Full text data of PCCB
PCCB
[Confidence: low (only semi-automatic identification from reviews)]
Propionyl-CoA carboxylase beta chain, mitochondrial; PCCase subunit beta; 6.4.1.3 (Propanoyl-CoA:carbon dioxide ligase subunit beta; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Propionyl-CoA carboxylase beta chain, mitochondrial; PCCase subunit beta; 6.4.1.3 (Propanoyl-CoA:carbon dioxide ligase subunit beta; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P05166
ID PCCB_HUMAN Reviewed; 539 AA.
AC P05166; B7Z2Z4; Q16813; Q96CX0;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 141.
DE RecName: Full=Propionyl-CoA carboxylase beta chain, mitochondrial;
DE Short=PCCase subunit beta;
DE EC=6.4.1.3;
DE AltName: Full=Propanoyl-CoA:carbon dioxide ligase subunit beta;
DE Flags: Precursor;
GN Name=PCCB;
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 VARIANT SER-287.
RC TISSUE=Fibroblast, Kidney, and Liver;
RX PubMed=8188292; DOI=10.1006/geno.1994.1099;
RA Lamhonwah A.-M., Leclerc D., Loyer M., Clarizio R., Gravel R.A.;
RT "Correction of the metabolic defect in propionic acidemia fibroblasts
RT by microinjection of a full-length cDNA or RNA transcript encoding the
RT propionyl-CoA carboxylase beta subunit.";
RL Genomics 19:500-505(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver, and Placenta;
RX PubMed=8225321; DOI=10.1007/BF01247343;
RA Ohura T., Ogasawara M., Ikeda H., Narisawa K., Tada K.;
RT "The molecular defect in propionic acidemia: exon skipping caused by
RT an 8-bp deletion from an intron in the PCCB allele.";
RL Hum. Genet. 92:397-402(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS PA-2.
RC TISSUE=Blood, and Skin fibroblast;
RX PubMed=9683601; DOI=10.1086/301970;
RA Rodriguez-Pombo P., Hoenicka J., Muro S., Perez B., Perez-Cerda C.,
RA Richard E., Desviat L.R., Ugarte M.;
RT "Human propionyl-CoA carboxylase beta subunit gene: exon-intron
RT definition and mutation spectrum in Spanish and Latin American
RT propionic acidemia patients.";
RL Am. J. Hum. Genet. 63:360-369(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Caudate nucleus;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [6]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Pancreas, and Skin;
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 NUCLEOTIDE SEQUENCE [MRNA] OF 289-443 (ISOFORM 1).
RX PubMed=3460076; DOI=10.1073/pnas.83.13.4864;
RA Lamhonwah A.-M., Barankiewicz T.J., Willard H.F., Mahuran D.J.,
RA Quan F., Gravel R.A.;
RT "Isolation of cDNA clones coding for the alpha and beta chains of
RT human propionyl-CoA carboxylase: chromosomal assignments and DNA
RT polymorphisms associated with PCCA and PCCB genes.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:4864-4868(1986).
RN [9]
RP PROTEIN SEQUENCE OF 29-33, AND SUBCELLULAR LOCATION.
RC TISSUE=Kidney;
RX PubMed=16023992; DOI=10.1016/j.bbrc.2005.06.190;
RA Stadler S.C., Polanetz R., Meier S., Mayerhofer P.U., Herrmann J.M.,
RA Anslinger K., Roscher A.A., Roschinger W., Holzinger A.;
RT "Mitochondrial targeting signals and mature peptides of 3-
RT methylcrotonyl-CoA carboxylase.";
RL Biochem. Biophys. Res. Commun. 334:939-946(2005).
RN [10]
RP SEQUENCE REVISION.
RA Lamhonwah A.-M.;
RL Submitted (DEC-1986) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 401-433, AND VARIANT PA-2 ILE-408
RP DEL.
RC TISSUE=Skin fibroblast;
RX PubMed=2154743; DOI=10.1073/pnas.87.4.1372;
RA Tahara T., Kraus J.P., Rosenberg L.E.;
RT "An unusual insertion/deletion in the gene encoding the beta-subunit
RT of propionyl-CoA carboxylase is a frequent mutation in Caucasian
RT propionic acidemia.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:1372-1376(1990).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [13]
RP VARIANTS PA-2 TRP-410 AND ILE-408 DEL.
RX PubMed=8411997; DOI=10.1007/BF00710282;
RA Tahara T., Kraus J.P., Ohura T., Rosenberg L.E., Fenton W.A.;
RT "Three independent mutations in the same exon of the PCCB gene:
RT differences between Caucasian and Japanese propionic acidaemia.";
RL J. Inherit. Metab. Dis. 16:353-360(1993).
RN [14]
RP VARIANTS PA-2 MET-17; LYS-168; ASP-205 AND THR-442.
RX PubMed=10447268;
RX DOI=10.1002/(SICI)1098-1004(1999)14:1<89::AID-HUMU18>3.3.CO;2-X;
RA Muro S., Rodriguez-Pombo P., Perez B., Perez-Cerda C., Desviat L.R.,
RA Sperl W., Skladal D., Sass J.O., Ugarte M.;
RT "Identification of novel mutations in the PCCB gene in European
RT propionic acidemia patients.";
RL Hum. Mutat. 14:89-90(1999).
RN [15]
RP REVIEW ON PA VARIANTS.
RX PubMed=10502773;
RX DOI=10.1002/(SICI)1098-1004(199910)14:4<275::AID-HUMU1>3.3.CO;2-E;
RA Ugarte M., Perez-Cerda C., Rodriguez-Pombo P., Desviat L.R., Perez B.,
RA Richard E., Muro S., Campeau E., Ohura T., Gravel R.A.;
RT "Overview of mutations in the PCCA and PCCB genes causing propionic
RT acidemia.";
RL Hum. Mutat. 14:275-282(1999).
RN [16]
RP CHARACTERIZATION OF VARIANTS PA-2 GLN-165; VAL-497; CYS-512; PRO-519
RP AND ASP-536.
RX PubMed=11749052; DOI=10.1006/mgme.2001.3254;
RA Muro S., Perez B., Desviat L.R., Rodriguez-Pombo P., Perez-Cerda C.,
RA Clavero S., Ugarte M.;
RT "Effect of PCCB gene mutations on the heteromeric and homomeric
RT assembly of propionyl-CoA carboxylase.";
RL Mol. Genet. Metab. 74:476-483(2001).
RN [17]
RP VARIANTS PA-2 ILE-428; LEU-430; CYS-435; CYS-439 AND THR-468.
RX PubMed=12189489; DOI=10.1007/s00439-002-0761-z;
RA Yorifuji T., Kawai M., Muroi J., Mamada M., Kurokawa K.,
RA Shigematsu Y., Hirano S., Sakura N., Yoshida I., Kuhara T., Endo F.,
RA Mitsubuchi H., Nakahata T.;
RT "Unexpectedly high prevalence of the mild form of propionic acidemia
RT in Japan: presence of a common mutation and possible clinical
RT implications.";
RL Hum. Genet. 111:161-165(2002).
RN [18]
RP VARIANTS PA-2 SER-67; MET-107; ASP-112; GLN-165; LYS-168; ARG-188;
RP VAL-246; ILE-341 DEL AND TRP-410.
RX PubMed=12559849; DOI=10.1016/S1096-7192(02)00197-X;
RA Perez B., Desviat L.R., Rodriguez-Pombo P., Clavero S., Navarrete R.,
RA Perez-Cerda C., Ugarte M.;
RT "Propionic acidemia: identification of twenty-four novel mutations in
RT Europe and North America.";
RL Mol. Genet. Metab. 78:59-67(2003).
RN [19]
RP VARIANTS PA-2 PRO-153; TRP-165; TRP-410; ILE-428 AND CYS-512.
RX PubMed=15059621; DOI=10.1016/j.ymgme.2004.01.003;
RA Yang X., Sakamoto O., Matsubara Y., Kure S., Suzuki Y., Aoki Y.,
RA Yamaguchi S., Takahashi Y., Nishikubo T., Kawaguchi C., Yoshioka A.,
RA Kimura T., Hayasaka K., Kohno Y., Iinuma K., Ohura T.;
RT "Mutation spectrum of the PCCA and PCCB genes in Japanese patients
RT with propionic acidemia.";
RL Mol. Genet. Metab. 81:335-342(2004).
CC -!- CATALYTIC ACTIVITY: ATP + propanoyl-CoA + HCO(3)(-) = ADP +
CC phosphate + (S)-methylmalonyl-CoA.
CC -!- PATHWAY: Metabolic intermediate metabolism; propanoyl-CoA
CC degradation; succinyl-CoA from propanoyl-CoA: step 1/3.
CC -!- SUBUNIT: Probably a dodecamer composed of six biotin-containing
CC alpha subunits and six beta subunits.
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P05166-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P05166-2; Sequence=VSP_042568;
CC Note=No experimental confirmation available;
CC -!- DISEASE: Propionic acidemia type II (PA-2) [MIM:606054]: Life-
CC threatening disease characterized by episodic vomiting, lethargy
CC and ketosis, neutropenia, periodic thrombocytopenia,
CC hypogammaglobulinemia, developmental retardation, and intolerance
CC to protein. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the AccD/PCCB family.
CC -!- SIMILARITY: Contains 1 carboxyltransferase domain.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PCCB";
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DR EMBL; X73424; CAA51825.1; -; mRNA.
DR EMBL; S67325; AAB28900.1; -; mRNA.
DR EMBL; AJ006487; CAA07066.1; -; Genomic_DNA.
DR EMBL; AJ006488; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006489; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006490; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006491; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006492; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006493; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006494; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006495; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006496; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006497; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006498; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006499; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AK295312; BAH12030.1; -; mRNA.
DR EMBL; AC069524; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471052; EAW79118.1; -; Genomic_DNA.
DR EMBL; BC013768; AAH13768.1; -; mRNA.
DR EMBL; BC053661; AAH53661.1; -; mRNA.
DR EMBL; M13573; AAA60036.1; -; mRNA.
DR EMBL; M31167; AAA60037.1; -; Genomic_DNA.
DR EMBL; M31169; AAA60038.1; -; Genomic_DNA.
DR PIR; T45009; T45009.
DR RefSeq; NP_000523.2; NM_000532.4.
DR RefSeq; NP_001171485.1; NM_001178014.1.
DR UniGene; Hs.63788; -.
DR ProteinModelPortal; P05166; -.
DR SMR; P05166; 37-539.
DR DIP; DIP-38244N; -.
DR IntAct; P05166; 8.
DR MINT; MINT-3004663; -.
DR STRING; 9606.ENSP00000251654; -.
DR DrugBank; DB00121; Biotin.
DR DrugBank; DB00161; L-Valine.
DR PhosphoSite; P05166; -.
DR DMDM; 124106304; -.
DR PaxDb; P05166; -.
DR PeptideAtlas; P05166; -.
DR PRIDE; P05166; -.
DR DNASU; 5096; -.
DR Ensembl; ENST00000251654; ENSP00000251654; ENSG00000114054.
DR Ensembl; ENST00000469217; ENSP00000419027; ENSG00000114054.
DR GeneID; 5096; -.
DR KEGG; hsa:5096; -.
DR UCSC; uc003eqy.2; human.
DR CTD; 5096; -.
DR GeneCards; GC03P135969; -.
DR HGNC; HGNC:8654; PCCB.
DR HPA; HPA036939; -.
DR HPA; HPA036940; -.
DR MIM; 232050; gene.
DR MIM; 606054; phenotype.
DR neXtProt; NX_P05166; -.
DR Orphanet; 35; Propionic acidemia.
DR PharmGKB; PA32993; -.
DR eggNOG; COG4799; -.
DR HOGENOM; HOG000218693; -.
DR HOVERGEN; HBG003970; -.
DR InParanoid; P05166; -.
DR KO; K01966; -.
DR PhylomeDB; P05166; -.
DR BRENDA; 6.4.1.3; 2681.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR SABIO-RK; P05166; -.
DR UniPathway; UPA00945; UER00908.
DR GenomeRNAi; 5096; -.
DR NextBio; 19660; -.
DR PRO; PR:P05166; -.
DR ArrayExpress; P05166; -.
DR Bgee; P05166; -.
DR CleanEx; HS_PCCB; -.
DR Genevestigator; P05166; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004658; F:propionyl-CoA carboxylase activity; TAS:ProtInc.
DR GO; GO:0006768; P:biotin metabolic process; TAS:Reactome.
DR GO; GO:0006635; P:fatty acid beta-oxidation; TAS:Reactome.
DR GO; GO:0019626; P:short-chain fatty acid catabolic process; TAS:Reactome.
DR InterPro; IPR000022; Carboxyl_trans.
DR InterPro; IPR011763; COA_CT_C.
DR InterPro; IPR011762; COA_CT_N.
DR Pfam; PF01039; Carboxyl_trans; 1.
DR PROSITE; PS50989; COA_CT_CTER; 1.
DR PROSITE; PS50980; COA_CT_NTER; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; ATP-binding; Complete proteome;
KW Direct protein sequencing; Disease mutation; Ligase; Mitochondrion;
KW Nucleotide-binding; Polymorphism; Reference proteome; Transit peptide.
FT TRANSIT 1 28 Mitochondrion.
FT CHAIN 29 539 Propionyl-CoA carboxylase beta chain,
FT mitochondrial.
FT /FTId=PRO_0000000293.
FT DOMAIN 38 531 Carboxyltransferase.
FT REGION 325 358 Acyl-CoA binding (Potential).
FT MOD_RES 99 99 N6-acetyllysine (By similarity).
FT MOD_RES 474 474 N6-acetyllysine (By similarity).
FT MOD_RES 489 489 N6-acetyllysine (By similarity).
FT VAR_SEQ 124 124 Q -> QQIIGWAQWLPLVISALWEAE (in isoform
FT 2).
FT /FTId=VSP_042568.
FT VARIANT 17 17 L -> M (in PA-2).
FT /FTId=VAR_009080.
FT VARIANT 44 44 R -> P (in PA-2).
FT /FTId=VAR_000271.
FT VARIANT 67 67 R -> S (in PA-2).
FT /FTId=VAR_023847.
FT VARIANT 106 106 S -> R (in PA-2).
FT /FTId=VAR_000272.
FT VARIANT 107 107 V -> M (in PA-2).
FT /FTId=VAR_023848.
FT VARIANT 112 112 G -> D (in PA-2).
FT /FTId=VAR_023849.
FT VARIANT 131 131 G -> R (in PA-2).
FT /FTId=VAR_000273.
FT VARIANT 140 140 K -> KICK (in PA-2).
FT /FTId=VAR_009081.
FT VARIANT 153 153 A -> P (in PA-2).
FT /FTId=VAR_023850.
FT VARIANT 165 165 R -> Q (in PA-2; does not affect either
FT heteromeric or homomeric assembly).
FT /FTId=VAR_023851.
FT VARIANT 165 165 R -> W (in PA-2).
FT /FTId=VAR_000274.
FT VARIANT 168 168 E -> K (in PA-2; common mutation).
FT /FTId=VAR_000275.
FT VARIANT 188 188 G -> R (in PA-2).
FT /FTId=VAR_023852.
FT VARIANT 198 198 G -> D (in PA-2).
FT /FTId=VAR_000276.
FT VARIANT 205 205 V -> D (in PA-2).
FT /FTId=VAR_009082.
FT VARIANT 228 228 P -> L (in PA-2).
FT /FTId=VAR_009083.
FT VARIANT 246 246 G -> V (in PA-2).
FT /FTId=VAR_023853.
