_DNA.
DR EMBL; U50317; AAA98668.1; JOINED; Genomic_DNA.
DR EMBL; U50318; AAA98668.1; JOINED; Genomic_DNA.
DR EMBL; U50319; AAA98668.1; JOINED; Genomic_DNA.
DR EMBL; U50320; AAA98668.1; JOINED; Genomic_DNA.
DR EMBL; U50321; AAA98668.1; JOINED; Genomic_DNA.
DR EMBL; U50322; AAA98668.1; JOINED; Genomic_DNA.
DR EMBL; U50323; AAA98668.1; JOINED; Genomic_DNA.
DR EMBL; U50324; AAA98668.1; JOINED; Genomic_DNA.
DR EMBL; U50325; AAA98668.1; JOINED; Genomic_DNA.
DR EMBL; AF144075; AAF66686.1; -; mRNA.
DR EMBL; BT009858; AAP88860.1; -; mRNA.
DR EMBL; AK290433; BAF83122.1; -; mRNA.
DR EMBL; AC008481; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC024575; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC013586; AAH13586.2; -; mRNA.
DR EMBL; BC015154; AAH15154.1; ALT_INIT; mRNA.
DR PIR; A32469; A32469.
DR RefSeq; NP_001001329.1; NM_001001329.1.
DR RefSeq; NP_002734.2; NM_002743.2.
DR UniGene; Hs.610830; -.
DR ProteinModelPortal; P14314; -.
DR SMR; P14314; 423-512.
DR IntAct; P14314; 13.
DR MINT; MINT-1380114; -.
DR STRING; 9606.ENSP00000252455; -.
DR PhosphoSite; P14314; -.
DR DMDM; 116242499; -.
DR PaxDb; P14314; -.
DR PRIDE; P14314; -.
DR DNASU; 5589; -.
DR Ensembl; ENST00000252455; ENSP00000252455; ENSG00000130175.
DR Ensembl; ENST00000412601; ENSP00000395616; ENSG00000130175.
DR Ensembl; ENST00000586486; ENSP00000465948; ENSG00000130175.
DR Ensembl; ENST00000587327; ENSP00000466012; ENSG00000130175.
DR Ensembl; ENST00000589838; ENSP00000465461; ENSG00000130175.
DR Ensembl; ENST00000591462; ENSP00000465489; ENSG00000130175.
DR GeneID; 5589; -.
DR KEGG; hsa:5589; -.
DR UCSC; uc002mrt.3; human.
DR CTD; 5589; -.
DR GeneCards; GC19P011546; -.
DR HGNC; HGNC:9411; PRKCSH.
DR HPA; CAB004465; -.
DR MIM; 174050; phenotype.
DR MIM; 177060; gene.
DR neXtProt; NX_P14314; -.
DR Orphanet; 2924; Isolated polycystic liver disease.
DR PharmGKB; PA33774; -.
DR eggNOG; NOG289998; -.
DR HOGENOM; HOG000007805; -.
DR HOVERGEN; HBG051738; -.
DR InParanoid; P14314; -.
DR KO; K08288; -.
DR OrthoDB; EOG7DZ8JX; -.
DR PhylomeDB; P14314; -.
DR BRENDA; 3.2.1.84; 2681.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P14314; -.
DR UniPathway; UPA00957; -.
DR ChiTaRS; PRKCSH; human.
DR GeneWiki; PRKCSH; -.
DR GenomeRNAi; 5589; -.
DR NextBio; 21678; -.
DR PMAP-CutDB; P14314; -.
DR PRO; PR:P14314; -.
DR ArrayExpress; P14314; -.
DR Bgee; P14314; -.
DR CleanEx; HS_PRKCSH; -.
DR Genevestigator; P14314; -.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0003723; F:RNA binding; IEA:Ensembl.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0007243; P:intracellular protein kinase cascade; NAS:UniProtKB.
DR GO; GO:0001889; P:liver development; IEA:Ensembl.
DR GO; GO:0006491; P:N-glycan processing; IEA:InterPro.
DR GO; GO:0010977; P:negative regulation of neuron projection development; IEA:Ensembl.
DR GO; GO:0006807; P:nitrogen compound metabolic process; IEA:Ensembl.
DR GO; GO:0043687; P:post-translational protein modification; TAS:Reactome.
DR GO; GO:0006457; P:protein folding; TAS:Reactome.
DR GO; GO:0051291; P:protein heterooligomerization; IEA:Ensembl.
DR GO; GO:0018279; P:protein N-linked glycosylation via asparagine; TAS:Reactome.
DR GO; GO:0072001; P:renal system development; IEA:Ensembl.
DR Gene3D; 4.10.400.10; -; 2.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR026874; Glucosidase_2_bsu.
DR InterPro; IPR002172; LDrepeatLR_classA_rpt.
DR InterPro; IPR009011; Man6P_isomerase_rcpt-bd_dom.
DR InterPro; IPR028146; PRKCSH_N.
DR PANTHER; PTHR12630:SF1; PTHR12630:SF1; 1.
DR Pfam; PF13202; EF-hand_5; 2.
DR Pfam; PF12999; PRKCSH-like; 1.
DR SMART; SM00192; LDLa; 1.
DR SUPFAM; SSF50911; SSF50911; 1.
DR SUPFAM; SSF57424; SSF57424; 1.
DR PROSITE; PS00018; EF_HAND_1; 1.
DR PROSITE; PS50222; EF_HAND_2; 1.
DR PROSITE; PS00014; ER_TARGET; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Calcium; Complete proteome;
KW Direct protein sequencing; Endoplasmic reticulum; Glycoprotein;
KW Metal-binding; Phosphoprotein; Polymorphism; Reference proteome;
KW Repeat; Signal.
FT SIGNAL 1 14
FT CHAIN 15 528 Glucosidase 2 subunit beta.
FT /FTId=PRO_0000004143.
FT DOMAIN 209 244 EF-hand 1.
FT DOMAIN 245 290 EF-hand 2.
FT DOMAIN 413 468 PRKCSH.
FT CA_BIND 213 236 1 (Potential).
FT MOTIF 525 528 Prevents secretion from ER (Potential).
FT COMPBIAS 313 336 Glu-rich (acidic).
FT MOD_RES 89 89 Phosphoserine; by PKC (Potential).
FT MOD_RES 383 383 Phosphoserine; by PKC (Potential).
FT MOD_RES 390 390 Phosphoserine; by PKC (Potential).
FT MOD_RES 434 434 Phosphoserine; by PKC (Potential).
FT CARBOHYD 72 72 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 476 476 N-linked (GlcNAc...) (Potential).
FT VAR_SEQ 337 346 EAPPPLSPPQ -> VQGEQPK (in isoform 2).
FT /FTId=VSP_043749.
FT VARIANT 74 74 S -> N (in dbSNP:rs10406672).
FT /FTId=VAR_028761.
FT VARIANT 291 291 A -> T (in dbSNP:rs11557488).
