RBCC Red Blood Cell Collection

PCCA [Confidence: low (only semi-automatic identification from reviews)]
Propionyl-CoA carboxylase alpha chain, mitochondrial; PCCase subunit alpha; 6.4.1.3 (Propanoyl-CoA:carbon dioxide ligase subunit alpha; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P05165
ID PCCA_HUMAN Reviewed; 728 AA.
AC P05165; B4DKY8; B4DPF9; C9JPQ8; Q15979; Q8WXQ7;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
read moreDT 05-OCT-2010, sequence version 4.
DT 22-JAN-2014, entry version 165.
DE RecName: Full=Propionyl-CoA carboxylase alpha chain, mitochondrial;
DE Short=PCCase subunit alpha;
DE EC=6.4.1.3;
DE AltName: Full=Propanoyl-CoA:carbon dioxide ligase subunit alpha;
DE Flags: Precursor;
GN Name=PCCA;
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 [GENOMIC DNA / MRNA] (ISOFORM 1).
RX PubMed=11592820; DOI=10.1006/mgme.2001.3210;
RA Campeau E., Desviat L.R., Leclerc D., Wu X., Perez B., Ugarte M.,
RA Gravel R.A.;
RT "Structure of the PCCA gene and distribution of mutations causing
RT propionic acidemia.";
RL Mol. Genet. Metab. 74:238-247(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
RC TISSUE=Kidney, and Tongue;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057823; DOI=10.1038/nature02379;
RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L.,
RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E.,
RA Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T.,
RA Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R.,
RA Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S.,
RA Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M.,
RA Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J.,
RA Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E.,
RA Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L.,
RA Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J.,
RA Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S.,
RA Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J.,
RA Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M.,
RA King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A.,
RA Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S.,
RA Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S.,
RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S.,
RA Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A.,
RA Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L.,
RA Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M.,
RA Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T.;
RT "The DNA sequence and analysis of human chromosome 13.";
RL Nature 428:522-528(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 9-728 (ISOFORM 1).
RC TISSUE=Placenta;
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 [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 10-728 (ISOFORM 1).
RX PubMed=2740237; DOI=10.1093/nar/17.11.4396;
RA Lamhonwah A.-M., Mahuran D.J., Gravel R.A.;
RT "Human mitochondrial propionyl-CoA carboxylase: localization of the N-
RT terminus of the pro- and mature alpha chains in the deduced primary
RT sequence of a full-length cDNA.";
RL Nucleic Acids Res. 17:4396-4396(1989).
RN [7]
RP SEQUENCE REVISION.
RA Gravel R.A.;
RL Submitted (APR-1993) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP PROTEIN SEQUENCE OF 53-58, 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 [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 364-392.
RC TISSUE=Liver;
RX PubMed=8434582;
RA Stankovics J., Ledley F.D.;
RT "Cloning of functional alpha propionyl CoA carboxylase and correction
RT of enzyme deficiency in pccA fibroblasts.";
RL Am. J. Hum. Genet. 52:144-151(1993).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 369-561.
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 [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 633-728.
RX PubMed=3555348; DOI=10.1016/0003-9861(87)90146-9;
RA Lamhonwah A.-M., Quan F., Gravel R.A.;
RT "Sequence homology around the biotin-binding site of human propionyl-
RT CoA carboxylase and pyruvate carboxylase.";
RL Arch. Biochem. Biophys. 254:631-636(1987).
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 STRUCTURE BY NMR OF 175-270.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of B domain from human propionyl-CoA carboxylase
RT alpha subunit.";
RL Submitted (NOV-2005) to the PDB data bank.
RN [14]
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 [15]
RP VARIANTS PA-1 TRP-77; THR-138; THR-164; LYS-373 AND ARG-631.
RX PubMed=10101253; DOI=10.1016/S0925-4439(99)00008-3;
RA Richard E., Desviat L.R., Perez B., Perez-Cerda C., Ugarte M.;
RT "Genetic heterogeneity in propionic acidemia patients with alpha-
RT subunit defects: identification of five novel mutations, one of them
RT causing instability of the protein.";
RL Biochim. Biophys. Acta 1453:351-358(1999).
RN [16]
RP VARIANT PHE-551, AND VARIANT PA-1 LEU-532 DEL.
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 [17]
RP VARIANTS PA-1 TRP-77; GLU-197; ARG-297; ARG-398; GLN-399; LEU-423 AND
RP LEU-559.
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).
RN [18]
RP VARIANTS PA-1 PRO-75; LYS-229; GLY-368; VAL-379; ARG-668 AND CYS-712
RP DEL.