FT VARIANT 287 287 P -> S (in dbSNP:rs2228310).
FT /FTId=VAR_048163.
FT VARIANT 341 341 Missing (in PA-2).
FT /FTId=VAR_023854.
FT VARIANT 408 408 Missing (in PA-2).
FT /FTId=VAR_000277.
FT VARIANT 410 410 R -> W (in PA-2).
FT /FTId=VAR_000278.
FT VARIANT 428 428 T -> I (in PA-2; dbSNP:rs28934887).
FT /FTId=VAR_009084.
FT VARIANT 430 430 I -> L (in PA-2).
FT /FTId=VAR_023855.
FT VARIANT 435 435 Y -> C (in PA-2).
FT /FTId=VAR_023856.
FT VARIANT 439 439 Y -> C (in PA-2).
FT /FTId=VAR_023857.
FT VARIANT 442 442 M -> T (in PA-2).
FT /FTId=VAR_009085.
FT VARIANT 468 468 A -> T (in PA-2).
FT /FTId=VAR_023858.
FT VARIANT 497 497 A -> V (in PA-2; common mutation; does
FT not affect either heteromeric or
FT homomeric assembly; dbSNP:rs142403318).
FT /FTId=VAR_000279.
FT VARIANT 512 512 R -> C (in PA-2; affects heteromeric and
FT homomeric assembly; dbSNP:rs186710233).
FT /FTId=VAR_000280.
FT VARIANT 519 519 L -> P (in PA-2; affects heteromeric and
FT homomeric assembly).
FT /FTId=VAR_000281.
FT VARIANT 536 536 N -> D (in PA-2; affects heteromeric and
FT homomeric assembly).
FT /FTId=VAR_009086.
FT CONFLICT 58 59 QH -> HD (in Ref. 2; AAB28900).
SQ SEQUENCE 539 AA; 58216 MW; A2DAAC00312D3C0F CRC64;
MAAALRVAAV GARLSVLASG LRAAVRSLCS QATSVNERIE NKRRTALLGG GQRRIDAQHK
RGKLTARERI SLLLDPGSFV ESDMFVEHRC ADFGMAADKN KFPGDSVVTG RGRINGRLVY
VFSQDFTVFG GSLSGAHAQK ICKIMDQAIT VGAPVIGLND SGGARIQEGV ESLAGYADIF
LRNVTASGVI PQISLIMGPC AGGAVYSPAL TDFTFMVKDT SYLFITGPDV VKSVTNEDVT
QEELGGAKTH TTMSGVAHRA FENDVDALCN LRDFFNYLPL SSQDPAPVRE CHDPSDRLVP
ELDTIVPLES TKAYNMVDII HSVVDEREFF EIMPNYAKNI IVGFARMNGR TVGIVGNQPK
VASGCLDINS SVKGARFVRF CDAFNIPLIT FVDVPGFLPG TAQEYGGIIR HGAKLLYAFA
EATVPKVTVI TRKAYGGAYD VMSSKHLCGD TNYAWPTAEI AVMGAKGAVE IIFKGHENVE
AAQAEYIEKF ANPFPAAVRG FVDDIIQPSS TRARICCDLD VLASKKVQRP WRKHANIPL
//
ID PCCB_HUMAN Reviewed; 539 AA.
AC P05166; B7Z2Z4; Q16813; Q96CX0;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 141.
DE RecName: Full=Propionyl-CoA carboxylase beta chain, mitochondrial;
DE Short=PCCase subunit beta;
DE EC=6.4.1.3;
DE AltName: Full=Propanoyl-CoA:carbon dioxide ligase subunit beta;
DE Flags: Precursor;
GN Name=PCCB;
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 VARIANT SER-287.
RC TISSUE=Fibroblast, Kidney, and Liver;
RX PubMed=8188292; DOI=10.1006/geno.1994.1099;
RA Lamhonwah A.-M., Leclerc D., Loyer M., Clarizio R., Gravel R.A.;
RT "Correction of the metabolic defect in propionic acidemia fibroblasts
RT by microinjection of a full-length cDNA or RNA transcript encoding the
RT propionyl-CoA carboxylase beta subunit.";
RL Genomics 19:500-505(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver, and Placenta;
RX PubMed=8225321; DOI=10.1007/BF01247343;
RA Ohura T., Ogasawara M., Ikeda H., Narisawa K., Tada K.;
RT "The molecular defect in propionic acidemia: exon skipping caused by
RT an 8-bp deletion from an intron in the PCCB allele.";
RL Hum. Genet. 92:397-402(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS PA-2.
RC TISSUE=Blood, and Skin fibroblast;
RX PubMed=9683601; DOI=10.1086/301970;
RA Rodriguez-Pombo P., Hoenicka J., Muro S., Perez B., Perez-Cerda C.,
RA Richard E., Desviat L.R., Ugarte M.;
RT "Human propionyl-CoA carboxylase beta subunit gene: exon-intron
RT definition and mutation spectrum in Spanish and Latin American
RT propionic acidemia patients.";
RL Am. J. Hum. Genet. 63:360-369(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Caudate nucleus;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [6]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Pancreas, and Skin;
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 NUCLEOTIDE SEQUENCE [MRNA] OF 289-443 (ISOFORM 1).
RX PubMed=3460076; DOI=10.1073/pnas.83.13.4864;
RA Lamhonwah A.-M., Barankiewicz T.J., Willard H.F., Mahuran D.J.,
RA Quan F., Gravel R.A.;
RT "Isolation of cDNA clones coding for the alpha and beta chains of
RT human propionyl-CoA carboxylase: chromosomal assignments and DNA
RT polymorphisms associated with PCCA and PCCB genes.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:4864-4868(1986).
RN [9]
RP PROTEIN SEQUENCE OF 29-33, AND SUBCELLULAR LOCATION.
RC TISSUE=Kidney;
RX PubMed=16023992; DOI=10.1016/j.bbrc.2005.06.190;
RA Stadler S.C., Polanetz R., Meier S., Mayerhofer P.U., Herrmann J.M.,
RA Anslinger K., Roscher A.A., Roschinger W., Holzinger A.;
RT "Mitochondrial targeting signals and mature peptides of 3-
RT methylcrotonyl-CoA carboxylase.";
RL Biochem. Biophys. Res. Commun. 334:939-946(2005).
RN [10]
RP SEQUENCE REVISION.
RA Lamhonwah A.-M.;
RL Submitted (DEC-1986) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 401-433, AND VARIANT PA-2 ILE-408
RP DEL.
RC TISSUE=Skin fibroblast;
RX PubMed=2154743; DOI=10.1073/pnas.87.4.1372;
RA Tahara T., Kraus J.P., Rosenberg L.E.;
RT "An unusual insertion/deletion in the gene encoding the beta-subunit
RT of propionyl-CoA carboxylase is a frequent mutation in Caucasian
RT propionic acidemia.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:1372-1376(1990).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [13]
RP VARIANTS PA-2 TRP-410 AND ILE-408 DEL.
RX PubMed=8411997; DOI=10.1007/BF00710282;
RA Tahara T., Kraus J.P., Ohura T., Rosenberg L.E., Fenton W.A.;
RT "Three independent mutations in the same exon of the PCCB gene:
RT differences between Caucasian and Japanese propionic acidaemia.";
RL J. Inherit. Metab. Dis. 16:353-360(1993).
RN [14]
RP VARIANTS PA-2 MET-17; LYS-168; ASP-205 AND THR-442.
RX PubMed=10447268;
RX DOI=10.1002/(SICI)1098-1004(1999)14:1<89::AID-HUMU18>3.3.CO;2-X;
RA Muro S., Rodriguez-Pombo P., Perez B., Perez-Cerda C., Desviat L.R.,
RA Sperl W., Skladal D., Sass J.O., Ugarte M.;
RT "Identification of novel mutations in the PCCB gene in European
RT propionic acidemia patients.";
RL Hum. Mutat. 14:89-90(1999).
RN [15]
RP REVIEW ON PA VARIANTS.
RX PubMed=10502773;
RX DOI=10.1002/(SICI)1098-1004(199910)14:4<275::AID-HUMU1>3.3.CO;2-E;
RA Ugarte M., Perez-Cerda C., Rodriguez-Pombo P., Desviat L.R., Perez B.,
RA Richard E., Muro S., Campeau E., Ohura T., Gravel R.A.;
RT "Overview of mutations in the PCCA and PCCB genes causing propionic
RT acidemia.";
RL Hum. Mutat. 14:275-282(1999).
RN [16]
RP CHARACTERIZATION OF VARIANTS PA-2 GLN-165; VAL-497; CYS-512; PRO-519
RP AND ASP-536.
RX PubMed=11749052; DOI=10.1006/mgme.2001.3254;
RA Muro S., Perez B., Desviat L.R., Rodriguez-Pombo P., Perez-Cerda C.,
RA Clavero S., Ugarte M.;
RT "Effect of PCCB gene mutations on the heteromeric and homomeric
RT assembly of propionyl-CoA carboxylase.";
RL Mol. Genet. Metab. 74:476-483(2001).
RN [17]
RP VARIANTS PA-2 ILE-428; LEU-430; CYS-435; CYS-439 AND THR-468.
RX PubMed=12189489; DOI=10.1007/s00439-002-0761-z;
RA Yorifuji T., Kawai M., Muroi J., Mamada M., Kurokawa K.,
RA Shigematsu Y., Hirano S., Sakura N., Yoshida I., Kuhara T., Endo F.,
RA Mitsubuchi H., Nakahata T.;
RT "Unexpectedly high prevalence of the mild form of propionic acidemia
RT in Japan: presence of a common mutation and possible clinical
RT implications.";
RL Hum. Genet. 111:161-165(2002).
RN [18]
RP VARIANTS PA-2 SER-67; MET-107; ASP-112; GLN-165; LYS-168; ARG-188;
RP VAL-246; ILE-341 DEL AND TRP-410.
RX PubMed=12559849; DOI=10.1016/S1096-7192(02)00197-X;
RA Perez B., Desviat L.R., Rodriguez-Pombo P., Clavero S., Navarrete R.,
RA Perez-Cerda C., Ugarte M.;
RT "Propionic acidemia: identification of twenty-four novel mutations in
RT Europe and North America.";
RL Mol. Genet. Metab. 78:59-67(2003).
RN [19]
RP VARIANTS PA-2 PRO-153; TRP-165; TRP-410; ILE-428 AND CYS-512.
RX PubMed=15059621; DOI=10.1016/j.ymgme.2004.01.003;
RA Yang X., Sakamoto O., Matsubara Y., Kure S., Suzuki Y., Aoki Y.,
RA Yamaguchi S., Takahashi Y., Nishikubo T., Kawaguchi C., Yoshioka A.,
RA Kimura T., Hayasaka K., Kohno Y., Iinuma K., Ohura T.;
RT "Mutation spectrum of the PCCA and PCCB genes in Japanese patients
RT with propionic acidemia.";
RL Mol. Genet. Metab. 81:335-342(2004).
CC -!- CATALYTIC ACTIVITY: ATP + propanoyl-CoA + HCO(3)(-) = ADP +
CC phosphate + (S)-methylmalonyl-CoA.
CC -!- PATHWAY: Metabolic intermediate metabolism; propanoyl-CoA
CC degradation; succinyl-CoA from propanoyl-CoA: step 1/3.
CC -!- SUBUNIT: Probably a dodecamer composed of six biotin-containing
CC alpha subunits and six beta subunits.
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P05166-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P05166-2; Sequence=VSP_042568;
CC Note=No experimental confirmation available;
CC -!- DISEASE: Propionic acidemia type II (PA-2) [MIM:606054]: Life-
CC threatening disease characterized by episodic vomiting, lethargy
CC and ketosis, neutropenia, periodic thrombocytopenia,
CC hypogammaglobulinemia, developmental retardation, and intolerance
CC to protein. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the AccD/PCCB family.
CC -!- SIMILARITY: Contains 1 carboxyltransferase domain.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PCCB";
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DR EMBL; X73424; CAA51825.1; -; mRNA.
DR EMBL; S67325; AAB28900.1; -; mRNA.
DR EMBL; AJ006487; CAA07066.1; -; Genomic_DNA.
DR EMBL; AJ006488; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006489; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006490; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006491; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006492; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006493; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006494; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006495; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006496; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006497; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006498; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AJ006499; CAA07066.1; JOINED; Genomic_DNA.
DR EMBL; AK295312; BAH12030.1; -; mRNA.
DR EMBL; AC069524; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471052; EAW79118.1; -; Genomic_DNA.
DR EMBL; BC013768; AAH13768.1; -; mRNA.
DR EMBL; BC053661; AAH53661.1; -; mRNA.
DR EMBL; M13573; AAA60036.1; -; mRNA.
DR EMBL; M31167; AAA60037.1; -; Genomic_DNA.
DR EMBL; M31169; AAA60038.1; -; Genomic_DNA.
DR PIR; T45009; T45009.
DR RefSeq; NP_000523.2; NM_000532.4.
DR RefSeq; NP_001171485.1; NM_001178014.1.
DR UniGene; Hs.63788; -.
DR ProteinModelPortal; P05166; -.
DR SMR; P05166; 37-539.
DR DIP; DIP-38244N; -.
DR IntAct; P05166; 8.
DR MINT; MINT-3004663; -.
DR STRING; 9606.ENSP00000251654; -.
DR DrugBank; DB00121; Biotin.
DR DrugBank; DB00161; L-Valine.
DR PhosphoSite; P05166; -.
DR DMDM; 124106304; -.
DR PaxDb; P05166; -.
DR PeptideAtlas; P05166; -.
DR PRIDE; P05166; -.
DR DNASU; 5096; -.
DR Ensembl; ENST00000251654; ENSP00000251654; ENSG00000114054.
DR Ensembl; ENST00000469217; ENSP00000419027; ENSG00000114054.
DR GeneID; 5096; -.
DR KEGG; hsa:5096; -.
DR UCSC; uc003eqy.2; human.
DR CTD; 5096; -.
DR GeneCards; GC03P135969; -.
DR HGNC; HGNC:8654; PCCB.
DR HPA; HPA036939; -.
DR HPA; HPA036940; -.
DR MIM; 232050; gene.
DR MIM; 606054; phenotype.
DR neXtProt; NX_P05166; -.
DR Orphanet; 35; Propionic acidemia.
DR PharmGKB; PA32993; -.
DR eggNOG; COG4799; -.
DR HOGENOM; HOG000218693; -.
DR HOVERGEN; HBG003970; -.
DR InParanoid; P05166; -.
DR KO; K01966; -.
DR PhylomeDB; P05166; -.
DR BRENDA; 6.4.1.3; 2681.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR SABIO-RK; P05166; -.
DR UniPathway; UPA00945; UER00908.
DR GenomeRNAi; 5096; -.
DR NextBio; 19660; -.
DR PRO; PR:P05166; -.
DR ArrayExpress; P05166; -.
DR Bgee; P05166; -.
DR CleanEx; HS_PCCB; -.
DR Genevestigator; P05166; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004658; F:propionyl-CoA carboxylase activity; TAS:ProtInc.
DR GO; GO:0006768; P:biotin metabolic process; TAS:Reactome.
DR GO; GO:0006635; P:fatty acid beta-oxidation; TAS:Reactome.
DR GO; GO:0019626; P:short-chain fatty acid catabolic process; TAS:Reactome.
DR InterPro; IPR000022; Carboxyl_trans.
DR InterPro; IPR011763; COA_CT_C.
DR InterPro; IPR011762; COA_CT_N.
DR Pfam; PF01039; Carboxyl_trans; 1.
DR PROSITE; PS50989; COA_CT_CTER; 1.