FT /FTId=VAR_028762.
FT VARIANT 338 338 A -> G (in dbSNP:rs35847588).
FT /FTId=VAR_048658.
FT CONFLICT 325 325 Missing (in Ref. 1; AAA52493, 2;
FT AAA98668, 4; AAP88860 and 6; AAH13586).
SQ SEQUENCE 528 AA; 59425 MW; 8DAD9776037E878E CRC64;
MLLPLLLLLP MCWAVEVKRP RGVSLTNHHF YDESKPFTCL DGSATIPFDQ VNDDYCDCKD
GSDEPGTAAC PNGSFHCTNT GYKPLYIPSN RVNDGVCDCC DGTDEYNSGV ICENTCKEKG
RKERESLQQM AEVTREGFRL KKILIEDWKK AREEKQKKLI ELQAGKKSLE DQVEMLRTVK
EEAEKPEREA KEQHQKLWEE QLAAAKAQQE QELAADAFKE LDDDMDGTVS VTELQTHPEL
DTDGDGALSE AEAQALLSGD TQTDATSFYD RVWAAIRDKY RSEALPTDLP APSAPDLTEP
KEEQPPVPSS PTEEEEEEEE EEEEEAEEEE EEEDSEEAPP PLSPPQPASP AEEDKMPPYD
EQTQAFIDAA QEARNKFEEA ERSLKDMEES IRNLEQEISF DFGPNGEFAY LYSQCYELTT
NEYVYRLCPF KLVSQKPKLG GSPTSLGTWG SWIGPDHDKF SAMKYEQGTG CWQGPNRSTT
VRLLCGKETM VTSTTEPSRC EYLMELMTPA ACPEPPPEAP TEDDHDEL
//
MIM
174050
*RECORD*
*FIELD* NO
174050
*FIELD* TI
#174050 POLYCYSTIC LIVER DISEASE; PCLD
*FIELD* TX
A number sign (#) is used with this entry because isolated polycystic
read moreliver disease can be caused by mutations in the PRKCSH gene (177060).
Mutations in the SEC63 gene (608648) also cause autosomal dominant
polycystic liver disease.
CLINICAL FEATURES
Berrebi et al. (1982) suggested that polycystic liver disease exists as
an autosomal dominant entity independent of polycystic kidney disease
(PKD; 173900), which in a considerable but uncertain proportion of cases
is associated with hepatic cysts. They described a family in which 2
sisters and the 2 daughters of 1 of the sisters had polycystic liver
disease without involvement of the kidneys. One of the 'daughters' had 4
children and 7 grandchildren, all apparently unaffected. The authors
suggested that either the 4 'children' did not inherit their mother's
PCLD gene or had not yet expressed it because of younger age, none being
over age 35 years. In fact, the affected women in the family of Berrebi
et al. (1982) did show single cysts or a small number of cysts in the
kidney, and at least 1 had 'numerous small 2-3 mm cysts...throughout the
pancreas.' The authors pointed to the family reported by Sotaniemi et
al. (1979) and Luoma et al. (1980) as another probable example of the
distinct entity. Karhunen and Tenhu (1986) also presented evidence
supporting the notion that adult polycystic liver disease is an entity
separate from adult polycystic kidney disease. In 22 cases of either
polycystic disease of the liver or polycystic disease of the kidney that
were found in 33,700 medicolegal autopsies, both organs were affected in
only 1 case. In another case of adult PKD, the liver was macroscopically
normal but contained microcysts and typical von Meyenburg complexes from
which the cysts originate. Cerebral hemorrhage was found only with adult
PKD and was not observed in cases of only PCLD. The authors planned to
study the families of their probands with PCLD.
Strong genetic evidence that adult polycystic liver disease is an entity
distinct from either polycystic kidney disease type 1 (PKD1; 601313) or
PKD2 (613095) was presented by Pirson et al. (1996) who traced the
disorder through 3 generations, excluded the presence of kidney cysts,
and excluded linkage of the disease in this family to the genetic
markers of PKD1 and PKD2. The proband was a 61-year-old man with highly
symptomatic PCLD, diagnosed at age 50. The patient's mother also had
massive PCLD without known kidney disease; she died of cancer of unknown
origin at age 80. The proband's sister had extensive PCLD with mild
hepatomegaly and without kidney cysts. The proband's daughter had marked
PCLD with normal liver size. The proband's son had no liver cysts.
Information added in proof seemed to establish the autosomal dominant
inheritance of the disorder: a 56-year-old maternal first cousin of the
proband was found to have extensive PCLD with mild hepatomegaly without
cysts in the kidneys, pancreas, or spleen. He presumably inherited the
disorder from his father, the maternal uncle of the proband.
MAPPING
- Linkage to Chromosome 19p13
The clinical presentation and histologic features of polycystic liver
disease in the presence or absence of autosomal dominant polycystic
kidney disease are indistinguishable, suggesting that PCLD may be
allelic to one of the forms of autosomal dominant PKD. The genetically
distinct nature of isolated polycystic liver disease was supported by
the finding of Reynolds et al. (2000) that the causative gene in a
family with PCLD mapped to 19p13.2-p13.1 by linkage analysis, with a
maximum lod score of 10.3. The authors suggested that availability of
genetic linkage information should facilitate diagnosis and study of
this underdiagnosed disease entity, and that identification of the PCLD
gene will be instrumental in understanding the pathogenesis of cyst
formation in the liver, both in isolated PCLD and in autosomal dominant
PKD.
- Linkage to Chromosome 6q21
Davila et al. (2004) performed genomewide linkage analysis on 10
individuals with autosomal dominant PCLD from multiply affected families
in whom mutations in the PRKCSH gene (177060) were excluded. They found
linkage to chromosome 6q21-q23.
MOLECULAR GENETICS
- PCLD Due to Mutation in the PRKCSH Gene
Drenth et al. (2003) narrowed the linkage assignment of the PCLD locus
on 19p to a genomic interval containing 78 genes and EST clusters. In
the absence of a clear candidate gene, they carried out exon screening
using flanking intronic primers. After sequencing 677 exons representing
94% of exons in the genetic region, they detected a heterozygous
mutation at a splice acceptor site of the PRKCSH gene (177060.0001) in
affected members of 3 families and heterozygosity for a splice donor
site mutation (177060.0002) in affected members of a fourth family.
Li et al. (2003) found mutation in the PRKCSH gene in several families
with PCLD, including 2 families studied by Reynolds et al. (2000).
- PCLD Due to Mutation in the SEC63 Gene
Davila et al. (2004) found that mutations in the SEC63 gene (608648)
also cause autosomal dominant polycystic liver disease. The SEC63 gene
encodes a component of the protein translocation machinery in the
endoplasmic reticulum; the PRKCSH gene encodes the beta-subunit of
glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic
reticulum. Thus, these findings together suggest a role for
cotranslational protein-processing pathways in maintaining epithelial
luminal structure and implicate noncilial endoplasmic reticulum proteins
in a human polycystic disease.