RX PubMed=10329019; DOI=10.1006/mgme.1999.2850;
RA Campeau E., Dupuis L., Leon-Del-Rio A., Gravel R.;
RT "Coding sequence mutations in the alpha subunit of propionyl-CoA
RT carboxylase in patients with propionic acidemia.";
RL Mol. Genet. Metab. 67:11-22(1999).
CC -!- CATALYTIC ACTIVITY: ATP + propanoyl-CoA + HCO(3)(-) = ADP +
CC phosphate + (S)-methylmalonyl-CoA.
CC -!- COFACTOR: Biotin.
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=3;
CC Name=1;
CC IsoId=P05165-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P05165-2; Sequence=VSP_039857;
CC Name=3;
CC IsoId=P05165-3; Sequence=VSP_044458;
CC -!- DISEASE: Propionic acidemia type I (PA-1) [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: Contains 1 ATP-grasp domain.
CC -!- SIMILARITY: Contains 1 biotin carboxylation domain.
CC -!- SIMILARITY: Contains 1 biotinyl-binding domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA60035.1; Type=Frameshift; Positions=374, 378, 380, 395;
CC Sequence=AAH00140.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAK61392.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=CAA32763.1; Type=Frameshift; Positions=23;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PCCA";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF385926; AAL66189.1; -; mRNA.
DR EMBL; AY035808; AAK61392.1; ALT_INIT; Genomic_DNA.
DR EMBL; AY035786; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035787; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035788; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035789; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035790; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035791; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035792; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035793; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035794; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035795; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035796; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035797; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035798; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035799; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035800; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035801; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035802; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035803; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035804; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035805; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035806; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AY035807; AAK61392.1; JOINED; Genomic_DNA.
DR EMBL; AK296771; BAG59350.1; -; mRNA.
DR EMBL; AK298318; BAG60571.1; -; mRNA.
DR EMBL; AL355338; CAH70370.2; -; Genomic_DNA.
DR EMBL; AL136526; CAH70370.2; JOINED; Genomic_DNA.
DR EMBL; AL353697; CAH70370.2; JOINED; Genomic_DNA.
DR EMBL; AL356575; CAH70370.2; JOINED; Genomic_DNA.
DR EMBL; AL356575; CAH72681.2; -; Genomic_DNA.
DR EMBL; AL136526; CAH72681.2; JOINED; Genomic_DNA.
DR EMBL; AL353697; CAH72681.2; JOINED; Genomic_DNA.
DR EMBL; AL355338; CAH72681.2; JOINED; Genomic_DNA.
DR EMBL; AL136526; CAI39557.2; -; Genomic_DNA.
DR EMBL; AL353697; CAI39557.2; JOINED; Genomic_DNA.
DR EMBL; AL355338; CAI39557.2; JOINED; Genomic_DNA.
DR EMBL; AL356575; CAI39557.2; JOINED; Genomic_DNA.
DR EMBL; AL353697; CAI40434.2; -; Genomic_DNA.
DR EMBL; AL136526; CAI40434.2; JOINED; Genomic_DNA.
DR EMBL; AL355338; CAI40434.2; JOINED; Genomic_DNA.
DR EMBL; AL356575; CAI40434.2; JOINED; Genomic_DNA.
DR EMBL; CH471085; EAX09034.1; -; Genomic_DNA.
DR EMBL; BC000140; AAH00140.1; ALT_INIT; mRNA.
DR EMBL; X14608; CAA32763.1; ALT_FRAME; mRNA.
DR EMBL; S55656; AAB25345.1; -; mRNA.
DR EMBL; M13572; AAA60035.1; ALT_FRAME; mRNA.
DR EMBL; M26121; AAA36424.1; -; mRNA.
DR PIR; S04613; A27883.
DR RefSeq; NP_000273.2; NM_000282.3.
DR RefSeq; NP_001121164.1; NM_001127692.2.
DR RefSeq; NP_001171475.1; NM_001178004.1.
DR UniGene; Hs.80741; -.
DR PDB; 2CQY; NMR; -; A=169-270.
DR PDB; 2JKU; X-ray; 1.50 A; A=658-728.
DR PDBsum; 2CQY; -.
DR PDBsum; 2JKU; -.
DR ProteinModelPortal; P05165; -.
DR SMR; P05165; 63-728.
DR DIP; DIP-57493N; -.
DR IntAct; P05165; 6.
DR STRING; 9606.ENSP00000365462; -.
DR DrugBank; DB00121; Biotin.