DR PROSITE; PS50980; COA_CT_NTER; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; ATP-binding; Complete proteome;
KW Direct protein sequencing; Disease mutation; Ligase; Mitochondrion;
KW Nucleotide-binding; Polymorphism; Reference proteome; Transit peptide.
FT TRANSIT 1 28 Mitochondrion.
FT CHAIN 29 539 Propionyl-CoA carboxylase beta chain,
FT mitochondrial.
FT /FTId=PRO_0000000293.
FT DOMAIN 38 531 Carboxyltransferase.
FT REGION 325 358 Acyl-CoA binding (Potential).
FT MOD_RES 99 99 N6-acetyllysine (By similarity).
FT MOD_RES 474 474 N6-acetyllysine (By similarity).
FT MOD_RES 489 489 N6-acetyllysine (By similarity).
FT VAR_SEQ 124 124 Q -> QQIIGWAQWLPLVISALWEAE (in isoform
FT 2).
FT /FTId=VSP_042568.
FT VARIANT 17 17 L -> M (in PA-2).
FT /FTId=VAR_009080.
FT VARIANT 44 44 R -> P (in PA-2).
FT /FTId=VAR_000271.
FT VARIANT 67 67 R -> S (in PA-2).
FT /FTId=VAR_023847.
FT VARIANT 106 106 S -> R (in PA-2).
FT /FTId=VAR_000272.
FT VARIANT 107 107 V -> M (in PA-2).
FT /FTId=VAR_023848.
FT VARIANT 112 112 G -> D (in PA-2).
FT /FTId=VAR_023849.
FT VARIANT 131 131 G -> R (in PA-2).
FT /FTId=VAR_000273.
FT VARIANT 140 140 K -> KICK (in PA-2).
FT /FTId=VAR_009081.
FT VARIANT 153 153 A -> P (in PA-2).
FT /FTId=VAR_023850.
FT VARIANT 165 165 R -> Q (in PA-2; does not affect either
FT heteromeric or homomeric assembly).
FT /FTId=VAR_023851.
FT VARIANT 165 165 R -> W (in PA-2).
FT /FTId=VAR_000274.
FT VARIANT 168 168 E -> K (in PA-2; common mutation).
FT /FTId=VAR_000275.
FT VARIANT 188 188 G -> R (in PA-2).
FT /FTId=VAR_023852.
FT VARIANT 198 198 G -> D (in PA-2).
FT /FTId=VAR_000276.
FT VARIANT 205 205 V -> D (in PA-2).
FT /FTId=VAR_009082.
FT VARIANT 228 228 P -> L (in PA-2).
FT /FTId=VAR_009083.
FT VARIANT 246 246 G -> V (in PA-2).
FT /FTId=VAR_023853.
FT VARIANT 287 287 P -> S (in dbSNP:rs2228310).
FT /FTId=VAR_048163.
FT VARIANT 341 341 Missing (in PA-2).
FT /FTId=VAR_023854.
FT VARIANT 408 408 Missing (in PA-2).
FT /FTId=VAR_000277.
FT VARIANT 410 410 R -> W (in PA-2).
FT /FTId=VAR_000278.
FT VARIANT 428 428 T -> I (in PA-2; dbSNP:rs28934887).
FT /FTId=VAR_009084.
FT VARIANT 430 430 I -> L (in PA-2).
FT /FTId=VAR_023855.
FT VARIANT 435 435 Y -> C (in PA-2).
FT /FTId=VAR_023856.
FT VARIANT 439 439 Y -> C (in PA-2).
FT /FTId=VAR_023857.
FT VARIANT 442 442 M -> T (in PA-2).
FT /FTId=VAR_009085.
FT VARIANT 468 468 A -> T (in PA-2).
FT /FTId=VAR_023858.
FT VARIANT 497 497 A -> V (in PA-2; common mutation; does
FT not affect either heteromeric or
FT homomeric assembly; dbSNP:rs142403318).
FT /FTId=VAR_000279.
FT VARIANT 512 512 R -> C (in PA-2; affects heteromeric and
FT homomeric assembly; dbSNP:rs186710233).
FT /FTId=VAR_000280.
FT VARIANT 519 519 L -> P (in PA-2; affects heteromeric and
FT homomeric assembly).
FT /FTId=VAR_000281.
FT VARIANT 536 536 N -> D (in PA-2; affects heteromeric and
FT homomeric assembly).
FT /FTId=VAR_009086.
FT CONFLICT 58 59 QH -> HD (in Ref. 2; AAB28900).
SQ SEQUENCE 539 AA; 58216 MW; A2DAAC00312D3C0F CRC64;
MAAALRVAAV GARLSVLASG LRAAVRSLCS QATSVNERIE NKRRTALLGG GQRRIDAQHK
RGKLTARERI SLLLDPGSFV ESDMFVEHRC ADFGMAADKN KFPGDSVVTG RGRINGRLVY
VFSQDFTVFG GSLSGAHAQK ICKIMDQAIT VGAPVIGLND SGGARIQEGV ESLAGYADIF
LRNVTASGVI PQISLIMGPC AGGAVYSPAL TDFTFMVKDT SYLFITGPDV VKSVTNEDVT
QEELGGAKTH TTMSGVAHRA FENDVDALCN LRDFFNYLPL SSQDPAPVRE CHDPSDRLVP
ELDTIVPLES TKAYNMVDII HSVVDEREFF EIMPNYAKNI IVGFARMNGR TVGIVGNQPK
VASGCLDINS SVKGARFVRF CDAFNIPLIT FVDVPGFLPG TAQEYGGIIR HGAKLLYAFA
EATVPKVTVI TRKAYGGAYD VMSSKHLCGD TNYAWPTAEI AVMGAKGAVE IIFKGHENVE
AAQAEYIEKF ANPFPAAVRG FVDDIIQPSS TRARICCDLD VLASKKVQRP WRKHANIPL
//
MIM
232050
*RECORD*
*FIELD* NO
232050
*FIELD* TI
*232050 PROPIONYL-CoA CARBOXYLASE, BETA SUBUNIT; PCCB
;;pccBC COMPLEMENTATION GROUP
read more*FIELD* TX
Propionyl-CoA is an important intermediate in the metabolism of several
amino acids and is also produced by oxidation of odd-numbered fatty
acids. Propionyl-CoA carboxylase (PCC), comprised of alpha and beta
subunits, catalyzes the first step in the catabolism of propionyl-CoA.
The alpha subunit is encoded by the PCCA gene (232000) and the beta
subunit by the PCCB gene. Cells from patients with propionic acidemia
(606054) who have mutations in the PCCB gene fall into 2 complementation
subgroups, pccB and pccC. Mutations in the pccB subgroup occur in the N
terminus of the beta subunit, which includes the biotin-binding site,
whereas mutations in the pccC subgroup occur in the C terminus (Fenton
et al., 2001).
CLONING
Lamhonwah et al. (1994) cloned a full-length cDNA encoding the beta
subunit of human PCC. The open reading frame encoded a pre-beta
polypeptide of 539 amino acids (58,205 Da). The cDNA was introduced into
an expression vector and microinjected into the nucleus or, as
ribotranscripts, into the cytoplasm of fibroblast lines from propionic
acidemia patients with defects of the beta subunit. Restoration of
function was demonstrated by autoradiography of PCC-dependent
(14)C-propionate incorporation into cellular protein. These results
confirmed the completeness of the clone and demonstrated the capacity
for the microinjected material to be transported into mitochondria and
assembled with endogenously derived alpha subunits to form functional
PCC.
GENE STRUCTURE
Rodriguez-Pombo et al. (1998) described the genomic organization of the
coding sequence of the human PCCB gene. The PCCB gene consists of 15
exons of 57 to 183 bp. All splice sites are consistent with the gt/ag
rule.
MAPPING
Yang-Feng et al. (1985) used rat cDNA probes to assign the human PCCB
gene to 3q13.3-q22 by in situ hybridization and corroborated the
assignment to chromosome 3 by Southern blot analysis of somatic cell
hybrid DNAs. Assignment of PCCB to chromosome 3 was also reported by
Lamhonwah et al. (1986). Levy et al. (1991) refined the localization of
the PCCB gene to 3q21-q22 by demonstrating the loss of a polymorphic
band in a clonal population of blast cells from an individual suffering
from myelodysplastic syndrome who had been found to have an interstitial
deletion of 3q21-q25.
MOLECULAR GENETICS
Two main complementation groups for propionyl-CoA carboxylase deficiency
were demonstrated by Gravel et al. (1977) in studies of Sendai
virus-induced heterokaryons of mutant fibroblast strains. Three of 7
strains studied fell into a first group. The second group, composed of 4
mutants, was a complex one with intragroup complementation. The
complementation groups could not be correlated with patterns of clinical
heterogeneity. Although Gravel et al. (1977) referred to the 2 types as
pccA and pccC, they are now referred to as pccB and pccC. In a study of
heterozygotes from families of the 2 types, Wolf and Rosenberg (1978)
found the expected half-normal level of PCC in type B heterozygotes,
whereas type C heterozygotes showed normal levels of the enzyme.
Kidd et al. (1980) studied propionic acidemia of the pccC type in 4
Amish sibships. Three ancestral couples were shared in common by all 8
parents. The authors calculated that the relative likelihoods of the 3
couples as the origin of the mutant allele were 1,539, 278, and 1. The
highest relative likelihood was for Jacob Hochstetler and his wife, nee
Lorenz. The first symptoms generally appeared in infancy and included
vomiting, lethargy, hypotonia, and failure to thrive. Exacerbations can
be produced by increased protein intake or acute infection and are
characterized by ketoacidosis, hyperglycinemia, hyperglycinuria, and
hyperammonemia. Although affected persons who are not placed on
protein-restricted diets were thought to develop mental retardation and
seizures and die early, experience in the Amish indicates that a milder
course may occur. Relatively late onset of symptoms may be related to
breast-feeding; breast milk has a lower protein content than formulas or
cow's milk.
Using cDNA clones coding for the alpha and beta chains as probes,
Lamhonwah and Gravel (1987) found absence of alpha mRNA in 4 of 6 pccA
strains and presence of both alpha and beta mRNAs in 3 pccBC, 2 pccB,
and 3 pccC mutants. Their data supported the view that pccA patients
synthesize a normal beta chain that is rapidly degraded in the absence
of complexing with alpha chains. Waye et al. (1988) described 2 RFLPs in
the PCCB gene. Lamhonwah et al. (1989, 1990) provided evidence in
support of their hypothesis that intragenic complementation of subgroups
pccB and pccC (Saunders et al., 1979) is due to the fact that patients
from the pccC subgroup produce enzymatically active but unstable beta
subunits which are capable of complementing enzymatically inactive pccB
subunits in fibroblast fusion experiments. In a patient from the pccC
complementation group whose DNA was examined by direct sequencing of
PCR-amplified reverse transcripts of mRNA and amplified genomic DNA, one
mutation inherited from the father was an in-frame 3-bp deletion that
removed an amino acid in the beta subunit. The second mutation,
inherited from the mother, was a deletion of 14 bp and an addition of 12
bp of new sequence. The net effect of the mother's mutation was
generation of the frameshift and a downstream stop codon, consistent
with the finding of only the father's sequence in the patient's mRNA.
The father's mutation, compatible with successful mRNA and protein
synthesis, was apparently responsible for the synthesis of a beta
subunit that participated in the intragenic complementation with the
pccB group.
Tahara et al. (1989) found an unusual mutation of the PCCB gene in 3 BC
and 5 of 9 C patients: a unique insertion/deletion replacing 14 bp in
the control with 12 bp of unrelated sequence in the mutants. Tahara et
al. (1990) pointed out that the mutation results in elimination of an
MspI restriction site, a 2-bp deletion, a frameshift, and a stop codon
in the new frame about 100 amino acid residues proximal to the normal
carboxyl terminus. This unique mutation was found in 8 of 28 mutant
alleles carried by 14 unrelated Caucasian patients. Hybridization
studies with amplified genomic DNAs using a mutant allele-specific
oligonucleotide showed that the inserted 12 bp did not originate in a
1-kb region around the mutation. In the course of their studies, Tahara
et al. (1990) identified another mutation in the same exon: a 3-bp
in-frame deletion that eliminated 1 of 2 isoleucine codons immediately
preceding the MspI site. Two unrelated patients were compound
heterozygotes for this single-codon deletion and for the
insertion/deletion described above. In 3 of 8 Japanese patients with
defects in the beta subunit, Ohura et al. (1991) found a unique 2.7-kb
band by probing DNA digested with MspI using PCCB cDNA.
Gravel et al. (1994) defined mutations that are involved in interallelic
complementation and showed that they are located in domains that can
interact between beta subunits in the PCC heteromer to restore enzymatic
function. On the basis of sequence homology with the Propionibacterium
shermanii transcarboxylase 12S subunit, they suggested that the pccC
domain, defined by ile408 and arg410, may involve the propionyl-CoA
binding site.
Rodriguez-Pombo et al. (1998) characterized mutations causing propionic
acidemia in 29 unrelated patients, 21 from Spain and 8 from Latin
America. The mutation was defined in 56 of the 58 mutant chromosomes of
the 29 unrelated patients, with detection of 16 different mutations. The
mutation spectrum included 1 insertion/deletion, 2 insertions, 10
missense mutations, 1 nonsense mutation, and 2 splicing defects.
Thirteen of these mutations had not previously been described. The
mutation profile found in the chromosomes from Latin American patients
basically resembled that of the Spanish patients.
Ugarte et al. (1999) reviewed mutations in the PCCA and PCCB genes. A
total of 29 mutations had been reported in the PCCB gene, mostly
missense mutations and a variety of splicing defects. Among Caucasians,
1218del14ins12 (232050.0003) is the most frequent, although 1170insT
(231050.0004) and E168K (232050.0005) are also prevalent specifically in
the Spanish and Latin American populations. In Japanese, T428I
(232050.0006) and R410W (232050.0001) appear to be the most common.
Muro et al. (1999) reported prenatal diagnosis of an affected fetus
based on DNA analysis in chorionic villus tissue in a family where the
proband had previously been shown to carry the 1170insT mutation
(232050.0004) and a private leu519-to-pro (L519P) mutation in the PCCB
gene. Muro et al. (1999) also assessed carrier status in this family by
DNA analysis.
Chloupkova et al. (2002) characterized 13 mutations in the PCCB gene
associated with propionic acidemia. They found a functional dichotomy
with 7 mutations capable of varying degrees of assembly but forming
catalytically inactive PCC proteins. Other PCCB mutants that were
PCC-deficient in patient-derived fibroblasts were found to be capable of
expressing wildtype level PCC activity when assembled in a
chaperone-assisted E. coli expression system. The result indicated that
these mutations exert their pathogenic effect due to an inability to
assemble correctly in patients' cells.
Among 10 patients with propionic acidemia, Desviat et al. (2006)
identified 4 different PCCA splice site mutations and 3 different PCCB
splice site mutations. The authors emphasized the different molecular
effects of splicing mutations and the possible phenotypic consequences.
In cultured cells, Rincon et al. (2007) used antisense morpholino
oligonucleotides (AMOs) to restore normal splicing caused by intronic
molecular defects in methylmalonic acidemia (251000) and propionic
acidemia (606054). One of the insertions studied involved the PCCB gene
(see 232050.0009).