HETEROGENEITY
Autosomal dominant polycystic liver disease can be caused by mutation in
the PRKCSH or the SEC63 gene. Davila et al. (2004) noted that mutations
in PRKCSH and SEC63 together accounted for less than one-third of cases
in their cohort, indicating the presence of at least one more locus
associated with this disorder.
*FIELD* RF
1. Berrebi, G.; Erickson, R. P.; Marks, B. W.: Autosomal dominant
polycystic liver disease: a second family. Clin. Genet. 21: 342-347,
1982.
2. Davila, S.; Furu, L.; Gharavi, A. G.; Tian, X.; Onoe, T.; Qian,
Q.; Li, A.; Cai, Y.; Kamath, P. S.; King, B. F.; Azurmendi, P. J.;
Tahvanainen, P.; and 9 others: Mutations in SEC63 cause autosomal
dominant polycystic liver disease. Nature Genet. 36: 575-576, 2004.
3. Drenth, J. P. H.; te Morsche, R. H. M.; Smink, R.; Bonifacino,
J. S.; Jansen, J. B. M. J.: Germline mutations in PRKCSH are associated
with autosomal dominant polycystic liver disease. Nature Genet. 33:
345-348, 2003.
4. Karhunen, P. J.; Tenhu, M.: Adult polycystic liver and kidney
diseases are separate entities. Clin. Genet. 30: 29-37, 1986.
5. Li, A.; Davila, S.; Furu, L.; Qian, Q.; Tian, X.; Kamath, P. S.;
King, B. F.; Torres, V. E.; Somlo, S.: Mutations in PRKCSH cause
isolated autosomal dominant polycystic liver disease. Am. J. Hum.
Genet. 72: 691-703, 2003.
6. Luoma, P. V.; Sotaniemi, E. A.; Ehnholm, C.: Low high-density
lipoprotein and reduced antipyrine metabolism in members of a family
with polycystic liver disease. Scand. J. Gastroent. 15: 869-873,
1980.
7. Pirson, Y.; Lannoy, N.; Peters, D.; Geubel, A.; Gigot, J.-F.; Breuning,
M.; Verellen-Dumoulin, C.: Isolated polycystic liver disease as a
distinct genetic disease, unlinked to polycystic kidney disease 1
and polycystic kidney disease 2. Hepatology 23: 249-252, 1996.
8. Reynolds, D. M.; Falk, C. T.; Li, A.; King, B. F.; Kamath, P. S.;
Huston, J., III; Shub, C.; Iglesias, D. M.; Martin, R. S.; Pirson,
Y.; Torres, V. E.; Somlo, S.: Identification of a locus for autosomal
dominant polycystic liver disease, on chromosome 19p13.2-13.1. Am.
J. Hum. Genet. 67: 1598-1604, 2000.
9. Sotaniemi, E. A.; Luoma, P. V.; Arvensivu, P. M.; Sotaniemi, K.
A.: Impairment of drug metabolism in polycystic non-parasitic kidney
disease. Brit. J. Clin. Pharm. 8: 331-335, 1979.
*FIELD* CS
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Vascular];
Rare compression of inferior vena cava (secondary lower extremity
edema)
RESPIRATORY:
Dyspnea due to mass effect of liver
ABDOMEN:
[Liver];
Abdominal distention due to mass effect of liver;
Multiple fluid-filled cysts throughout the liver;
Cysts of biliary epithelial origin;
Usually asymptomatic;
Rare hemorrhage from cysts;
Rare infection of cysts;
Rare rupture of cysts;
Rare obstruction of hepatic venous outflow (ascites);
[Gastrointestinal];
Early satiety due to mass effect of liver
SKELETAL:
[Spine];
Back pain due to mass effect of liver
GENITOURINARY:
[Kidneys];
No evidence of renal cysts;
No kidney disease
NEUROLOGIC:
[Central nervous system];
Absence of cerebral aneurysms
LABORATORY ABNORMALITIES:
Slightly increased serum alkaline phosphatase may occur;
Increased total bilirubin may occur;
Lower total cholesterol;
Lower triglycerides
MOLECULAR BASIS:
Caused by mutation in the protein kinase C substrate, 80-kD heavy
chain gene (PRKCSH, 177060.0001), or in the gene encoding the human
homolog of S. cerevisiae Sec63 (SEC63, 608648.0001)
*FIELD* CN
Cassandra L. Kniffin - revised: 10/2/2003
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
wwang: 02/22/2010
ckniffin: 10/3/2005
alopez: 6/1/2004
ckniffin: 10/2/2003
alopez: 2/21/2003
*FIELD* CN
Victor A. McKusick - updated: 5/14/2004
Victor A. McKusick - updated: 3/3/2003
Ada Hamosh - updated: 2/21/2003
Victor A. McKusick - updated: 12/12/2000
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
mgross: 10/16/2009
alopez: 6/1/2004
alopez: 5/28/2004
alopez: 5/17/2004
terry: 5/14/2004
alopez: 3/3/2003
alopez: 2/28/2003
alopez: 2/21/2003
terry: 2/21/2003
mcapotos: 1/8/2001
mcapotos: 12/28/2000
terry: 12/12/2000
carol: 1/22/1999
mark: 3/31/1996
terry: 3/21/1996
mimadm: 2/25/1995
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
root: 4/22/1988
marie: 3/25/1988
*RECORD*
*FIELD* NO
174050
*FIELD* TI
#174050 POLYCYSTIC LIVER DISEASE; PCLD
*FIELD* TX
A number sign (#) is used with this entry because isolated polycystic
read moreliver disease can be caused by mutations in the PRKCSH gene (177060).
Mutations in the SEC63 gene (608648) also cause autosomal dominant
polycystic liver disease.
CLINICAL FEATURES
Berrebi et al. (1982) suggested that polycystic liver disease exists as
an autosomal dominant entity independent of polycystic kidney disease
(PKD; 173900), which in a considerable but uncertain proportion of cases
is associated with hepatic cysts. They described a family in which 2
sisters and the 2 daughters of 1 of the sisters had polycystic liver
disease without involvement of the kidneys. One of the 'daughters' had 4
children and 7 grandchildren, all apparently unaffected. The authors
suggested that either the 4 'children' did not inherit their mother's
PCLD gene or had not yet expressed it because of younger age, none being
over age 35 years. In fact, the affected women in the family of Berrebi
et al. (1982) did show single cysts or a small number of cysts in the
kidney, and at least 1 had 'numerous small 2-3 mm cysts...throughout the
pancreas.' The authors pointed to the family reported by Sotaniemi et
al. (1979) and Luoma et al. (1980) as another probable example of the
distinct entity. Karhunen and Tenhu (1986) also presented evidence
supporting the notion that adult polycystic liver disease is an entity
separate from adult polycystic kidney disease. In 22 cases of either
polycystic disease of the liver or polycystic disease of the kidney that
were found in 33,700 medicolegal autopsies, both organs were affected in
only 1 case. In another case of adult PKD, the liver was macroscopically
normal but contained microcysts and typical von Meyenburg complexes from
which the cysts originate. Cerebral hemorrhage was found only with adult
PKD and was not observed in cases of only PCLD. The authors planned to
study the families of their probands with PCLD.