DR PhosphoSite; P05165; -.
DR DMDM; 308153661; -.
DR PaxDb; P05165; -.
DR PRIDE; P05165; -.
DR Ensembl; ENST00000376279; ENSP00000365456; ENSG00000175198.
DR Ensembl; ENST00000376285; ENSP00000365462; ENSG00000175198.
DR Ensembl; ENST00000376286; ENSP00000365463; ENSG00000175198.
DR GeneID; 5095; -.
DR KEGG; hsa:5095; -.
DR UCSC; uc001voo.3; human.
DR CTD; 5095; -.
DR GeneCards; GC13P100741; -.
DR HGNC; HGNC:8653; PCCA.
DR HPA; HPA041716; -.
DR HPA; HPA047792; -.
DR MIM; 232000; gene.
DR MIM; 606054; phenotype.
DR neXtProt; NX_P05165; -.
DR Orphanet; 35; Propionic acidemia.
DR PharmGKB; PA32992; -.
DR eggNOG; COG4770; -.
DR HOGENOM; HOG000008989; -.
DR HOVERGEN; HBG000555; -.
DR KO; K01965; -.
DR OMA; SSTWNLA; -.
DR OrthoDB; EOG7RZ5PH; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR SABIO-RK; P05165; -.
DR UniPathway; UPA00945; UER00908.
DR ChiTaRS; PCCA; human.
DR EvolutionaryTrace; P05165; -.
DR GenomeRNAi; 5095; -.
DR NextBio; 19656; -.
DR PRO; PR:P05165; -.
DR ArrayExpress; P05165; -.
DR Bgee; P05165; -.
DR CleanEx; HS_PCCA; -.
DR Genevestigator; P05165; -.
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:0009374; F:biotin binding; TAS:ProtInc.
DR GO; GO:0004075; F:biotin carboxylase activity; IEA:InterPro.
DR GO; GO:0046872; F:metal ion binding; IEA:InterPro.
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 Gene3D; 3.30.1490.20; -; 1.
DR Gene3D; 3.30.470.20; -; 1.
DR Gene3D; 3.40.50.20; -; 1.
DR InterPro; IPR011761; ATP-grasp.
DR InterPro; IPR013815; ATP_grasp_subdomain_1.
DR InterPro; IPR013816; ATP_grasp_subdomain_2.
DR InterPro; IPR001882; Biotin_BS.
DR InterPro; IPR011764; Biotin_carboxylation_dom.
DR InterPro; IPR005482; Biotin_COase_C.
DR InterPro; IPR000089; Biotin_lipoyl.
DR InterPro; IPR005481; CarbamoylP_synth_lsu_N.
DR InterPro; IPR005479; CbamoylP_synth_lsu-like_ATP-bd.
DR InterPro; IPR016185; PreATP-grasp_dom.
DR InterPro; IPR011054; Rudment_hybrid_motif.
DR InterPro; IPR011053; Single_hybrid_motif.
DR Pfam; PF02785; Biotin_carb_C; 1.
DR Pfam; PF00364; Biotin_lipoyl; 1.
DR Pfam; PF00289; CPSase_L_chain; 1.
DR Pfam; PF02786; CPSase_L_D2; 1.
DR SMART; SM00878; Biotin_carb_C; 1.
DR SUPFAM; SSF51230; SSF51230; 1.
DR SUPFAM; SSF51246; SSF51246; 1.
DR SUPFAM; SSF52440; SSF52440; 1.
DR PROSITE; PS50975; ATP_GRASP; 1.
DR PROSITE; PS50979; BC; 1.
DR PROSITE; PS00188; BIOTIN; 1.
DR PROSITE; PS50968; BIOTINYL_LIPOYL; 1.
DR PROSITE; PS00866; CPSASE_1; 1.
DR PROSITE; PS00867; CPSASE_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; ATP-binding; Biotin;
KW Complete proteome; Direct protein sequencing; Disease mutation;
KW Ligase; Mitochondrion; Nucleotide-binding; Phosphoprotein;
KW Polymorphism; Reference proteome; Transit peptide.
FT TRANSIT 1 52 Mitochondrion.
FT CHAIN 53 728 Propionyl-CoA carboxylase alpha chain,
FT mitochondrial.
FT /FTId=PRO_0000002837.
FT DOMAIN 62 509 Biotin carboxylation.
FT DOMAIN 181 378 ATP-grasp.
FT DOMAIN 660 727 Biotinyl-binding.
FT ACT_SITE 353 353 By similarity.
FT BINDING 177 177 ATP (By similarity).