*FIELD* AV
.0001
PROPIONIC ACIDEMIA
PCCB, ARG412TRP
Tahara et al. (1993) identified a C-to-T transition at nucleotide 1240,
which replaced arg412 with tryptophan in the predicted amino acid
sequence. This change was found in 3 patients with propionic acidemia
(606054), all Japanese, of whom 2 were sibs; all were homozygous for the
transition. The mutation was in the same exon as the insertion/deletion
described by Tahara et al. (1990) and was detected only in Caucasian
patients, among whom it represented 11 of 34 mutant alleles. (This
mutation was described as a C-to-T transition at nucleotide 1228 in exon
12, causing an ARG410TRP substitution, by Ugarte et al. (1999).)
.0002
PROPIONIC ACIDEMIA
PCCB, 8-BP DEL, NT3
In a Japanese patient with propionic acidemia (606054), Ohura et al.
(1993) found deletion of 101 bp between nucleotides 1199 and 1299 of the
mRNA. Analysis of PCR products of genomic DNA showed an 8-bp deletion
that started with the third base of the intron and extended downstream
of the deleted exon. The 5-prime and 3-prime splice junctions of the
preceding intron and the 3-prime splice signal of the following intron
were normal. The deletion of nucleotides 3-10 resulted in skipping of
the preceding intron.
.0003
PROPIONIC ACIDEMIA
PCCB, 12-BP INS, 14-BP DEL, NT1218
Rodriguez-Pombo et al. (1998) found that the most frequent mutation
causing PCCB deficiency (606054) in Spain and Latin America was an
insertion/deletion of 12 bp and 14 bp, respectively, following
nucleotide 1218. This mutation accounted for 31% of the alleles from
Spanish patients and 47% of the alleles from Latin American patients.
The ins/del caused a frameshift and a premature stop codon in the coding
sequence.
.0004
PROPIONIC ACIDEMIA
PCCB, 1-BP INS, 1170T
Rodriguez-Pombo et al. (1998) found that the second most frequent
mutation in patients with propionic acidemia (606054) in Spain,
accounting for 16.7% of mutant PCCB alleles, was insertion of a thymine
after nucleotide 1170 of the cDNA. This mutation was found in a Chilean
patient in the Latin American group (frequency 6%).
.0005
PROPIONIC ACIDEMIA
PCCB, GLU168LYS
In 14.3% of the mutant alleles of Spanish patients with propionic
acidemia (606054) and in 25% of the mutant alleles of Latin American
patients, Rodriguez-Pombo et al. (1998) found a G-to-A transition at
nucleotide 502 of the PCCB gene, resulting in a glu168-to-lys amino acid
substitution.
.0006
PROPIONIC ACIDEMIA
PCCB, THR428ILE
In Japanese patients with propionic acidemia (606054), Ohura et al.
(1993) identified a 1283C-T change in the PCCB gene, resulting in a
thr428-to-ile substitution.
.0007
PROPIONIC ACIDEMIA
PCCB, 3-BP INS, 1540CCC
Propionic acidemia (606054) has a high prevalence among Inuits in
Greenland. Ravn et al. (2000) found a 3-bp insertion, 1540insCCC, in
homozygous form in 3 patients and in compound heterozygous form in 1
patient. They found a carrier frequency of 5% for the heterozygous state
in the Greenlandic Inuit population. Analysis of alleles of a very
closely linked marker, D3S2453, showed a high degree of linkage
disequilibrium with one specific allele, suggesting that this was a
founder mutation.
.0008
PROPIONIC ACIDEMIA
PCCB, TYR435CYS
In a neonatal screen of more than 130,000 Japanese newborns, Yorifuji et
al. (2002) detected a frequency of patients with propionic acidemia
(606054) more than 10 times higher than previously reported, most of
them with mild phenotypes. The mutation spectrum was quite different
from that of patients with the severe form and there was a common
tyr435-to-cys (Y435C) mutation in the beta subunit of the PCC gene.
Since patients with the mild form can present with unusual symptoms and
therefore easily remain unrecognized, Yorifuji et al. (2002) emphasized
the importance of identifying those patients and clarifying their
natural history.
.0009
PROPIONIC ACIDEMIA
PCCB, IVS6, A-G, +462
In a PCCB-deficient (606054) patient, Rincon et al. (2007) identified a
72-bp insertion between exons 6 and 7 in PCCB mRNA (654ins72) in
homozygous state, corresponding to an intron 6 region resembling an exon
with 3-prime and 5-prime splice sites with high splicing scores. Direct
sequencing of the genomic region identified an A-to-G substitution at
position +5 relative to the inserted sequence (IVS6+462A-G), increasing
the cryptic 5-prime donor splicing score.
*FIELD* RF
1. Chloupkova, M.; Maclean, K. N.; Alkhateeb, A.; Kraus, J. P.: Propionic
acidemia: analysis of mutant propionyl-CoA carboxylase enzymes expressed
in Escherichia coli. Hum. Mutat. 19: 629-640, 2002.
2. Desviat, L. R.; Clavero, S.; Perez-Cerda, C.; Navarrete, R.; Ugarte,
M.; Perez, B.: New splicing mutations in propionic acidemia. J.
Hum. Genet. 51: 992-997, 2006.
3. Fenton, W. A.; Gravel, R. A.; Rosenblatt, D. S.: Disorders of
propionate and methylmalonate metabolism.In: Scriver, C. R.; Beaudet,
A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular
Bases of Inherited Disease. Vol. II. (8th ed.) New York: McGraw-Hill
2001. P. 2176.
4. Gravel, R. A.; Akerman, B. R.; Lamhonwah, A.-M.; Loyer, M.; Leon-del-Rio,
A.; Italiano, I.: Mutations participating in interallelic complementation
in propionic acidemia. Am. J. Hum. Genet. 55: 51-58, 1994.
5. Gravel, R. A.; Lam, K.-F.; Scully, K. J.; Hsia, Y. E.: Genetic
complementation of propionyl-CoA carboxylase deficiency in cultured
human fibroblasts. Am. J. Hum. Genet. 29: 378-388, 1977.
6. Kidd, J. R.; Wolf, B.; Hsia, Y. E.; Kidd, K. K.: Genetics of propionic
acidemia in a Mennonite-Amish kindred. Am. J. Hum. Genet. 32: 236-245,
1980.
7. Lamhonwah, A.-M.; Barankiewicz, T. J.; Willard, H. F.; Mahuran,
D. J.; Quan, F.; Gravel, R. A.: Isolation of cDNA clones coding for
the alpha and beta chains of human propionyl-CoA carboxylase: chromosomal
assignments and DNA polymorphisms associated with PCCA and PCCB genes. Proc.
Nat. Acad. Sci. 83: 4864-4868, 1986.
8. Lamhonwah, A.-M.; Gravel, R. A.: Propionicacidemia: absence of
alpha-chain mRNA in fibroblasts from patients of the pccA complementation
group. Am. J. Hum. Genet. 41: 1124-1131, 1987.
9. Lamhonwah, A.-M.; Leclerc, D.; Loyer, M.; Clarizio, R.; Gravel,
R. A.: Correction of the metabolic defect in propionic acidemia fibroblasts
by microinjection of a full-length cDNA or RNA transcript encoding
the propionyl-CoA carboxylase beta-subunit. Genomics 19: 500-505,
1994.
10. Lamhonwah, A.-M.; Troxel, C.; Schuster, S.; Gravel, R. A.: Molecular
basis of intragenic complementation in propionicacidemia: identification
of mutations in the pccC complementation group. (Abstract) Am. J.
Hum. Genet. 45 (suppl.): A8 only, 1989.
11. Lamhonwah, A.-M.; Troxel, C. E.; Schuster, S.; Gravel, R. A.:
Two distinct mutations at the same site in the PCCB gene in propionicacidemia. Genomics 8:
249-254, 1990.
12. Levy, E. R.; Rack, K.; Buckle, V. J.: Refined localization of
PCCB to 3q21-q22. (Abstract) Cytogenet. Cell Genet. 58: 1878 only,
1991.
13. Muro, S.; Perez-Cerda, C.; Rodriguez-Pombo, P.; Perez, B.; Briones,
P.; Ribes, A.; Ugarte, M.: Feasibility of DNA based methods for prenatal
diagnosis and carrier detection of propionic acidaemia. J. Med. Genet. 36:
412-414, 1999.
14. Ohura, T.; Miyabayashi, S.; Narisawa, K.; Tada, K.: Genetic heterogeneity
of propionic acidemia: analysis of 15 Japanese patients. Hum. Genet. 87:
41-44, 1991.
15. Ohura, T.; Narisawa, K.; Tada, K.: Propionic acidaemia: sequence
analysis of mutant mRNAs from Japanese beta subunit-deficient patients. J.
Inherit. Metab. Dis. 16: 863-867, 1993.
16. Ohura, T.; Ogasawara, M.; Ikeda, H.; Narisawa, K.; Tada, K.:
The molecular defect in propionic acidemia: exon skipping caused by
an 8-bp deletion from an intron in the PCCB allele. Hum. Genet. 92:
397-402, 1993.
17. Ravn, K.; Chloupkova, M.; Christensen, E.; Brandt, N. J.; Simonsen,
H.; Kraus, J. P.; Nielsen, I. M.; Skovby, F.; Schwartz, M.: High
incidence of propionic acidemia in Greenland is due to a prevalent
mutation, 1540insCCC, in the gene for the beta-subunit of propionyl
CoA carboxylase. Am. J. Hum. Genet. 67: 203-206, 2000. Note: Erratum:
Am. J. Hum. Genet. 67: 270 only, 2000.
18. Rincon, A.; Aguado, C.; Desviat, L. R.; Sanchez-Alcudia, R.; Ugarte,
M.; Perez, B.: Propionic and methylmalonic acidemia: antisense therapeutics
for intronic variations causing aberrantly spliced messenger RNA. Am.
J. Hum. Genet. 81: 1262-1270, 2007.
19. Rodriguez-Pombo, P.; Hoenicka, J.; Muro, S.; Perez, B.; Perez-Cerda,
C.; Richard, E.; Desviat, L. R.; Ugarte, M.: Human propionyl-CoA
carboxylase beta subunit gene: exon-intron definition and mutation
spectrum in Spanish and Latin American propionic acidemia patients. Am.
J. Hum. Genet. 63: 360-369, 1998.
20. Saunders, M.; Sweetman, L.; Robinson, B.; Roth, K.; Cohn, R.;
Gravel, R. A.: Biotin-response organicaciduria: multiple carboxylase
defects and complementation studies with propionicacidemia in cultured
fibroblasts. J. Clin. Invest. 64: 1695-1702, 1979.
21. Tahara, T.; Kraus, J. P.; Ohura, T.; Rosenberg, L. E.; Fenton,
W. A.: Three independent mutations in the same exon of the PCCB gene:
differences between Caucasian and Japanese propionic acidaemia. J.
Inherit. Metab. Dis. 16: 353-360, 1993.
22. Tahara, T.; Kraus, J. P.; Rosenberg, L. E.: An unusual insertion/deletion
in the gene for the beta-subunit of propionyl CoA carboxylase: a common
mutation in propionic acidemia. (Abstract) Am. J. Hum. Genet. 45
(suppl.): A222 only, 1989.
23. Tahara, T.; Kraus, J. P.; Rosenberg, L. E.: An unusual insertion/deletion
in the gene encoding the beta-subunit of propionyl-CoA carboxylase
is a frequent mutation in Caucasian propionic acidemia. Proc. Nat.
Acad. Sci. 87: 1372-1376, 1990.
24. Ugarte, M.; Perez-Cerda, C.; Rodriguez-Pombo, P.; Desviat, L.
R.; Perez, B.; Richard, E.; Muro, S.; Campeau, E.; Ohura, T.; Gravel,
R. A.: Overview of mutations in the PCCA and PCCB genes causing propionic
acidemia. Hum. Mutat. 14: 275-282, 1999.
25. Waye, J. S.; Gravel, R. A.; Willard, H. F.: Two PstI RFLPs in
the PCCB gene on the long arm of chromosome 3. Nucleic Acids Res. 16:
2362 only, 1988.
26. Wolf, B.; Rosenberg, L. E.: Heterozygote expression in propionyl
coenzyme A carboxylase deficiency: differences between major complementation
groups. J. Clin. Invest. 62: 931-936, 1978.
27. Yang-Feng, T. L.; Kraus, J. P.; Francke, U.: Gene for the beta-subunit
of propionyl CoA carboxylase (PCCB) is located on the long arm of
human chromosome 3 (3q13.3-q22). (Abstract) Cytogenet. Cell Genet. 40:
783 only, 1985.
28. Yorifuji, T.; Kawai, M.; Muroi, J.; Mamada, M.; Kurokawa, K.;
Shigematsu, Y.; Hirano, S.; Sakura, N.; Yoshida, I.; Kuhara, T.; Endo,
F.; Mitsubuchi, H.; Nakahata, T.: Unexpectedly high prevalence of
the mild form of propionic acidemia in Japan: presence of a common
mutation and possible clinical implications. Hum. Genet. 111: 161-165,
2002. Note: Erratum: Hum. Genet. 112: 100 only, 2003.
*FIELD* CN
Victor A. McKusick - updated: 11/28/2007
Cassandra L. Kniffin - updated: 3/16/2007
Victor A. McKusick - updated: 10/2/2002
Victor A. McKusick - updated: 6/14/2002
Ada Hamosh - reorganized: 6/22/2001
Victor A. McKusick - updated: 9/5/2000
Wilson H. Y. Lo - updated: 11/17/1999
Michael J. Wright - updated: 7/12/1999
Victor A. McKusick - updated: 9/11/1998
*FIELD* CD
Victor A. McKusick: 6/24/1986
*FIELD* ED
terry: 09/04/2012
alopez: 12/11/2007
terry: 11/28/2007
wwang: 4/2/2007
ckniffin: 3/16/2007
terry: 4/6/2005
tkritzer: 10/10/2002
tkritzer: 10/4/2002
terry: 10/2/2002
cwells: 6/18/2002
terry: 6/14/2002
mcapotos: 12/21/2001
carol: 9/10/2001
carol: 6/22/2001
mcapotos: 9/27/2000
mcapotos: 9/19/2000
terry: 9/5/2000
carol: 11/22/1999
carol: 11/17/1999
jlewis: 7/23/1999
jlewis: 7/19/1999
terry: 7/12/1999
carol: 9/16/1998
terry: 9/11/1998
terry: 6/4/1998
terry: 8/30/1994
mimadm: 4/8/1994
carol: 3/14/1994
carol: 12/20/1993
carol: 9/23/1993
carol: 9/13/1993
*RECORD*
*FIELD* NO
232050
*FIELD* TI
*232050 PROPIONYL-CoA CARBOXYLASE, BETA SUBUNIT; PCCB
;;pccBC COMPLEMENTATION GROUP
read more*FIELD* TX
Propionyl-CoA is an important intermediate in the metabolism of several
amino acids and is also produced by oxidation of odd-numbered fatty
acids. Propionyl-CoA carboxylase (PCC), comprised of alpha and beta
subunits, catalyzes the first step in the catabolism of propionyl-CoA.
The alpha subunit is encoded by the PCCA gene (232000) and the beta
subunit by the PCCB gene. Cells from patients with propionic acidemia
(606054) who have mutations in the PCCB gene fall into 2 complementation
subgroups, pccB and pccC. Mutations in the pccB subgroup occur in the N
terminus of the beta subunit, which includes the biotin-binding site,
whereas mutations in the pccC subgroup occur in the C terminus (Fenton
et al., 2001).