Strong genetic evidence that adult polycystic liver disease is an entity
distinct from either polycystic kidney disease type 1 (PKD1; 601313) or
PKD2 (613095) was presented by Pirson et al. (1996) who traced the
disorder through 3 generations, excluded the presence of kidney cysts,
and excluded linkage of the disease in this family to the genetic
markers of PKD1 and PKD2. The proband was a 61-year-old man with highly
symptomatic PCLD, diagnosed at age 50. The patient's mother also had
massive PCLD without known kidney disease; she died of cancer of unknown
origin at age 80. The proband's sister had extensive PCLD with mild
hepatomegaly and without kidney cysts. The proband's daughter had marked
PCLD with normal liver size. The proband's son had no liver cysts.
Information added in proof seemed to establish the autosomal dominant
inheritance of the disorder: a 56-year-old maternal first cousin of the
proband was found to have extensive PCLD with mild hepatomegaly without
cysts in the kidneys, pancreas, or spleen. He presumably inherited the
disorder from his father, the maternal uncle of the proband.
MAPPING
- Linkage to Chromosome 19p13
The clinical presentation and histologic features of polycystic liver
disease in the presence or absence of autosomal dominant polycystic
kidney disease are indistinguishable, suggesting that PCLD may be
allelic to one of the forms of autosomal dominant PKD. The genetically
distinct nature of isolated polycystic liver disease was supported by
the finding of Reynolds et al. (2000) that the causative gene in a
family with PCLD mapped to 19p13.2-p13.1 by linkage analysis, with a
maximum lod score of 10.3. The authors suggested that availability of
genetic linkage information should facilitate diagnosis and study of
this underdiagnosed disease entity, and that identification of the PCLD
gene will be instrumental in understanding the pathogenesis of cyst
formation in the liver, both in isolated PCLD and in autosomal dominant
PKD.
- Linkage to Chromosome 6q21
Davila et al. (2004) performed genomewide linkage analysis on 10
individuals with autosomal dominant PCLD from multiply affected families
in whom mutations in the PRKCSH gene (177060) were excluded. They found
linkage to chromosome 6q21-q23.
MOLECULAR GENETICS
- PCLD Due to Mutation in the PRKCSH Gene
Drenth et al. (2003) narrowed the linkage assignment of the PCLD locus
on 19p to a genomic interval containing 78 genes and EST clusters. In
the absence of a clear candidate gene, they carried out exon screening
using flanking intronic primers. After sequencing 677 exons representing
94% of exons in the genetic region, they detected a heterozygous
mutation at a splice acceptor site of the PRKCSH gene (177060.0001) in
affected members of 3 families and heterozygosity for a splice donor
site mutation (177060.0002) in affected members of a fourth family.
Li et al. (2003) found mutation in the PRKCSH gene in several families
with PCLD, including 2 families studied by Reynolds et al. (2000).
- PCLD Due to Mutation in the SEC63 Gene
Davila et al. (2004) found that mutations in the SEC63 gene (608648)
also cause autosomal dominant polycystic liver disease. The SEC63 gene
encodes a component of the protein translocation machinery in the
endoplasmic reticulum; the PRKCSH gene encodes the beta-subunit of
glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic
reticulum. Thus, these findings together suggest a role for
cotranslational protein-processing pathways in maintaining epithelial
luminal structure and implicate noncilial endoplasmic reticulum proteins
in a human polycystic disease.
HETEROGENEITY
Autosomal dominant polycystic liver disease can be caused by mutation in
the PRKCSH or the SEC63 gene. Davila et al. (2004) noted that mutations
in PRKCSH and SEC63 together accounted for less than one-third of cases
in their cohort, indicating the presence of at least one more locus
associated with this disorder.
*FIELD* RF
1. Berrebi, G.; Erickson, R. P.; Marks, B. W.: Autosomal dominant
polycystic liver disease: a second family. Clin. Genet. 21: 342-347,
1982.
2. Davila, S.; Furu, L.; Gharavi, A. G.; Tian, X.; Onoe, T.; Qian,
Q.; Li, A.; Cai, Y.; Kamath, P. S.; King, B. F.; Azurmendi, P. J.;
Tahvanainen, P.; and 9 others: Mutations in SEC63 cause autosomal
dominant polycystic liver disease. Nature Genet. 36: 575-576, 2004.
3. Drenth, J. P. H.; te Morsche, R. H. M.; Smink, R.; Bonifacino,
J. S.; Jansen, J. B. M. J.: Germline mutations in PRKCSH are associated
with autosomal dominant polycystic liver disease. Nature Genet. 33:
345-348, 2003.
4. Karhunen, P. J.; Tenhu, M.: Adult polycystic liver and kidney
diseases are separate entities. Clin. Genet. 30: 29-37, 1986.
5. Li, A.; Davila, S.; Furu, L.; Qian, Q.; Tian, X.; Kamath, P. S.;
King, B. F.; Torres, V. E.; Somlo, S.: Mutations in PRKCSH cause
isolated autosomal dominant polycystic liver disease. Am. J. Hum.
Genet. 72: 691-703, 2003.
6. Luoma, P. V.; Sotaniemi, E. A.; Ehnholm, C.: Low high-density
lipoprotein and reduced antipyrine metabolism in members of a family
with polycystic liver disease. Scand. J. Gastroent. 15: 869-873,
1980.
7. Pirson, Y.; Lannoy, N.; Peters, D.; Geubel, A.; Gigot, J.-F.; Breuning,
M.; Verellen-Dumoulin, C.: Isolated polycystic liver disease as a
distinct genetic disease, unlinked to polycystic kidney disease 1
and polycystic kidney disease 2. Hepatology 23: 249-252, 1996.
8. Reynolds, D. M.; Falk, C. T.; Li, A.; King, B. F.; Kamath, P. S.;
Huston, J., III; Shub, C.; Iglesias, D. M.; Martin, R. S.; Pirson,
Y.; Torres, V. E.; Somlo, S.: Identification of a locus for autosomal
dominant polycystic liver disease, on chromosome 19p13.2-13.1. Am.
J. Hum. Genet. 67: 1598-1604, 2000.
9. Sotaniemi, E. A.; Luoma, P. V.; Arvensivu, P. M.; Sotaniemi, K.
A.: Impairment of drug metabolism in polycystic non-parasitic kidney
disease. Brit. J. Clin. Pharm. 8: 331-335, 1979.