CLONING
Lamhonwah et al. (1994) cloned a full-length cDNA encoding the beta
subunit of human PCC. The open reading frame encoded a pre-beta
polypeptide of 539 amino acids (58,205 Da). The cDNA was introduced into
an expression vector and microinjected into the nucleus or, as
ribotranscripts, into the cytoplasm of fibroblast lines from propionic
acidemia patients with defects of the beta subunit. Restoration of
function was demonstrated by autoradiography of PCC-dependent
(14)C-propionate incorporation into cellular protein. These results
confirmed the completeness of the clone and demonstrated the capacity
for the microinjected material to be transported into mitochondria and
assembled with endogenously derived alpha subunits to form functional
PCC.
GENE STRUCTURE
Rodriguez-Pombo et al. (1998) described the genomic organization of the
coding sequence of the human PCCB gene. The PCCB gene consists of 15
exons of 57 to 183 bp. All splice sites are consistent with the gt/ag
rule.
MAPPING
Yang-Feng et al. (1985) used rat cDNA probes to assign the human PCCB
gene to 3q13.3-q22 by in situ hybridization and corroborated the
assignment to chromosome 3 by Southern blot analysis of somatic cell
hybrid DNAs. Assignment of PCCB to chromosome 3 was also reported by
Lamhonwah et al. (1986). Levy et al. (1991) refined the localization of
the PCCB gene to 3q21-q22 by demonstrating the loss of a polymorphic
band in a clonal population of blast cells from an individual suffering
from myelodysplastic syndrome who had been found to have an interstitial
deletion of 3q21-q25.
MOLECULAR GENETICS
Two main complementation groups for propionyl-CoA carboxylase deficiency
were demonstrated by Gravel et al. (1977) in studies of Sendai
virus-induced heterokaryons of mutant fibroblast strains. Three of 7
strains studied fell into a first group. The second group, composed of 4
mutants, was a complex one with intragroup complementation. The
complementation groups could not be correlated with patterns of clinical
heterogeneity. Although Gravel et al. (1977) referred to the 2 types as
pccA and pccC, they are now referred to as pccB and pccC. In a study of
heterozygotes from families of the 2 types, Wolf and Rosenberg (1978)
found the expected half-normal level of PCC in type B heterozygotes,
whereas type C heterozygotes showed normal levels of the enzyme.
Kidd et al. (1980) studied propionic acidemia of the pccC type in 4
Amish sibships. Three ancestral couples were shared in common by all 8
parents. The authors calculated that the relative likelihoods of the 3
couples as the origin of the mutant allele were 1,539, 278, and 1. The
highest relative likelihood was for Jacob Hochstetler and his wife, nee
Lorenz. The first symptoms generally appeared in infancy and included
vomiting, lethargy, hypotonia, and failure to thrive. Exacerbations can
be produced by increased protein intake or acute infection and are
characterized by ketoacidosis, hyperglycinemia, hyperglycinuria, and
hyperammonemia. Although affected persons who are not placed on
protein-restricted diets were thought to develop mental retardation and
seizures and die early, experience in the Amish indicates that a milder
course may occur. Relatively late onset of symptoms may be related to
breast-feeding; breast milk has a lower protein content than formulas or
cow's milk.
Using cDNA clones coding for the alpha and beta chains as probes,
Lamhonwah and Gravel (1987) found absence of alpha mRNA in 4 of 6 pccA
strains and presence of both alpha and beta mRNAs in 3 pccBC, 2 pccB,
and 3 pccC mutants. Their data supported the view that pccA patients
synthesize a normal beta chain that is rapidly degraded in the absence
of complexing with alpha chains. Waye et al. (1988) described 2 RFLPs in
the PCCB gene. Lamhonwah et al. (1989, 1990) provided evidence in
support of their hypothesis that intragenic complementation of subgroups
pccB and pccC (Saunders et al., 1979) is due to the fact that patients
from the pccC subgroup produce enzymatically active but unstable beta
subunits which are capable of complementing enzymatically inactive pccB
subunits in fibroblast fusion experiments. In a patient from the pccC
complementation group whose DNA was examined by direct sequencing of
PCR-amplified reverse transcripts of mRNA and amplified genomic DNA, one
mutation inherited from the father was an in-frame 3-bp deletion that
removed an amino acid in the beta subunit. The second mutation,
inherited from the mother, was a deletion of 14 bp and an addition of 12
bp of new sequence. The net effect of the mother's mutation was
generation of the frameshift and a downstream stop codon, consistent
with the finding of only the father's sequence in the patient's mRNA.
The father's mutation, compatible with successful mRNA and protein
synthesis, was apparently responsible for the synthesis of a beta
subunit that participated in the intragenic complementation with the
pccB group.
Tahara et al. (1989) found an unusual mutation of the PCCB gene in 3 BC
and 5 of 9 C patients: a unique insertion/deletion replacing 14 bp in
the control with 12 bp of unrelated sequence in the mutants. Tahara et
al. (1990) pointed out that the mutation results in elimination of an
MspI restriction site, a 2-bp deletion, a frameshift, and a stop codon
in the new frame about 100 amino acid residues proximal to the normal
carboxyl terminus. This unique mutation was found in 8 of 28 mutant
alleles carried by 14 unrelated Caucasian patients. Hybridization
studies with amplified genomic DNAs using a mutant allele-specific
oligonucleotide showed that the inserted 12 bp did not originate in a
1-kb region around the mutation. In the course of their studies, Tahara
et al. (1990) identified another mutation in the same exon: a 3-bp
in-frame deletion that eliminated 1 of 2 isoleucine codons immediately
preceding the MspI site. Two unrelated patients were compound
heterozygotes for this single-codon deletion and for the
insertion/deletion described above. In 3 of 8 Japanese patients with
defects in the beta subunit, Ohura et al. (1991) found a unique 2.7-kb
band by probing DNA digested with MspI using PCCB cDNA.
Gravel et al. (1994) defined mutations that are involved in interallelic
complementation and showed that they are located in domains that can
interact between beta subunits in the PCC heteromer to restore enzymatic
function. On the basis of sequence homology with the Propionibacterium
shermanii transcarboxylase 12S subunit, they suggested that the pccC
domain, defined by ile408 and arg410, may involve the propionyl-CoA
binding site.
Rodriguez-Pombo et al. (1998) characterized mutations causing propionic
acidemia in 29 unrelated patients, 21 from Spain and 8 from Latin
America. The mutation was defined in 56 of the 58 mutant chromosomes of
the 29 unrelated patients, with detection of 16 different mutations. The
mutation spectrum included 1 insertion/deletion, 2 insertions, 10
missense mutations, 1 nonsense mutation, and 2 splicing defects.
Thirteen of these mutations had not previously been described. The
mutation profile found in the chromosomes from Latin American patients
basically resembled that of the Spanish patients.
Ugarte et al. (1999) reviewed mutations in the PCCA and PCCB genes. A
total of 29 mutations had been reported in the PCCB gene, mostly
missense mutations and a variety of splicing defects. Among Caucasians,
1218del14ins12 (232050.0003) is the most frequent, although 1170insT
(231050.0004) and E168K (232050.0005) are also prevalent specifically in
the Spanish and Latin American populations. In Japanese, T428I
(232050.0006) and R410W (232050.0001) appear to be the most common.
Muro et al. (1999) reported prenatal diagnosis of an affected fetus
based on DNA analysis in chorionic villus tissue in a family where the
proband had previously been shown to carry the 1170insT mutation
(232050.0004) and a private leu519-to-pro (L519P) mutation in the PCCB
gene. Muro et al. (1999) also assessed carrier status in this family by
DNA analysis.
Chloupkova et al. (2002) characterized 13 mutations in the PCCB gene
associated with propionic acidemia. They found a functional dichotomy
with 7 mutations capable of varying degrees of assembly but forming
catalytically inactive PCC proteins. Other PCCB mutants that were
PCC-deficient in patient-derived fibroblasts were found to be capable of
expressing wildtype level PCC activity when assembled in a
chaperone-assisted E. coli expression system. The result indicated that
these mutations exert their pathogenic effect due to an inability to
assemble correctly in patients' cells.
Among 10 patients with propionic acidemia, Desviat et al. (2006)
identified 4 different PCCA splice site mutations and 3 different PCCB
splice site mutations. The authors emphasized the different molecular
effects of splicing mutations and the possible phenotypic consequences.
In cultured cells, Rincon et al. (2007) used antisense morpholino
oligonucleotides (AMOs) to restore normal splicing caused by intronic
molecular defects in methylmalonic acidemia (251000) and propionic
acidemia (606054). One of the insertions studied involved the PCCB gene
(see 232050.0009).
*FIELD* AV
.0001
PROPIONIC ACIDEMIA
PCCB, ARG412TRP
Tahara et al. (1993) identified a C-to-T transition at nucleotide 1240,
which replaced arg412 with tryptophan in the predicted amino acid
sequence. This change was found in 3 patients with propionic acidemia
(606054), all Japanese, of whom 2 were sibs; all were homozygous for the
transition. The mutation was in the same exon as the insertion/deletion
described by Tahara et al. (1990) and was detected only in Caucasian
patients, among whom it represented 11 of 34 mutant alleles. (This
mutation was described as a C-to-T transition at nucleotide 1228 in exon
12, causing an ARG410TRP substitution, by Ugarte et al. (1999).)
.0002
PROPIONIC ACIDEMIA
PCCB, 8-BP DEL, NT3
In a Japanese patient with propionic acidemia (606054), Ohura et al.
(1993) found deletion of 101 bp between nucleotides 1199 and 1299 of the
mRNA. Analysis of PCR products of genomic DNA showed an 8-bp deletion
that started with the third base of the intron and extended downstream
of the deleted exon. The 5-prime and 3-prime splice junctions of the
preceding intron and the 3-prime splice signal of the following intron
were normal. The deletion of nucleotides 3-10 resulted in skipping of
the preceding intron.
.0003
PROPIONIC ACIDEMIA
PCCB, 12-BP INS, 14-BP DEL, NT1218
Rodriguez-Pombo et al. (1998) found that the most frequent mutation
causing PCCB deficiency (606054) in Spain and Latin America was an
insertion/deletion of 12 bp and 14 bp, respectively, following
nucleotide 1218. This mutation accounted for 31% of the alleles from
Spanish patients and 47% of the alleles from Latin American patients.
The ins/del caused a frameshift and a premature stop codon in the coding
sequence.
.0004
PROPIONIC ACIDEMIA
PCCB, 1-BP INS, 1170T
Rodriguez-Pombo et al. (1998) found that the second most frequent
mutation in patients with propionic acidemia (606054) in Spain,
accounting for 16.7% of mutant PCCB alleles, was insertion of a thymine
after nucleotide 1170 of the cDNA. This mutation was found in a Chilean
patient in the Latin American group (frequency 6%).
.0005
PROPIONIC ACIDEMIA
PCCB, GLU168LYS
In 14.3% of the mutant alleles of Spanish patients with propionic
acidemia (606054) and in 25% of the mutant alleles of Latin American
patients, Rodriguez-Pombo et al. (1998) found a G-to-A transition at
nucleotide 502 of the PCCB gene, resulting in a glu168-to-lys amino acid
substitution.
.0006
PROPIONIC ACIDEMIA
PCCB, THR428ILE
In Japanese patients with propionic acidemia (606054), Ohura et al.
(1993) identified a 1283C-T change in the PCCB gene, resulting in a
thr428-to-ile substitution.
.0007
PROPIONIC ACIDEMIA
PCCB, 3-BP INS, 1540CCC
Propionic acidemia (606054) has a high prevalence among Inuits in
Greenland. Ravn et al. (2000) found a 3-bp insertion, 1540insCCC, in
homozygous form in 3 patients and in compound heterozygous form in 1
patient. They found a carrier frequency of 5% for the heterozygous state
in the Greenlandic Inuit population. Analysis of alleles of a very
closely linked marker, D3S2453, showed a high degree of linkage
disequilibrium with one specific allele, suggesting that this was a
founder mutation.
.0008
PROPIONIC ACIDEMIA
PCCB, TYR435CYS
In a neonatal screen of more than 130,000 Japanese newborns, Yorifuji et
al. (2002) detected a frequency of patients with propionic acidemia
(606054) more than 10 times higher than previously reported, most of
them with mild phenotypes. The mutation spectrum was quite different
from that of patients with the severe form and there was a common
tyr435-to-cys (Y435C) mutation in the beta subunit of the PCC gene.
Since patients with the mild form can present with unusual symptoms and
therefore easily remain unrecognized, Yorifuji et al. (2002) emphasized
the importance of identifying those patients and clarifying their
natural history.
.0009
PROPIONIC ACIDEMIA
PCCB, IVS6, A-G, +462
In a PCCB-deficient (606054) patient, Rincon et al. (2007) identified a
72-bp insertion between exons 6 and 7 in PCCB mRNA (654ins72) in
homozygous state, corresponding to an intron 6 region resembling an exon
with 3-prime and 5-prime splice sites with high splicing scores. Direct
sequencing of the genomic region identified an A-to-G substitution at
position +5 relative to the inserted sequence (IVS6+462A-G), increasing
the cryptic 5-prime donor splicing score.
*FIELD* RF
1. Chloupkova, M.; Maclean, K. N.; Alkhateeb, A.; Kraus, J. P.: Propionic
acidemia: analysis of mutant propionyl-CoA carboxylase enzymes expressed
in Escherichia coli. Hum. Mutat. 19: 629-640, 2002.
2. Desviat, L. R.; Clavero, S.; Perez-Cerda, C.; Navarrete, R.; Ugarte,
M.; Perez, B.: New splicing mutations in propionic acidemia. J.
Hum. Genet. 51: 992-997, 2006.
3. Fenton, W. A.; Gravel, R. A.; Rosenblatt, D. S.: Disorders of
propionate and methylmalonate metabolism.In: Scriver, C. R.; Beaudet,
A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular
Bases of Inherited Disease. Vol. II. (8th ed.) New York: McGraw-Hill
2001. P. 2176.
4. Gravel, R. A.; Akerman, B. R.; Lamhonwah, A.-M.; Loyer, M.; Leon-del-Rio,
A.; Italiano, I.: Mutations participating in interallelic complementation
in propionic acidemia. Am. J. Hum. Genet. 55: 51-58, 1994.
5. Gravel, R. A.; Lam, K.-F.; Scully, K. J.; Hsia, Y. E.: Genetic
complementation of propionyl-CoA carboxylase deficiency in cultured
human fibroblasts. Am. J. Hum. Genet. 29: 378-388, 1977.
6. Kidd, J. R.; Wolf, B.; Hsia, Y. E.; Kidd, K. K.: Genetics of propionic
acidemia in a Mennonite-Amish kindred. Am. J. Hum. Genet. 32: 236-245,
1980.
7. Lamhonwah, A.-M.; Barankiewicz, T. J.; Willard, H. F.; Mahuran,
D. J.; Quan, F.; Gravel, R. A.: Isolation of cDNA clones coding for
the alpha and beta chains of human propionyl-CoA carboxylase: chromosomal
assignments and DNA polymorphisms associated with PCCA and PCCB genes. Proc.
Nat. Acad. Sci. 83: 4864-4868, 1986.
8. Lamhonwah, A.-M.; Gravel, R. A.: Propionicacidemia: absence of
alpha-chain mRNA in fibroblasts from patients of the pccA complementation
group. Am. J. Hum. Genet. 41: 1124-1131, 1987.
9. Lamhonwah, A.-M.; Leclerc, D.; Loyer, M.; Clarizio, R.; Gravel,
R. A.: Correction of the metabolic defect in propionic acidemia fibroblasts
by microinjection of a full-length cDNA or RNA transcript encoding
the propionyl-CoA carboxylase beta-subunit. Genomics 19: 500-505,
1994.
10. Lamhonwah, A.-M.; Troxel, C.; Schuster, S.; Gravel, R. A.: Molecular
basis of intragenic complementation in propionicacidemia: identification
of mutations in the pccC complementation group. (Abstract) Am. J.
Hum. Genet. 45 (suppl.): A8 only, 1989.
11. Lamhonwah, A.-M.; Troxel, C. E.; Schuster, S.; Gravel, R. A.:
Two distinct mutations at the same site in the PCCB gene in propionicacidemia. Genomics 8:
249-254, 1990.
12. Levy, E. R.; Rack, K.; Buckle, V. J.: Refined localization of
PCCB to 3q21-q22. (Abstract) Cytogenet. Cell Genet. 58: 1878 only,
1991.
13. Muro, S.; Perez-Cerda, C.; Rodriguez-Pombo, P.; Perez, B.; Briones,
P.; Ribes, A.; Ugarte, M.: Feasibility of DNA based methods for prenatal
diagnosis and carrier detection of propionic acidaemia. J. Med. Genet. 36:
412-414, 1999.
14. Ohura, T.; Miyabayashi, S.; Narisawa, K.; Tada, K.: Genetic heterogeneity
of propionic acidemia: analysis of 15 Japanese patients. Hum. Genet. 87:
41-44, 1991.
15. Ohura, T.; Narisawa, K.; Tada, K.: Propionic acidaemia: sequence
analysis of mutant mRNAs from Japanese beta subunit-deficient patients. J.
Inherit. Metab. Dis. 16: 863-867, 1993.
16. Ohura, T.; Ogasawara, M.; Ikeda, H.; Narisawa, K.; Tada, K.:
The molecular defect in propionic acidemia: exon skipping caused by
an 8-bp deletion from an intron in the PCCB allele. Hum. Genet. 92:
397-402, 1993.
17. Ravn, K.; Chloupkova, M.; Christensen, E.; Brandt, N. J.; Simonsen,
H.; Kraus, J. P.; Nielsen, I. M.; Skovby, F.; Schwartz, M.: High
incidence of propionic acidemia in Greenland is due to a prevalent
mutation, 1540insCCC, in the gene for the beta-subunit of propionyl
CoA carboxylase. Am. J. Hum. Genet. 67: 203-206, 2000. Note: Erratum:
Am. J. Hum. Genet. 67: 270 only, 2000.
18. Rincon, A.; Aguado, C.; Desviat, L. R.; Sanchez-Alcudia, R.; Ugarte,
M.; Perez, B.: Propionic and methylmalonic acidemia: antisense therapeutics
for intronic variations causing aberrantly spliced messenger RNA. Am.
J. Hum. Genet. 81: 1262-1270, 2007.
19. Rodriguez-Pombo, P.; Hoenicka, J.; Muro, S.; Perez, B.; Perez-Cerda,
C.; Richard, E.; Desviat, L. R.; Ugarte, M.: Human propionyl-CoA
carboxylase beta subunit gene: exon-intron definition and mutation
spectrum in Spanish and Latin American propionic acidemia patients. Am.
J. Hum. Genet. 63: 360-369, 1998.
20. Saunders, M.; Sweetman, L.; Robinson, B.; Roth, K.; Cohn, R.;
Gravel, R. A.: Biotin-response organicaciduria: multiple carboxylase
defects and complementation studies with propionicacidemia in cultured
fibroblasts. J. Clin. Invest. 64: 1695-1702, 1979.
21. Tahara, T.; Kraus, J. P.; Ohura, T.; Rosenberg, L. E.; Fenton,
W. A.: Three independent mutations in the same exon of the PCCB gene:
differences between Caucasian and Japanese propionic acidaemia. J.
Inherit. Metab. Dis. 16: 353-360, 1993.
22. Tahara, T.; Kraus, J. P.; Rosenberg, L. E.: An unusual insertion/deletion
in the gene for the beta-subunit of propionyl CoA carboxylase: a common
mutation in propionic acidemia. (Abstract) Am. J. Hum. Genet. 45
(suppl.): A222 only, 1989.
23. Tahara, T.; Kraus, J. P.; Rosenberg, L. E.: An unusual insertion/deletion
in the gene encoding the beta-subunit of propionyl-CoA carboxylase
is a frequent mutation in Caucasian propionic acidemia. Proc. Nat.
Acad. Sci. 87: 1372-1376, 1990.
24. Ugarte, M.; Perez-Cerda, C.; Rodriguez-Pombo, P.; Desviat, L.
R.; Perez, B.; Richard, E.; Muro, S.; Campeau, E.; Ohura, T.; Gravel,
R. A.: Overview of mutations in the PCCA and PCCB genes causing propionic
acidemia. Hum. Mutat. 14: 275-282, 1999.
25. Waye, J. S.; Gravel, R. A.; Willard, H. F.: Two PstI RFLPs in
the PCCB gene on the long arm of chromosome 3. Nucleic Acids Res. 16:
2362 only, 1988.
26. Wolf, B.; Rosenberg, L. E.: Heterozygote expression in propionyl
coenzyme A carboxylase deficiency: differences between major complementation
groups. J. Clin. Invest. 62: 931-936, 1978.
27. Yang-Feng, T. L.; Kraus, J. P.; Francke, U.: Gene for the beta-subunit
of propionyl CoA carboxylase (PCCB) is located on the long arm of
human chromosome 3 (3q13.3-q22). (Abstract) Cytogenet. Cell Genet. 40:
783 only, 1985.
28. Yorifuji, T.; Kawai, M.; Muroi, J.; Mamada, M.; Kurokawa, K.;
Shigematsu, Y.; Hirano, S.; Sakura, N.; Yoshida, I.; Kuhara, T.; Endo,
F.; Mitsubuchi, H.; Nakahata, T.: Unexpectedly high prevalence of
the mild form of propionic acidemia in Japan: presence of a common
mutation and possible clinical implications. Hum. Genet. 111: 161-165,
2002. Note: Erratum: Hum. Genet. 112: 100 only, 2003.
*FIELD* CN
Victor A. McKusick - updated: 11/28/2007
Cassandra L. Kniffin - updated: 3/16/2007
Victor A. McKusick - updated: 10/2/2002
Victor A. McKusick - updated: 6/14/2002
Ada Hamosh - reorganized: 6/22/2001
Victor A. McKusick - updated: 9/5/2000
Wilson H. Y. Lo - updated: 11/17/1999
Michael J. Wright - updated: 7/12/1999
Victor A. McKusick - updated: 9/11/1998
*FIELD* CD
Victor A. McKusick: 6/24/1986
*FIELD* ED
terry: 09/04/2012
alopez: 12/11/2007
terry: 11/28/2007
wwang: 4/2/2007
ckniffin: 3/16/2007
terry: 4/6/2005
tkritzer: 10/10/2002
tkritzer: 10/4/2002
terry: 10/2/2002
cwells: 6/18/2002
terry: 6/14/2002
mcapotos: 12/21/2001
carol: 9/10/2001
carol: 6/22/2001
mcapotos: 9/27/2000
mcapotos: 9/19/2000
terry: 9/5/2000
carol: 11/22/1999
carol: 11/17/1999
jlewis: 7/23/1999
jlewis: 7/19/1999
terry: 7/12/1999
carol: 9/16/1998
terry: 9/11/1998
terry: 6/4/1998
terry: 8/30/1994
mimadm: 4/8/1994
carol: 3/14/1994
carol: 12/20/1993
carol: 9/23/1993
carol: 9/13/1993
MIM
606054
*RECORD*
*FIELD* NO
606054
*FIELD* TI
#606054 PROPIONIC ACIDEMIA
;;PROPIONYL-CoA CARBOXYLASE DEFICIENCY;;
PCC DEFICIENCY;;
read moreGLYCINEMIA, KETOTIC;;
HYPERGLYCINEMIA WITH KETOACIDOSIS AND LEUKOPENIA;;
KETOTIC HYPERGLYCINEMIA
*FIELD* TX
A number sign (#) is used with this entry because propionic acidemia is
caused by mutation in the genes encoding propionyl-CoA carboxylase, PCCA
(232000) or PCCB (232050). Cells from patients with mutations in the
PCCA gene fall into complementation group pccA. Cells from patients with
mutations in the PCCB gene fall into complementation group pccBC.
Mutations in the pccB subgroup occur in the N terminus of the PCCB gene,
which includes the biotin-binding site, whereas mutations in the pccC
subgroup occur in the C terminus of the PCCB gene (Fenton et al., 2001).
CLINICAL FEATURES
The features of propionic acidemia are episodic vomiting, lethargy and
ketosis, neutropenia, periodic thrombocytopenia, hypogammaglobulinemia,
developmental retardation, and intolerance to protein. Outstanding
chemical features are hyperglycinemia and hyperglycinuria. This disorder
is not to be confused with hereditary glycinuria (138500), which is
presumably transmitted as a dominant.
Soriano et al. (1967) suggested that in the disorder first described by
Childs et al. (1961), a generalized defect in utilization of amino acids
results in excessive deamination of certain amino acids in muscle, with
consequent hyperammonemia and ketoacidosis. In a second group of
patients whose disorder is also termed hyperglycinemia, ketoacidosis,
neutropenia, and thrombocytopenia have not been observed and glycine is
the only amino acid present in excess in serum and urine; see glycine
encephalopathy (605899).
Hsia et al. (1969) studied fibroblasts from a sister of the boy
described by Childs et al. (1961) and demonstrated deficient propionate
carboxylation as the basic defect in ketotic hyperglycinemia. Hsia et
al. (1971) also showed that 'ketotic hyperglycinemia' is the same as
propionic acidemia and is the result of a defect in PCC. In further
studies on this patient, Brandt et al. (1974) demonstrated that with low
protein diet, growth and intelligence developed normally to age 9 years;
indeed, intelligence was superior. The family originally reported by
Childs et al. (1961) had the pccA type of propionic acidemia (Wolf,
1986).
In a male Pakistani offspring of first-cousin parents, Gompertz et al.
(1970) described acidosis and ketosis due to propionic acidemia, leading
to death at 8 days of age. A sib had died at 2 weeks of age with
metabolic acidosis and ketonuria. The defect was found to involve
mitochondrial propionyl-CoA carboxylase. The same condition was
described by Hommes et al. (1968).
Al Essa et al. (1998) pointed out that not only do acute intercurrent
infections precipitate acidosis in propionic acidemia, but such
infections are unusually frequent in propionic acidemia in Saudi Arabia.
Propionic acidemia is unusually frequent in Saudi Arabia, with a
frequency of 1 in 2,000 to 1 in 5,000, depending on the region. The
disorder has a severe phenotype in Saudi Arabia. Al Essa et al. (1998)
had information on approximately 90 patients; certain tribes accounted
for almost 80% of these cases, suggesting a founder effect. The number
of other cases of organic acidemias observed during the same period was
656. Longitudinal data, in some instances up to 8 years, were available
for 38 patients with propionic acidemia. A high frequency of infections
was observed in 80% of the patients. Most microorganisms implicated were
unusual, suggesting an underlying immune deficiency. The infections
occurred despite aggressive treatment with appropriate diets, carnitine,
and, during acute episodes of the disease, with metronidazole, which
suggested a global effect of the disease on T and B lymphocytes as well
as on the bone marrow cells.
In a review of inherited metabolic disorders and stroke, Testai and
Gorelick (2010) noted that patients with branched-chain organic
aciduria, including isovaleric aciduria (243500), propionic aciduria,
and methylmalonic aciduria (251000) can rarely have strokes. Cerebellar
hemorrhage has been described in all 3 disorders, and basal ganglia
ischemic stroke has been described in propionic aciduria and
methylmalonic aciduria. These events may occur in the absence of
metabolic decompensation.
BIOCHEMICAL FEATURES
Hillman et al. (1978) observed biotin-responsive propionic acidemia.
Wolf and Hsia (1978) suggested that biotin-responsiveness can be tested
by measuring propionyl-CoA carboxylase and beta-methylcrotonyl CoA
carboxylase (see 609010 and 609014) in peripheral blood leukocytes
before and after biotin. From kinetic analysis of complementations in
heterokaryons of propionyl CoA carboxylase-deficient fibroblasts, Wolf
et al. (1980) concluded that the 'bio' and 'pcc' mutations affect
different genes; that complementation between pccA and pccB, pccC or
pccBC lines is intergenic with subunit exchange and synthesis of new
carboxylase molecules and that complementation between pccB and pccC
mutants is interallelic. Wolf and Feldman (1982) considered it likely
that the pccBC complementation group reflects mutations of the alpha
subunit and the pccA group mutations of the beta subunit.
Using cDNA clones coding for the alpha and beta chains as probes,
Lamhonwah and Gravel (1987) found absence of alpha mRNA in 4 of 6 pccA
strains and the presence of beta mRNA in all pccA mutants studied. They
also found the presence of both alpha and beta mRNAs in 3 pccBC, 2 pccB,
and 3 pccC mutants. Ohura et al. (1989) presented evidence from which
they concluded that beta-chain subunits of propionyl-CoA carboxylase are
normally synthesized and imported into the mitochondria in excess of
alpha-chain subunits, but only that portion assembled with alpha
subunits escapes degradation. In pccA patients, the primary defect in
alpha-chain synthesis leads secondarily to degradation of normally
synthesized beta chains. The differential rates of synthesis of alpha
and beta chains appear to account for the finding that persons
heterozygous for pccBC mutations have normal carboxylase activity in
their cells. Among 15 Japanese patients with propionic acidemia, Ohura
et al. (1991) found that both the alpha and beta subunits were absent in
3 and low in 3 others; according to their previous data, they concluded
that these 6 patients had an alpha-subunit defect. In 8 other patients,
alpha subunits were normal, but the beta subunits were aberrant; these
patients were considered to have beta-subunit defects. One of the 15
patients had apparently normal alpha and beta subunits. An altered MspI
restriction pattern for PCCB cDNA, consisting of a unique 2.7-kb band,
was found in 3 patients with beta-subunit deficiency.
DIAGNOSIS
- Prenatal Diagnosis
Buchanan et al. (1980) pointed out that propionic acidemia can be
diagnosed either by an elevated quantity of the metabolite methylcitrate
in amniotic fluid or by deficient activity of propionyl-CoA carboxylase
in amniocytes. Contamination by maternal cells can give a normal value
for the latter determination; methylcitrate assay may be the most
reliable approach. Perez-Cerda et al. (1989) successfully diagnosed PCC
deficiency in the first trimester of pregnancy by direct enzyme assay in
uncultured chorionic villi.
Muro et al. (1999) reported prenatal diagnosis of an affected fetus
based on DNA analysis in chorionic villus tissue in a family where the
proband had previously been shown to carry the 1170insT mutation
(232050.0004) and a private leu519-to-pro (L519P) mutation in the PCCB
gene. Muro et al. (1999) also assessed carrier status in this family by
DNA analysis.
CLINICAL MANAGEMENT
The severe metabolic ketoacidosis in this disorder requires vigorous
alkali therapy and protein restriction. Oral antibiotic therapy to
reduce gut propionate production may also prove useful (Fenton et al.,
2001).
Van Calcar et al. (1992) described a 22-year-old woman whose first
episode of acute acidosis occurred at age 6 months following an upper
respiratory infection; diagnosis of propionic acidemia was delayed until
the age of 6.5 years. They gave detailed information on her pregnancy,
which resulted in the birth of a healthy infant.
MOLECULAR GENETICS
Ugarte et al. (1999) reviewed mutations in the PCCA and PCCB genes. A
total of 24 PCCA mutations had been reported, mostly missense point
mutations and a variety of splicing defects. No mutation was predominant
in the Caucasian or Oriental populations studied.