*FIELD* CS
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Vascular];
Rare compression of inferior vena cava (secondary lower extremity
edema)
RESPIRATORY:
Dyspnea due to mass effect of liver
ABDOMEN:
[Liver];
Abdominal distention due to mass effect of liver;
Multiple fluid-filled cysts throughout the liver;
Cysts of biliary epithelial origin;
Usually asymptomatic;
Rare hemorrhage from cysts;
Rare infection of cysts;
Rare rupture of cysts;
Rare obstruction of hepatic venous outflow (ascites);
[Gastrointestinal];
Early satiety due to mass effect of liver
SKELETAL:
[Spine];
Back pain due to mass effect of liver
GENITOURINARY:
[Kidneys];
No evidence of renal cysts;
No kidney disease
NEUROLOGIC:
[Central nervous system];
Absence of cerebral aneurysms
LABORATORY ABNORMALITIES:
Slightly increased serum alkaline phosphatase may occur;
Increased total bilirubin may occur;
Lower total cholesterol;
Lower triglycerides
MOLECULAR BASIS:
Caused by mutation in the protein kinase C substrate, 80-kD heavy
chain gene (PRKCSH, 177060.0001), or in the gene encoding the human
homolog of S. cerevisiae Sec63 (SEC63, 608648.0001)
*FIELD* CN
Cassandra L. Kniffin - revised: 10/2/2003
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
wwang: 02/22/2010
ckniffin: 10/3/2005
alopez: 6/1/2004
ckniffin: 10/2/2003
alopez: 2/21/2003
*FIELD* CN
Victor A. McKusick - updated: 5/14/2004
Victor A. McKusick - updated: 3/3/2003
Ada Hamosh - updated: 2/21/2003
Victor A. McKusick - updated: 12/12/2000
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
mgross: 10/16/2009
alopez: 6/1/2004
alopez: 5/28/2004
alopez: 5/17/2004
terry: 5/14/2004
alopez: 3/3/2003
alopez: 2/28/2003
alopez: 2/21/2003
terry: 2/21/2003
mcapotos: 1/8/2001
mcapotos: 12/28/2000
terry: 12/12/2000
carol: 1/22/1999
mark: 3/31/1996
terry: 3/21/1996
mimadm: 2/25/1995
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
root: 4/22/1988
marie: 3/25/1988
MIM
177060
*RECORD*
*FIELD* NO
177060
*FIELD* TI
*177060 PROTEIN KINASE C SUBSTRATE, 80-KD, HEAVY CHAIN; PRKCSH
;;G19P1;;
GLUCOSIDASE II, BETA SUBUNIT
read moreHEPATOCYSTIN, INCLUDED
*FIELD* TX
PRKCSH encodes the noncatalytic beta subunit of glucosidase II.
Glucosidase II activity (see 104160) is necessary for proper folding and
quality control of proteins passing through the endoplasmic reticulum
(ER) translocon (see 609213). The glucosidase II beta subunit encoded by
PRKCSH contains an ER luminal retention signal and is required for
glucosidase II function (summary by Fedeles et al., 2011).
CLONING
Acidic proteins with an approximate molecular mass of 80 kD are
prominent substrates for Ca(2+)/phospholipid-dependent protein kinase
(protein kinase C; 176960, 176970, 176980). On the basis of the previous
finding that human squamous carcinoma cells contain 2 distinct species
of the 80-kD protein, 80K-H and 80K-L (177061), Minoshima et al. (1989)
and Sakai et al. (1989) purified the 80K-H protein, determined a partial
amino acid sequence, and synthesized a corresponding DNA probe. The
PRKCSH cDNA encodes a protein of 527 amino acids. The deduced amino acid
sequence showed a highly glutamic acid-rich region.
Trombetta et al. (1996) isolated enzymatically active glucosidase II
from rat liver and found that it was composed of 2 subunits, alpha
(104160) and beta. Based on peptide sequences of the purified enzyme,
they identified the corresponding human cDNAs in existing sequence
databases. Trombetta et al. (1996) reported that the available sequence
of the beta subunit of human glucosidase II predicts a 514-amino acid
protein with a putative endoplasmic reticulum retention signal.
GENE FUNCTION
Drenth et al. (2003) referred to the protein product of the PRKCSH gene
as hepatocystin and predicted it to be localized to the endoplasmic
reticulum.
GENE STRUCTURE
Drenth et al. (2003) stated that the PRKCSH gene consists of 18 exons in
a 15-kb interval.
MAPPING
Using a DNA probe corresponding to the 80K-H protein, Sakai et al.
(1989) mapped the PRKCSH gene to chromosome 19 by spot blot
hybridization to flow-sorted human chromosomes. The PRKCSH gene lies
within the critical region on 19p13.2-p13.1 established for autosomal
dominant polycystic liver disease (174050) (Reynolds et al., 2000; Li et
al., 2003)
MOLECULAR GENETICS
Polycystic liver disease (PCLD; 174050) is a dominantly inherited
condition characterized by the presence of multiple liver cysts of
biliary epithelial origin. Although the clinical presentation and
histologic features of polycystic liver disease in the presence or
absence of autosomal dominant polycystic kidney disease are
indistinguishable, a genetically distinct form of isolated polycystic
liver disease is supported by the finding of linkage to 19p (Reynolds et
al., 2000), a site distinct from those of the 2 forms of autosomal
dominant polycystic kidney disease, PKD1 (173900) and PKD2 (613095).
Studying the same 2 large kindreds investigated by Reynolds et al.
(2000) and an additional family allowed Li et al. (2003) to define
flanking markers in a region of approximately 3 Mb containing more than
70 candidate genes. Using a combination of denaturing high-performance
liquid chromatography (DHPLC) heteroduplex analysis and direct
sequencing, they screened a panel of 15 unrelated affected individuals
for mutations in genes from this interval. They found sequence
variations in the PRKCSH gene that were not observed in control
individuals, that segregated with the disease haplotype, and that were
predicted to be chain-terminating mutations. They suggested that in
light of the focal nature of liver cysts in autosomal dominant
polycystic liver disease (ADPLD), the apparent loss-of-function
mutations in PRKCSH, and the 2-hit mechanism operational in dominant
polycystic kidney disease, they suggested that this disorder may also
occur by a 2-hit mechanism.
Drenth et al. (2003) narrowed the critical region for PCLD on 19p to a
2.1-cM interval containing 78 genes and EST clusters. After sequencing
677 exons representing 94% of those in the genetic region of question,
they detected a heterozygous mutation, 1138-2A-G (177060.0001), at the
splice acceptor site of exon 16 of the PRKCSH gene. This mutation
segregated in all affected members of 3 families. A second heterozygous
change, at the splice donor site of intron 4 (177060.0002), segregated
with all affected individuals in a fourth family.