Among 10 patients with propionic acidemia, Desviat et al. (2006)
identified 4 different PCCA splice site mutations and 3 different PCCB
splice site mutations. The authors emphasized the different molecular
effects of splicing mutations and the possible phenotypic consequences.
*FIELD* SA
Ando et al. (1971); Barnes et al. (1970); Gompertz et al. (1975);
Nyhan et al. (1961); Nyhan et al. (1963); Ravn et al. (2000); Steinman
et al. (1983); Wolf et al. (1979)
*FIELD* RF
1. Al Essa, M.; Rahbeeni, Z.; Jumaah, S.; Joshi, S.; Al Jishi, E.;
Rashed, M. S.; Al Amoudi, M.; Ozand, P. T.: Infectious complications
of propionic acidemia in Saudia (sic) Arabia. Clin. Genet. 54: 90-94,
1998.
2. Ando, T.; Rasmussen, K.; Nyhan, W. L.; Donnell, G. N.; Barnes,
N. D.: Propionicacidemia in patients with ketotic hyperglycinemia. J.
Pediat. 78: 827-832, 1971.
3. Barnes, N. D.; Hull, D.; Balgobin, L.; Gompertz, D.: Biotin-responsive
propionicacidaemia. Lancet 296: 244-245, 1970. Note: Originally
Volume II.
4. Brandt, I. K.; Hsia, E.; Clement, D. H.; Provence, S. A.: Propionicacidemia
(ketotic hyperglycinemia): dietary treatment resulting in normal growth
and development. Pediatrics 53: 391-395, 1974.
5. Buchanan, P. D.; Kahler, S. G.; Sweetman, L.; Nyhan, W. L.: Pitfalls
in the prenatal diagnosis of propionic acidemia. Clin. Genet. 18:
177-183, 1980.
6. Childs, B.; Nyhan, W. L.; Borden, M.; Bard, L.; Cooke, R. E.:
Idiopathic hyperglycinemia and hyperglycinuria: a new disorder of
amino acid metabolism. Pediatrics 27: 522-538, 1961.
7. Desviat, L. R.; Clavero, S.; Perez-Cerda, C.; Navarrete, R.; Ugarte,
M.; Perez, B.: New splicing mutations in propionic acidemia. J.
Hum. Genet. 51: 992-997, 2006.
8. Fenton, W. A.; Gravel, R. A.; Rosenblatt, D. S.: Disorders of
propionate and methylmalonate metabolism.In: Scriver, C. R.; Beaudet,
A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular
Bases of Inherited Disease. Vol. II. (8th ed.) New York: McGraw-Hill
2001. P. 2176.
9. Gompertz, D.; Bau, D. C. K.; Storrs, C. N.; Peters, T. J.; Hughes,
E. A.: Localisation of enzymic defect in propionicacidaemia. Lancet 295:
1140-1143, 1970. Note: Originally Volume I.
10. Gompertz, D.; Goodey, P. A.; Thom, H.; Russell, G.; Johnston,
A. W.; Mellor, D. H.; MacLean, M. W.; Ferguson-Smith, M. E.; Ferguson-Smith,
M. A.: Prenatal diagnosis and family studies in a case of propionicacidaemia. Clin.
Genet. 8: 244-250, 1975.
11. Hillman, R. E.; Keating, J. P.; Williams, J. C.: Biotin-responsive
propionic acidemia presenting as the rumination syndrome. J. Pediat. 92:
439-441, 1978.
12. Hommes, F. A.; Kuipers, J. R. G.; Elema, J. D.; Jansen, J. F.;
Jonxis, J. H. P.: Propionicacidemia, a new inborn error of metabolism. Pediat.
Res. 2: 519-524, 1968.
13. Hsia, Y. E.; Scully, K. J.; Rosenberg, L. E.: Inherited propionyl-CoA
carboxylase deficiency in 'ketotic hyperglycinemia'. J. Clin. Invest. 50:
127-130, 1971.
14. Hsia, Y. E.; Scully, K. J.; Rosenberg, L. E.: Defective propionate
carboxylation in ketotic hyperglycinaemia. Lancet 293: 757-758,
1969. Note: Originally Volume I.
15. Lamhonwah, A.-M.; Gravel, R. A.: Propionicacidemia: absence of
alpha-chain mRNA in fibroblasts from patients of the pccA complementation
group. Am. J. Hum. Genet. 41: 1124-1131, 1987.
16. Muro, S.; Perez-Cerda, C.; Rodriguez-Pombo, P.; Perez, B.; Briones,
P.; Ribes, A.; Ugarte, M.: Feasibility of DNA based methods for prenatal
diagnosis and carrier detection of propionic acidaemia. J. Med. Genet. 36:
412-414, 1999.
17. Nyhan, W. L.; Borden, M.; Childs, B.: Idiopathic hyperglycinemia:
a new disorder of amino-acids metabolism. II. The concentrations of
other amino-acids in the plasma and their modification by the administration
of leucine. Pediatrics 27: 539-550, 1961.
18. Nyhan, W. L.; Chisolm, J. J., Jr.; Edwards, R. O., Jr.: Idiopathic
hyperglycinuria. III. Report of a second case. J. Pediat. 62: 540-545,
1963.
19. Ohura, T.; Kraus, J. P.; Rosenberg, L. E.: Unequal synthesis
and differential degradation of propionyl CoA carboxylase subunits
in cells from normal and propionic acidemia patients. Am. J. Hum.
Genet. 45: 33-40, 1989.
20. Ohura, T.; Miyabayashi, S.; Narisawa, K.; Tada, K.: Genetic heterogeneity
of propionic acidemia: analysis of 15 Japanese patients. Hum. Genet. 87:
41-44, 1991.
21. Perez-Cerda, C.; Merinero, B.; Sanz, P.; Jimenez, A.; Garcia,
M. J.; Urbon, A.; Diaz Recasens, J.; Ramos, C.; Ayuso, C.; Ugarte,
M.: Successful first trimester diagnosis in a pregnancy at risk for
propionic acidaemia. J. Inherit. Metab. Dis. 12 (suppl. 2): 274-276,
1989.
22. Ravn, K.; Chloupkova, M.; Christensen, E.; Brandt, N. J.; Simonsen,
H.; Kraus, J. P.; Nielsen, I. M.; Skovby, F.; Schwartz, M.: High
incidence of propionic acidemia in Greenland is due to a prevalent
mutation, 1540insCCC, in the gene for the beta-subunit of propionyl
CoA carboxylase. Am. J. Hum. Genet. 67: 203-206, 2000. Note: Erratum:
Am. J. Hum. Genet. 67: 270 only, 2000.
23. Soriano, J. R.; Taitz, L. S.; Finberg, L.; Edelmann, C. M., Jr.
: Hyperglycinemia with ketoacidosis and leukopenia. Pediatrics 39:
818-828, 1967.
24. Steinman, L.; Clancy, R. R.; Cann, H.; Urich, H.: The neuropathology
of propionic acidemia. Dev. Med. Child Neurol. 25: 87-94, 1983.
25. Testai, F. D.; Gorelick, P. B.: Inherited metabolic disorders
and stroke part 2: homocystinuria, organic acidurias, and urea cycle
disorders. Arch. Neurol. 67: 148-153, 2010.
26. Ugarte, M.; Perez-Cerda, C.; Rodriguez-Pombo, P.; Desviat, L.
R.; Perez, B.; Richard, E.; Muro, S.; Campeau, E.; Ohura, T.; Gravel,
R. A.: Overview of mutations in the PCCA and PCCB genes causing propionic
acidemia. Hum. Genet. 14: 275-282, 1999.
27. Van Calcar, S. C.; Harding, C. O.; Davidson, S. R.; Barness, L.
A.; Wolff, J. A.: Case reports of successful pregnancy in women with
maple syrup urine disease and propionic acidemia. Am. J. Med. Genet. 44:
641-646, 1992.
28. Wolf, B.: Personal Communication. Richmond, Va. 1/2/1986.
29. Wolf, B.; Feldman, G. L.: The biotin-dependent carboxylase deficiencies. Am.
J. Hum. Genet. 34: 699-716, 1982.
30. Wolf, B.; Hsia, Y. E.: Biotin responsiveness in propionicacidaemia.
(Letter) Lancet 312: 901 only, 1978. Note: Originally Volume II.
31. Wolf, B.; Paulsen, E. P.; Hsia, Y. E.: Asymptomatic propionyl
CoA carboxylase deficiency in a 13-year-old girl. J. Pediat. 95:
563-565, 1979.
32. Wolf, B.; Willard, H. F.; Rosenberg, L. E.: Kinetic analysis
genetic complementation in heterokaryons of propionyl CoA carboxylase-deficient
human fibroblasts. Am. J. Hum. Genet. 32: 16-25, 1980.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature;
[Other];
Failure to thrive
CARDIOVASCULAR:
[Heart];
Cardiomyopathy
RESPIRATORY:
Tachypnea;
Apnea
ABDOMEN:
[Liver];
Hepatomegaly;
[Pancreas];
Pancreatitis;
[Gastrointestinal];
Decreased appetite;
Feeding difficulties;
Vomiting;
Dehydration
SKELETAL:
Osteoporosis
SKIN, NAILS, HAIR:
[Skin];
Dermatitis acidemica
NEUROLOGIC:
[Central nervous system];
Acute encephalopathy;
Lethargy;
Axial hypotonia;
Limb hypertonia;
Coma;
Seizure;
Psychomotor retardation;
Cerebral atrophy;
Dystonia;
Cerebellar hemorrhage (rare);
Ischemic stroke in the basal ganglia (rare)
METABOLIC FEATURES:
Metabolic acidosis
HEMATOLOGY:
Pancytopenia;
Neutropenia;
Anemia;
Thrombocytopenia
LABORATORY ABNORMALITIES:
Hyperammonemia;
Lactic acidosis;
Elevated propionate;
Elevated 3-hydroxypropionic acid;
Elevated 3-methylcitric acid;
Hyperglycinemia;
Hyperglycinuria;
Serum carnitine deficiency;
Propionyl-CoA carboxylase deficiency;
Hypoglycemia
MISCELLANEOUS:
Majority of patients develop symptoms within the first few weeks of
life;
Two complementation groups - pccA (secondary to defects in the alpha
chain of PCC, 232000) and pccBC (secondary to defects in the beta
subunit of PCC, 232050);
Course characterized by repeated relapses precipitated by excessive
protein intake, intercurrent infection, or constipation
MOLECULAR BASIS:
Caused by mutation in the propionyl Coenzyme A carboxylase, alpha
polypeptide gene (PCCA, 232000.0001);
Caused by mutation in the propionyl Coenzyme A carboxylase, beta polypeptide
gene (PCCB, 232050.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 10/11/2010
*FIELD* CD
Kelly A. Przylepa: 7/2/2002
*FIELD* ED
joanna: 07/17/2012
ckniffin: 10/11/2010
joanna: 1/18/2010
ckniffin: 5/16/2007
joanna: 7/3/2002
joanna: 7/2/2002
*FIELD* CN
Cassandra L. Kniffin - updated: 10/11/2010
Cassandra L. Kniffin - updated: 3/16/2007
*FIELD* CD
Ada Hamosh: 6/21/2001
*FIELD* ED
wwang: 10/29/2010
ckniffin: 10/11/2010
terry: 5/12/2010
terry: 4/3/2009
wwang: 4/2/2007
ckniffin: 3/16/2007
terry: 4/7/2005
ckniffin: 11/23/2004
mcapotos: 12/21/2001
carol: 6/22/2001
*RECORD*
*FIELD* NO
606054
*FIELD* TI
#606054 PROPIONIC ACIDEMIA
;;PROPIONYL-CoA CARBOXYLASE DEFICIENCY;;
PCC DEFICIENCY;;
read moreGLYCINEMIA, KETOTIC;;
HYPERGLYCINEMIA WITH KETOACIDOSIS AND LEUKOPENIA;;
KETOTIC HYPERGLYCINEMIA
*FIELD* TX
A number sign (#) is used with this entry because propionic acidemia is
caused by mutation in the genes encoding propionyl-CoA carboxylase, PCCA
(232000) or PCCB (232050). Cells from patients with mutations in the
PCCA gene fall into complementation group pccA. Cells from patients with
mutations in the PCCB gene fall into complementation group pccBC.
Mutations in the pccB subgroup occur in the N terminus of the PCCB gene,
which includes the biotin-binding site, whereas mutations in the pccC
subgroup occur in the C terminus of the PCCB gene (Fenton et al., 2001).
CLINICAL FEATURES
The features of propionic acidemia are episodic vomiting, lethargy and
ketosis, neutropenia, periodic thrombocytopenia, hypogammaglobulinemia,
developmental retardation, and intolerance to protein. Outstanding
chemical features are hyperglycinemia and hyperglycinuria. This disorder
is not to be confused with hereditary glycinuria (138500), which is
presumably transmitted as a dominant.
Soriano et al. (1967) suggested that in the disorder first described by
Childs et al. (1961), a generalized defect in utilization of amino acids
results in excessive deamination of certain amino acids in muscle, with
consequent hyperammonemia and ketoacidosis. In a second group of
patients whose disorder is also termed hyperglycinemia, ketoacidosis,
neutropenia, and thrombocytopenia have not been observed and glycine is
the only amino acid present in excess in serum and urine; see glycine
encephalopathy (605899).
Hsia et al. (1969) studied fibroblasts from a sister of the boy
described by Childs et al. (1961) and demonstrated deficient propionate
carboxylation as the basic defect in ketotic hyperglycinemia. Hsia et
al. (1971) also showed that 'ketotic hyperglycinemia' is the same as
propionic acidemia and is the result of a defect in PCC. In further
studies on this patient, Brandt et al. (1974) demonstrated that with low
protein diet, growth and intelligence developed normally to age 9 years;
indeed, intelligence was superior. The family originally reported by
Childs et al. (1961) had the pccA type of propionic acidemia (Wolf,
1986).
In a male Pakistani offspring of first-cousin parents, Gompertz et al.
(1970) described acidosis and ketosis due to propionic acidemia, leading
to death at 8 days of age. A sib had died at 2 weeks of age with
metabolic acidosis and ketonuria. The defect was found to involve
mitochondrial propionyl-CoA carboxylase. The same condition was
described by Hommes et al. (1968).
Al Essa et al. (1998) pointed out that not only do acute intercurrent
infections precipitate acidosis in propionic acidemia, but such
infections are unusually frequent in propionic acidemia in Saudi Arabia.
Propionic acidemia is unusually frequent in Saudi Arabia, with a
frequency of 1 in 2,000 to 1 in 5,000, depending on the region. The
disorder has a severe phenotype in Saudi Arabia. Al Essa et al. (1998)
had information on approximately 90 patients; certain tribes accounted
for almost 80% of these cases, suggesting a founder effect. The number
of other cases of organic acidemias observed during the same period was
656. Longitudinal data, in some instances up to 8 years, were available
for 38 patients with propionic acidemia. A high frequency of infections
was observed in 80% of the patients. Most microorganisms implicated were
unusual, suggesting an underlying immune deficiency. The infections
occurred despite aggressive treatment with appropriate diets, carnitine,
and, during acute episodes of the disease, with metronidazole, which
suggested a global effect of the disease on T and B lymphocytes as well
as on the bone marrow cells.
In a review of inherited metabolic disorders and stroke, Testai and
Gorelick (2010) noted that patients with branched-chain organic
aciduria, including isovaleric aciduria (243500), propionic aciduria,
and methylmalonic aciduria (251000) can rarely have strokes. Cerebellar
hemorrhage has been described in all 3 disorders, and basal ganglia
ischemic stroke has been described in propionic aciduria and
methylmalonic aciduria. These events may occur in the absence of
metabolic decompensation.
BIOCHEMICAL FEATURES
Hillman et al. (1978) observed biotin-responsive propionic acidemia.
Wolf and Hsia (1978) suggested that biotin-responsiveness can be tested
by measuring propionyl-CoA carboxylase and beta-methylcrotonyl CoA
carboxylase (see 609010 and 609014) in peripheral blood leukocytes
before and after biotin. From kinetic analysis of complementations in
heterokaryons of propionyl CoA carboxylase-deficient fibroblasts, Wolf
et al. (1980) concluded that the 'bio' and 'pcc' mutations affect
different genes; that complementation between pccA and pccB, pccC or
pccBC lines is intergenic with subunit exchange and synthesis of new
carboxylase molecules and that complementation between pccB and pccC
mutants is interallelic. Wolf and Feldman (1982) considered it likely
that the pccBC complementation group reflects mutations of the alpha
subunit and the pccA group mutations of the beta subunit.
Using cDNA clones coding for the alpha and beta chains as probes,
Lamhonwah and Gravel (1987) found absence of alpha mRNA in 4 of 6 pccA
strains and the presence of beta mRNA in all pccA mutants studied. They
also found the presence of both alpha and beta mRNAs in 3 pccBC, 2 pccB,
and 3 pccC mutants. Ohura et al. (1989) presented evidence from which
they concluded that beta-chain subunits of propionyl-CoA carboxylase are
normally synthesized and imported into the mitochondria in excess of
alpha-chain subunits, but only that portion assembled with alpha
subunits escapes degradation. In pccA patients, the primary defect in
alpha-chain synthesis leads secondarily to degradation of normally
synthesized beta chains. The differential rates of synthesis of alpha
and beta chains appear to account for the finding that persons
heterozygous for pccBC mutations have normal carboxylase activity in
their cells. Among 15 Japanese patients with propionic acidemia, Ohura
et al. (1991) found that both the alpha and beta subunits were absent in
3 and low in 3 others; according to their previous data, they concluded
that these 6 patients had an alpha-subunit defect. In 8 other patients,
alpha subunits were normal, but the beta subunits were aberrant; these
patients were considered to have beta-subunit defects. One of the 15
patients had apparently normal alpha and beta subunits. An altered MspI
restriction pattern for PCCB cDNA, consisting of a unique 2.7-kb band,
was found in 3 patients with beta-subunit deficiency.
DIAGNOSIS
- Prenatal Diagnosis
Buchanan et al. (1980) pointed out that propionic acidemia can be
diagnosed either by an elevated quantity of the metabolite methylcitrate
in amniotic fluid or by deficient activity of propionyl-CoA carboxylase
in amniocytes. Contamination by maternal cells can give a normal value
for the latter determination; methylcitrate assay may be the most
reliable approach. Perez-Cerda et al. (1989) successfully diagnosed PCC
deficiency in the first trimester of pregnancy by direct enzyme assay in
uncultured chorionic villi.
Muro et al. (1999) reported prenatal diagnosis of an affected fetus
based on DNA analysis in chorionic villus tissue in a family where the
proband had previously been shown to carry the 1170insT mutation
(232050.0004) and a private leu519-to-pro (L519P) mutation in the PCCB
gene. Muro et al. (1999) also assessed carrier status in this family by
DNA analysis.
CLINICAL MANAGEMENT
The severe metabolic ketoacidosis in this disorder requires vigorous
alkali therapy and protein restriction. Oral antibiotic therapy to
reduce gut propionate production may also prove useful (Fenton et al.,
2001).
Van Calcar et al. (1992) described a 22-year-old woman whose first
episode of acute acidosis occurred at age 6 months following an upper
respiratory infection; diagnosis of propionic acidemia was delayed until
the age of 6.5 years. They gave detailed information on her pregnancy,
which resulted in the birth of a healthy infant.
MOLECULAR GENETICS
Ugarte et al. (1999) reviewed mutations in the PCCA and PCCB genes. A
total of 24 PCCA mutations had been reported, mostly missense point
mutations and a variety of splicing defects. No mutation was predominant
in the Caucasian or Oriental populations studied.
Among 10 patients with propionic acidemia, Desviat et al. (2006)
identified 4 different PCCA splice site mutations and 3 different PCCB
splice site mutations. The authors emphasized the different molecular
effects of splicing mutations and the possible phenotypic consequences.
*FIELD* SA
Ando et al. (1971); Barnes et al. (1970); Gompertz et al. (1975);
Nyhan et al. (1961); Nyhan et al. (1963); Ravn et al. (2000); Steinman
et al. (1983); Wolf et al. (1979)
*FIELD* RF
1. Al Essa, M.; Rahbeeni, Z.; Jumaah, S.; Joshi, S.; Al Jishi, E.;
Rashed, M. S.; Al Amoudi, M.; Ozand, P. T.: Infectious complications
of propionic acidemia in Saudia (sic) Arabia. Clin. Genet. 54: 90-94,
1998.
2. Ando, T.; Rasmussen, K.; Nyhan, W. L.; Donnell, G. N.; Barnes,
N. D.: Propionicacidemia in patients with ketotic hyperglycinemia. J.
Pediat. 78: 827-832, 1971.
3. Barnes, N. D.; Hull, D.; Balgobin, L.; Gompertz, D.: Biotin-responsive
propionicacidaemia. Lancet 296: 244-245, 1970. Note: Originally
Volume II.
4. Brandt, I. K.; Hsia, E.; Clement, D. H.; Provence, S. A.: Propionicacidemia
(ketotic hyperglycinemia): dietary treatment resulting in normal growth
and development. Pediatrics 53: 391-395, 1974.
5. Buchanan, P. D.; Kahler, S. G.; Sweetman, L.; Nyhan, W. L.: Pitfalls
in the prenatal diagnosis of propionic acidemia. Clin. Genet. 18:
177-183, 1980.
6. Childs, B.; Nyhan, W. L.; Borden, M.; Bard, L.; Cooke, R. E.:
Idiopathic hyperglycinemia and hyperglycinuria: a new disorder of
amino acid metabolism. Pediatrics 27: 522-538, 1961.
7. Desviat, L. R.; Clavero, S.; Perez-Cerda, C.; Navarrete, R.; Ugarte,
M.; Perez, B.: New splicing mutations in propionic acidemia. J.
Hum. Genet. 51: 992-997, 2006.
8. Fenton, W. A.; Gravel, R. A.; Rosenblatt, D. S.: Disorders of
propionate and methylmalonate metabolism.In: Scriver, C. R.; Beaudet,
A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular
Bases of Inherited Disease. Vol. II. (8th ed.) New York: McGraw-Hill
2001. P. 2176.
9. Gompertz, D.; Bau, D. C. K.; Storrs, C. N.; Peters, T. J.; Hughes,
E. A.: Localisation of enzymic defect in propionicacidaemia. Lancet 295:
1140-1143, 1970. Note: Originally Volume I.
10. Gompertz, D.; Goodey, P. A.; Thom, H.; Russell, G.; Johnston,
A. W.; Mellor, D. H.; MacLean, M. W.; Ferguson-Smith, M. E.; Ferguson-Smith,
M. A.: Prenatal diagnosis and family studies in a case of propionicacidaemia. Clin.
Genet. 8: 244-250, 1975.
11. Hillman, R. E.; Keating, J. P.; Williams, J. C.: Biotin-responsive
propionic acidemia presenting as the rumination syndrome. J. Pediat. 92:
439-441, 1978.
12. Hommes, F. A.; Kuipers, J. R. G.; Elema, J. D.; Jansen, J. F.;
Jonxis, J. H. P.: Propionicacidemia, a new inborn error of metabolism. Pediat.
Res. 2: 519-524, 1968.
13. Hsia, Y. E.; Scully, K. J.; Rosenberg, L. E.: Inherited propionyl-CoA
carboxylase deficiency in 'ketotic hyperglycinemia'. J. Clin. Invest. 50:
127-130, 1971.
14. Hsia, Y. E.; Scully, K. J.; Rosenberg, L. E.: Defective propionate
carboxylation in ketotic hyperglycinaemia. Lancet 293: 757-758,
1969. Note: Originally Volume I.
15. Lamhonwah, A.-M.; Gravel, R. A.: Propionicacidemia: absence of
alpha-chain mRNA in fibroblasts from patients of the pccA complementation
group. Am. J. Hum. Genet. 41: 1124-1131, 1987.
16. Muro, S.; Perez-Cerda, C.; Rodriguez-Pombo, P.; Perez, B.; Briones,
P.; Ribes, A.; Ugarte, M.: Feasibility of DNA based methods for prenatal
diagnosis and carrier detection of propionic acidaemia. J. Med. Genet. 36:
412-414, 1999.
17. Nyhan, W. L.; Borden, M.; Childs, B.: Idiopathic hyperglycinemia:
a new disorder of amino-acids metabolism. II. The concentrations of
other amino-acids in the plasma and their modification by the administration
of leucine. Pediatrics 27: 539-550, 1961.
18. Nyhan, W. L.; Chisolm, J. J., Jr.; Edwards, R. O., Jr.: Idiopathic
hyperglycinuria. III. Report of a second case. J. Pediat. 62: 540-545,
1963.
19. Ohura, T.; Kraus, J. P.; Rosenberg, L. E.: Unequal synthesis
and differential degradation of propionyl CoA carboxylase subunits
in cells from normal and propionic acidemia patients. Am. J. Hum.
Genet. 45: 33-40, 1989.
20. Ohura, T.; Miyabayashi, S.; Narisawa, K.; Tada, K.: Genetic heterogeneity
of propionic acidemia: analysis of 15 Japanese patients. Hum. Genet. 87:
41-44, 1991.
21. Perez-Cerda, C.; Merinero, B.; Sanz, P.; Jimenez, A.; Garcia,
M. J.; Urbon, A.; Diaz Recasens, J.; Ramos, C.; Ayuso, C.; Ugarte,
M.: Successful first trimester diagnosis in a pregnancy at risk for
propionic acidaemia. J. Inherit. Metab. Dis. 12 (suppl. 2): 274-276,
1989.
22. Ravn, K.; Chloupkova, M.; Christensen, E.; Brandt, N. J.; Simonsen,
H.; Kraus, J. P.; Nielsen, I. M.; Skovby, F.; Schwartz, M.: High
incidence of propionic acidemia in Greenland is due to a prevalent
mutation, 1540insCCC, in the gene for the beta-subunit of propionyl
CoA carboxylase. Am. J. Hum. Genet. 67: 203-206, 2000. Note: Erratum:
Am. J. Hum. Genet. 67: 270 only, 2000.
23. Soriano, J. R.; Taitz, L. S.; Finberg, L.; Edelmann, C. M., Jr.
: Hyperglycinemia with ketoacidosis and leukopenia. Pediatrics 39:
818-828, 1967.
24. Steinman, L.; Clancy, R. R.; Cann, H.; Urich, H.: The neuropathology
of propionic acidemia. Dev. Med. Child Neurol. 25: 87-94, 1983.
25. Testai, F. D.; Gorelick, P. B.: Inherited metabolic disorders
and stroke part 2: homocystinuria, organic acidurias, and urea cycle
disorders. Arch. Neurol. 67: 148-153, 2010.
26. Ugarte, M.; Perez-Cerda, C.; Rodriguez-Pombo, P.; Desviat, L.
R.; Perez, B.; Richard, E.; Muro, S.; Campeau, E.; Ohura, T.; Gravel,
R. A.: Overview of mutations in the PCCA and PCCB genes causing propionic
acidemia. Hum. Genet. 14: 275-282, 1999.
27. Van Calcar, S. C.; Harding, C. O.; Davidson, S. R.; Barness, L.
A.; Wolff, J. A.: Case reports of successful pregnancy in women with
maple syrup urine disease and propionic acidemia. Am. J. Med. Genet. 44:
641-646, 1992.
28. Wolf, B.: Personal Communication. Richmond, Va. 1/2/1986.
29. Wolf, B.; Feldman, G. L.: The biotin-dependent carboxylase deficiencies. Am.
J. Hum. Genet. 34: 699-716, 1982.
30. Wolf, B.; Hsia, Y. E.: Biotin responsiveness in propionicacidaemia.
(Letter) Lancet 312: 901 only, 1978. Note: Originally Volume II.
31. Wolf, B.; Paulsen, E. P.; Hsia, Y. E.: Asymptomatic propionyl
CoA carboxylase deficiency in a 13-year-old girl. J. Pediat. 95:
563-565, 1979.
32. Wolf, B.; Willard, H. F.; Rosenberg, L. E.: Kinetic analysis
genetic complementation in heterokaryons of propionyl CoA carboxylase-deficient
human fibroblasts. Am. J. Hum. Genet. 32: 16-25, 1980.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature;
[Other];
Failure to thrive
CARDIOVASCULAR:
[Heart];
Cardiomyopathy
RESPIRATORY:
Tachypnea;
Apnea
ABDOMEN:
[Liver];
Hepatomegaly;
[Pancreas];
Pancreatitis;
[Gastrointestinal];
Decreased appetite;
Feeding difficulties;
Vomiting;
Dehydration
SKELETAL:
Osteoporosis
SKIN, NAILS, HAIR:
[Skin];
Dermatitis acidemica
NEUROLOGIC:
[Central nervous system];
Acute encephalopathy;
Lethargy;
Axial hypotonia;
Limb hypertonia;
Coma;
Seizure;
Psychomotor retardation;
Cerebral atrophy;
Dystonia;
Cerebellar hemorrhage (rare);
Ischemic stroke in the basal ganglia (rare)
METABOLIC FEATURES:
Metabolic acidosis
HEMATOLOGY:
Pancytopenia;
Neutropenia;
Anemia;
Thrombocytopenia
LABORATORY ABNORMALITIES:
Hyperammonemia;
Lactic acidosis;
Elevated propionate;
Elevated 3-hydroxypropionic acid;
Elevated 3-methylcitric acid;
Hyperglycinemia;
Hyperglycinuria;
Serum carnitine deficiency;
Propionyl-CoA carboxylase deficiency;
Hypoglycemia
MISCELLANEOUS:
Majority of patients develop symptoms within the first few weeks of
life;
Two complementation groups - pccA (secondary to defects in the alpha
chain of PCC, 232000) and pccBC (secondary to defects in the beta
subunit of PCC, 232050);
Course characterized by repeated relapses precipitated by excessive
protein intake, intercurrent infection, or constipation
MOLECULAR BASIS:
Caused by mutation in the propionyl Coenzyme A carboxylase, alpha
polypeptide gene (PCCA, 232000.0001);
Caused by mutation in the propionyl Coenzyme A carboxylase, beta polypeptide
gene (PCCB, 232050.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 10/11/2010
*FIELD* CD
Kelly A. Przylepa: 7/2/2002
*FIELD* ED
joanna: 07/17/2012
ckniffin: 10/11/2010
joanna: 1/18/2010
ckniffin: 5/16/2007
joanna: 7/3/2002
joanna: 7/2/2002
*FIELD* CN
Cassandra L. Kniffin - updated: 10/11/2010
Cassandra L. Kniffin - updated: 3/16/2007
*FIELD* CD
Ada Hamosh: 6/21/2001
*FIELD* ED
wwang: 10/29/2010
ckniffin: 10/11/2010
terry: 5/12/2010
terry: 4/3/2009
wwang: 4/2/2007
ckniffin: 3/16/2007
terry: 4/7/2005
ckniffin: 11/23/2004
mcapotos: 12/21/2001
carol: 6/22/2001