ANIMAL MODEL
Gao et al. (2010) showed that overexpression or depletion of Prkcsh in
zebrafish embryos led to pronephric cysts, abnormal body curvature, and
situs inversus. Identical phenotypic changes were induced by depletion
or overexpression of Pkd2 (173910). Increased Prkcsh levels ameliorated
developmental abnormalities caused by overexpressed Pkd2, whereas excess
Pkd2 could compensate the loss of Prkcsh, indicating that the proteins
may share a common signaling pathway. Prkcsh bound the C-terminal domain
of Pkd2, and both proteins colocalized within the ER. Furthermore,
Prkcsh interacted with Herp (HERPUD1; 608070) and inhibited
Herp-mediated ubiquitination of Pkd2. Gao et al. (2010) suggested that
PRKCSH may function as a chaperone-like molecule, which may prevent
ER-associated degradation (ERAD) of Pkd2. Disequilibrium between PKD2
and PRKCSH may lead to cyst formation in PCLD patients with PRKCSH
mutations, and thereby account for the overlapping manifestations
observed in PCLD and autosomal dominant polycystic kidney disease.
Mutations in PRKCSH or SEC63 (608648) cause autosomal dominant
polycystic liver disease. Fedeles et al. (2011) found that homozygous
deletion of either Prkcsh or Sec63 in mice led to early embryonic
lethality. Kidney- or liver-specific inactivation of either gene
resulted in polycystic kidney or liver disease, respectively. Knockout
of both genes increased the severity of cyst formation. Using a
combination of targeted knockout and overexpression with these 2 genes
and 3 other major genes mutated in polycystic kidney disease, Pkd1
(601313), Pkd2, and Pkhd1 (606702), Fedeles et al. (2011) produced a
spectrum of cystic disease severity. Cyst formation in all combinations
of these genes, except complete loss of Pkd2, was significantly
modulated by altering expression of Pkd1. Proteasome inhibition
increased the steady-state levels of Pkd1 in cells lacking Prkcsh and
reduced cystic disease in mouse models of autosomal dominant polycystic
liver disease. Fedeles et al. (2011) concluded that PRKCSH, SEC63, PKD1,
PKD2, and PKHD1 form an interaction network with PKD1 as the
rate-limiting component.
*FIELD* AV
.0001
POLYCYSTIC LIVER DISEASE
PRKCSH, IVS16, A-G, -2
In 3 Dutch families, Drenth et al. (2003) found that members affected by
autosomal dominant polycystic liver disease (174050) were heterozygous
for a mutation of adenine to guanine (1138-2A-G) at the splice acceptor
site of exon 16 of the PRKCSH gene.
.0002
POLYCYSTIC LIVER DISEASE
PRKCSH, IVS4, G-C, +1
In all affected members of a family with autosomal dominant polycystic
liver disease (174050), Drenth et al. (2003) found a heterozygous change
from guanine to cytosine (292+1G-C) in the splice donor site of intron 4
of the PRKCSH gene.
.0003
POLYCYSTIC LIVER DISEASE
PRKCSH, 2-BP DEL, IVS16GT, +1
In family 1 with autosomal dominant polycystic liver disease (174050) in
which linkage study was performed by Reynolds et al. (2000), Li et al.
(2003) demonstrated a deletion of 2 bp at the 5-prime splice site of
IVS16 of the PRKCSH gene. This resulted in skipping of exon 16 in a
transcript in which exon 15 was spliced to exon 17, causing a frameshift
and premature termination.
.0004
POLYCYSTIC LIVER DISEASE
PRKCSH, GLN413TER
In family 2 with autosomal dominant polycystic liver disease (174050) in
which Reynolds et al. (2000) demonstrated linkage between PCLD and 19p,
Li et al. (2003) found a 1237C-T transition in exon 14 of the PRKCSH
gene, resulting in a premature termination codon, gln413 to stop
(Q413X). This mutation segregated with the affected haplotype.
.0005
POLYCYSTIC LIVER DISEASE
PRKCSH, TYR422TER
In a family in which 3 members had autosomal dominant polycystic liver
disease (174050), Li et al. (2003) found a 1266C-G transversion in exon
15 of the PRKCSH gene resulting in a nonsense mutation, tyr422 to stop
(Y422X).
.0006
POLYCYSTIC LIVER DISEASE
PRKCSH, 1-BP INS, 216A
In 2 affected members of a family with autosomal dominant polycystic
liver disease (174050), Li et al. (2003) found a 1-bp insertion
(216insA) in exon 4 of the PRKSCH gene resulting in a frameshift and
premature termination at amino acid residue 84 (N72Xfs84).
*FIELD* RF
1. Drenth, J. P. H.; te Morsche, R. H. M.; Smink, R.; Bonifacino,
J. S.; Jansen, J. B. M. J.: Germline mutations in PRKCSH are associated
with autosomal dominant polycystic liver disease. Nature Genet. 33:
345-348, 2003.
2. Fedeles, S. V.; Tian, X.; Gallagher, A.-R.; Mitobe, M.; Nishio,
S.; Lee, S. H.; Cai, Y.; Geng, L.; Crews, C. M.; Somlo, S.: A genetic
interaction network of five genes for human polycystic kidney and
liver diseases defines polycystin-1 as the central determinant of
cyst formation. Nature Genet. 43: 639-647, 2011.
3. Gao, H.; Wang, Y.; Wegierski, T.; Skouloudaki, K.; Putz, M.; Fu,
X.; Engel, C.; Boehlke, C.; Peng, H.; Kuehn, E. W.; Kim, E.; Kramer-Zucker,
A.; Walz, G.: PRKCSH/80K-H, the protein mutated in polycystic liver
disease, protects polycystin-2/TRPP2 against HERP-mediated degradation. Hum.
Molec. Genet. 19: 16-24, 2010.
4. Li, A.; Davila, S.; Furu, L.; Qian, Q.; Tian, X.; Kamath, P. S.;
King, B. F.; Torres, V. E.; Somlo, S.: Mutations in PRKCSH cause
isolated autosomal dominant polycystic liver disease. Am. J. Hum.
Genet. 72: 691-703, 2003.
5. Minoshima, S.; Hirai, M.; Sakai, K.; Kudoh, J.; Fukuyama, R.; Maekawa,
M.; Shimizu, N.: Assignment of the gene for a protein kinase C substrate,
80K protein, to human chromosome 19. (Abstract) Cytogenet. Cell Genet. 51:
1045 only, 1989.
6. Reynolds, D. M.; Falk, C. T.; Li, A.; King, B. F.; Kamath, P. S.;
Huston, J., III; Shub, C.; Iglesias, D. M.; Martin, R. S.; Pirson,
Y.; Torres, V. E.; Somlo, S.: Identification of a locus for autosomal
dominant polycystic liver disease, on chromosome 19p13.2-13.1. Am.
J. Hum. Genet. 67: 1598-1604, 2000.
7. Sakai, K.; Hirai, M.; Minoshima, S.; Kudoh, J.; Fukuyama, R.; Shimizu,
N.: Isolation of cDNAs encoding a substrate for protein kinase C:
nucleotide sequence and chromosomal mapping of the gene for a human
80K protein. Genomics 5: 309-315, 1989.
8. Trombetta, E. S.; Simons, J. F.; Helenius, A.: Endoplasmic reticulum
glucosidase II is composed of a catalytic subunit, conserved from
yeast to mammals, and a tightly bound noncatalytic HDEL-containing
subunit. J. Biol. Chem. 271: 27509-27516, 1996.
*FIELD* CN
Patricia A. Hartz - updated: 8/10/2011
George E. Tiller - updated: 11/12/2010
Victor A. McKusick - updated: 2/26/2003
Ada Hamosh - updated: 2/21/2003
*FIELD* CD
Victor A. McKusick: 6/7/1989
*FIELD* ED
mgross: 08/11/2011
terry: 8/10/2011
wwang: 11/18/2010
terry: 11/12/2010
mgross: 10/16/2009
carol: 6/14/2005
alopez: 2/28/2003
terry: 2/26/2003
alopez: 2/21/2003
terry: 2/21/2003
carol: 5/4/1999
supermim: 3/16/1992
carol: 10/21/1991
carol: 8/8/1991
supermim: 3/20/1990
carol: 12/12/1989
ddp: 10/27/1989
*RECORD*
*FIELD* NO
177060
*FIELD* TI
*177060 PROTEIN KINASE C SUBSTRATE, 80-KD, HEAVY CHAIN; PRKCSH
;;G19P1;;
GLUCOSIDASE II, BETA SUBUNIT
read moreHEPATOCYSTIN, INCLUDED
*FIELD* TX
PRKCSH encodes the noncatalytic beta subunit of glucosidase II.
Glucosidase II activity (see 104160) is necessary for proper folding and
quality control of proteins passing through the endoplasmic reticulum
(ER) translocon (see 609213). The glucosidase II beta subunit encoded by
PRKCSH contains an ER luminal retention signal and is required for
glucosidase II function (summary by Fedeles et al., 2011).
CLONING
Acidic proteins with an approximate molecular mass of 80 kD are
prominent substrates for Ca(2+)/phospholipid-dependent protein kinase
(protein kinase C; 176960, 176970, 176980). On the basis of the previous
finding that human squamous carcinoma cells contain 2 distinct species
of the 80-kD protein, 80K-H and 80K-L (177061), Minoshima et al. (1989)
and Sakai et al. (1989) purified the 80K-H protein, determined a partial
amino acid sequence, and synthesized a corresponding DNA probe. The
PRKCSH cDNA encodes a protein of 527 amino acids. The deduced amino acid
sequence showed a highly glutamic acid-rich region.
Trombetta et al. (1996) isolated enzymatically active glucosidase II
from rat liver and found that it was composed of 2 subunits, alpha
(104160) and beta. Based on peptide sequences of the purified enzyme,
they identified the corresponding human cDNAs in existing sequence
databases. Trombetta et al. (1996) reported that the available sequence
of the beta subunit of human glucosidase II predicts a 514-amino acid
protein with a putative endoplasmic reticulum retention signal.
GENE FUNCTION
Drenth et al. (2003) referred to the protein product of the PRKCSH gene
as hepatocystin and predicted it to be localized to the endoplasmic
reticulum.
GENE STRUCTURE
Drenth et al. (2003) stated that the PRKCSH gene consists of 18 exons in
a 15-kb interval.
MAPPING
Using a DNA probe corresponding to the 80K-H protein, Sakai et al.
(1989) mapped the PRKCSH gene to chromosome 19 by spot blot
hybridization to flow-sorted human chromosomes. The PRKCSH gene lies
within the critical region on 19p13.2-p13.1 established for autosomal
dominant polycystic liver disease (174050) (Reynolds et al., 2000; Li et
al., 2003)
MOLECULAR GENETICS
Polycystic liver disease (PCLD; 174050) is a dominantly inherited
condition characterized by the presence of multiple liver cysts of
biliary epithelial origin. Although the clinical presentation and
histologic features of polycystic liver disease in the presence or
absence of autosomal dominant polycystic kidney disease are
indistinguishable, a genetically distinct form of isolated polycystic
liver disease is supported by the finding of linkage to 19p (Reynolds et
al., 2000), a site distinct from those of the 2 forms of autosomal
dominant polycystic kidney disease, PKD1 (173900) and PKD2 (613095).
Studying the same 2 large kindreds investigated by Reynolds et al.
(2000) and an additional family allowed Li et al. (2003) to define
flanking markers in a region of approximately 3 Mb containing more than
70 candidate genes. Using a combination of denaturing high-performance
liquid chromatography (DHPLC) heteroduplex analysis and direct
sequencing, they screened a panel of 15 unrelated affected individuals
for mutations in genes from this interval. They found sequence
variations in the PRKCSH gene that were not observed in control
individuals, that segregated with the disease haplotype, and that were
predicted to be chain-terminating mutations. They suggested that in
light of the focal nature of liver cysts in autosomal dominant
polycystic liver disease (ADPLD), the apparent loss-of-function
mutations in PRKCSH, and the 2-hit mechanism operational in dominant
polycystic kidney disease, they suggested that this disorder may also
occur by a 2-hit mechanism.
Drenth et al. (2003) narrowed the critical region for PCLD on 19p to a
2.1-cM interval containing 78 genes and EST clusters. After sequencing
677 exons representing 94% of those in the genetic region of question,
they detected a heterozygous mutation, 1138-2A-G (177060.0001), at the
splice acceptor site of exon 16 of the PRKCSH gene. This mutation
segregated in all affected members of 3 families. A second heterozygous
change, at the splice donor site of intron 4 (177060.0002), segregated
with all affected individuals in a fourth family.
ANIMAL MODEL
Gao et al. (2010) showed that overexpression or depletion of Prkcsh in
zebrafish embryos led to pronephric cysts, abnormal body curvature, and
situs inversus. Identical phenotypic changes were induced by depletion
or overexpression of Pkd2 (173910). Increased Prkcsh levels ameliorated
developmental abnormalities caused by overexpressed Pkd2, whereas excess
Pkd2 could compensate the loss of Prkcsh, indicating that the proteins
may share a common signaling pathway. Prkcsh bound the C-terminal domain
of Pkd2, and both proteins colocalized within the ER. Furthermore,
Prkcsh interacted with Herp (HERPUD1; 608070) and inhibited
Herp-mediated ubiquitination of Pkd2. Gao et al. (2010) suggested that
PRKCSH may function as a chaperone-like molecule, which may prevent
ER-associated degradation (ERAD) of Pkd2. Disequilibrium between PKD2
and PRKCSH may lead to cyst formation in PCLD patients with PRKCSH
mutations, and thereby account for the overlapping manifestations
observed in PCLD and autosomal dominant polycystic kidney disease.
Mutations in PRKCSH or SEC63 (608648) cause autosomal dominant
polycystic liver disease. Fedeles et al. (2011) found that homozygous
deletion of either Prkcsh or Sec63 in mice led to early embryonic
lethality. Kidney- or liver-specific inactivation of either gene
resulted in polycystic kidney or liver disease, respectively. Knockout
of both genes increased the severity of cyst formation. Using a
combination of targeted knockout and overexpression with these 2 genes
and 3 other major genes mutated in polycystic kidney disease, Pkd1
(601313), Pkd2, and Pkhd1 (606702), Fedeles et al. (2011) produced a
spectrum of cystic disease severity. Cyst formation in all combinations
of these genes, except complete loss of Pkd2, was significantly
modulated by altering expression of Pkd1. Proteasome inhibition
increased the steady-state levels of Pkd1 in cells lacking Prkcsh and
reduced cystic disease in mouse models of autosomal dominant polycystic
liver disease. Fedeles et al. (2011) concluded that PRKCSH, SEC63, PKD1,
PKD2, and PKHD1 form an interaction network with PKD1 as the
rate-limiting component.
*FIELD* AV
.0001
POLYCYSTIC LIVER DISEASE
PRKCSH, IVS16, A-G, -2
In 3 Dutch families, Drenth et al. (2003) found that members affected by
autosomal dominant polycystic liver disease (174050) were heterozygous
for a mutation of adenine to guanine (1138-2A-G) at the splice acceptor
site of exon 16 of the PRKCSH gene.
.0002
POLYCYSTIC LIVER DISEASE
PRKCSH, IVS4, G-C, +1
In all affected members of a family with autosomal dominant polycystic
liver disease (174050), Drenth et al. (2003) found a heterozygous change
from guanine to cytosine (292+1G-C) in the splice donor site of intron 4
of the PRKCSH gene.
.0003
POLYCYSTIC LIVER DISEASE
PRKCSH, 2-BP DEL, IVS16GT, +1
In family 1 with autosomal dominant polycystic liver disease (174050) in
which linkage study was performed by Reynolds et al. (2000), Li et al.
(2003) demonstrated a deletion of 2 bp at the 5-prime splice site of
IVS16 of the PRKCSH gene. This resulted in skipping of exon 16 in a
transcript in which exon 15 was spliced to exon 17, causing a frameshift
and premature termination.
.0004
POLYCYSTIC LIVER DISEASE
PRKCSH, GLN413TER
In family 2 with autosomal dominant polycystic liver disease (174050) in
which Reynolds et al. (2000) demonstrated linkage between PCLD and 19p,
Li et al. (2003) found a 1237C-T transition in exon 14 of the PRKCSH
gene, resulting in a premature termination codon, gln413 to stop
(Q413X). This mutation segregated with the affected haplotype.
.0005
POLYCYSTIC LIVER DISEASE
PRKCSH, TYR422TER
In a family in which 3 members had autosomal dominant polycystic liver
disease (174050), Li et al. (2003) found a 1266C-G transversion in exon
15 of the PRKCSH gene resulting in a nonsense mutation, tyr422 to stop
(Y422X).
.0006
POLYCYSTIC LIVER DISEASE
PRKCSH, 1-BP INS, 216A
In 2 affected members of a family with autosomal dominant polycystic
liver disease (174050), Li et al. (2003) found a 1-bp insertion
(216insA) in exon 4 of the PRKSCH gene resulting in a frameshift and
premature termination at amino acid residue 84 (N72Xfs84).
*FIELD* RF
1. Drenth, J. P. H.; te Morsche, R. H. M.; Smink, R.; Bonifacino,
J. S.; Jansen, J. B. M. J.: Germline mutations in PRKCSH are associated
with autosomal dominant polycystic liver disease. Nature Genet. 33:
345-348, 2003.
2. Fedeles, S. V.; Tian, X.; Gallagher, A.-R.; Mitobe, M.; Nishio,
S.; Lee, S. H.; Cai, Y.; Geng, L.; Crews, C. M.; Somlo, S.: A genetic
interaction network of five genes for human polycystic kidney and
liver diseases defines polycystin-1 as the central determinant of
cyst formation. Nature Genet. 43: 639-647, 2011.
3. Gao, H.; Wang, Y.; Wegierski, T.; Skouloudaki, K.; Putz, M.; Fu,
X.; Engel, C.; Boehlke, C.; Peng, H.; Kuehn, E. W.; Kim, E.; Kramer-Zucker,
A.; Walz, G.: PRKCSH/80K-H, the protein mutated in polycystic liver
disease, protects polycystin-2/TRPP2 against HERP-mediated degradation. Hum.
Molec. Genet. 19: 16-24, 2010.
4. Li, A.; Davila, S.; Furu, L.; Qian, Q.; Tian, X.; Kamath, P. S.;
King, B. F.; Torres, V. E.; Somlo, S.: Mutations in PRKCSH cause
isolated autosomal dominant polycystic liver disease. Am. J. Hum.
Genet. 72: 691-703, 2003.
5. Minoshima, S.; Hirai, M.; Sakai, K.; Kudoh, J.; Fukuyama, R.; Maekawa,
M.; Shimizu, N.: Assignment of the gene for a protein kinase C substrate,
80K protein, to human chromosome 19. (Abstract) Cytogenet. Cell Genet. 51:
1045 only, 1989.
6. Reynolds, D. M.; Falk, C. T.; Li, A.; King, B. F.; Kamath, P. S.;
Huston, J., III; Shub, C.; Iglesias, D. M.; Martin, R. S.; Pirson,
Y.; Torres, V. E.; Somlo, S.: Identification of a locus for autosomal
dominant polycystic liver disease, on chromosome 19p13.2-13.1. Am.
J. Hum. Genet. 67: 1598-1604, 2000.
7. Sakai, K.; Hirai, M.; Minoshima, S.; Kudoh, J.; Fukuyama, R.; Shimizu,
N.: Isolation of cDNAs encoding a substrate for protein kinase C:
nucleotide sequence and chromosomal mapping of the gene for a human
80K protein. Genomics 5: 309-315, 1989.
8. Trombetta, E. S.; Simons, J. F.; Helenius, A.: Endoplasmic reticulum
glucosidase II is composed of a catalytic subunit, conserved from
yeast to mammals, and a tightly bound noncatalytic HDEL-containing
subunit. J. Biol. Chem. 271: 27509-27516, 1996.
*FIELD* CN
Patricia A. Hartz - updated: 8/10/2011
George E. Tiller - updated: 11/12/2010
Victor A. McKusick - updated: 2/26/2003
Ada Hamosh - updated: 2/21/2003
*FIELD* CD
Victor A. McKusick: 6/7/1989
*FIELD* ED
mgross: 08/11/2011
terry: 8/10/2011
wwang: 11/18/2010
terry: 11/12/2010
mgross: 10/16/2009
carol: 6/14/2005
alopez: 2/28/2003
terry: 2/26/2003
alopez: 2/21/2003
terry: 2/21/2003
carol: 5/4/1999
supermim: 3/16/1992
carol: 10/21/1991
carol: 8/8/1991
supermim: 3/20/1990
carol: 12/12/1989
ddp: 10/27/1989