FT BINDING 261 261 ATP (By similarity).
FT BINDING 296 296 ATP (By similarity).
FT MOD_RES 65 65 N6-acetyllysine (By similarity).
FT MOD_RES 150 150 N6-acetyllysine (By similarity).
FT MOD_RES 200 200 N6-acetyllysine (By similarity).
FT MOD_RES 252 252 Phosphoserine (By similarity).
FT MOD_RES 328 328 N6-acetyllysine (By similarity).
FT MOD_RES 496 496 N6-acetyllysine (By similarity).
FT MOD_RES 694 694 N6-biotinyllysine (By similarity).
FT VAR_SEQ 36 61 Missing (in isoform 2).
FT /FTId=VSP_039857.
FT VAR_SEQ 634 680 Missing (in isoform 3).
FT /FTId=VSP_044458.
FT VARIANT 75 75 A -> P (in PA-1).
FT /FTId=VAR_009087.
FT VARIANT 77 77 R -> W (in PA-1).
FT /FTId=VAR_009088.
FT VARIANT 138 138 A -> T (in PA-1).
FT /FTId=VAR_009089.
FT VARIANT 164 164 I -> T (in PA-1).
FT /FTId=VAR_009090.
FT VARIANT 197 197 G -> E (in PA-1).
FT /FTId=VAR_023843.
FT VARIANT 229 229 M -> K (in PA-1).
FT /FTId=VAR_009091.
FT VARIANT 297 297 Q -> R (in PA-1).
FT /FTId=VAR_009092.
FT VARIANT 368 368 D -> G (in PA-1).
FT /FTId=VAR_009093.
FT VARIANT 373 373 M -> K (in PA-1; unstable protein).
FT /FTId=VAR_009094.
FT VARIANT 379 379 G -> V (in PA-1).
FT /FTId=VAR_009095.
FT VARIANT 398 398 C -> R (in PA-1).
FT /FTId=VAR_023844.
FT VARIANT 399 399 R -> Q (in PA-1).
FT /FTId=VAR_009096.
FT VARIANT 423 423 P -> L (in PA-1).
FT /FTId=VAR_009097.
FT VARIANT 475 475 I -> V (in dbSNP:rs35719359).
FT /FTId=VAR_009098.
FT VARIANT 532 532 Missing (in PA-1).
FT /FTId=VAR_023845.
FT VARIANT 551 551 V -> F (in dbSNP:rs61749895).
FT /FTId=VAR_023846.
FT VARIANT 559 559 W -> L (in PA-1; dbSNP:rs118169528).
FT /FTId=VAR_009099.
FT VARIANT 631 631 G -> R (in PA-1).
FT /FTId=VAR_009100.
FT VARIANT 668 668 G -> R (in PA-1).
FT /FTId=VAR_009101.
FT VARIANT 712 712 Missing (in PA-1).
FT /FTId=VAR_009102.
FT CONFLICT 61 61 K -> E (in Ref. 2; BAG60571).
FT CONFLICT 93 93 H -> Y (in Ref. 4; BAG59350).
FT CONFLICT 373 373 M -> R (in Ref. 10; AAA60035).
FT CONFLICT 378 379 KG -> RS (in Ref. 10; AAA60035).
FT CONFLICT 558 558 N -> H (in Ref. 10; AAA60035).
FT CONFLICT 610 610 T -> A (in Ref. 4; BAG59350).
FT CONFLICT 679 679 D -> A (in Ref. 11; AAA36424).
FT STRAND 199 201
FT HELIX 202 212
FT STRAND 214 220
FT TURN 226 228
FT STRAND 230 234
FT HELIX 235 252
FT STRAND 258 262
FT STRAND 265 268
FT STRAND 665 667
FT STRAND 669 673
FT STRAND 688 691
SQ SEQUENCE 728 AA; 80059 MW; 065F64186A0B8CCC CRC64;
MAGFWVGTAP LVAAGRRGRW PPQQLMLSAA LRTLKHVLYY SRQCLMVSRN LGSVGYDPNE
KTFDKILVAN RGEIACRVIR TCKKMGIKTV AIHSDVDASS VHVKMADEAV CVGPAPTSKS
YLNMDAIMEA IKKTRAQAVH PGYGFLSENK EFARCLAAED VVFIGPDTHA IQAMGDKIES
KLLAKKAEVN TIPGFDGVVK DAEEAVRIAR EIGYPVMIKA SAGGGGKGMR IAWDDEETRD
GFRLSSQEAA SSFGDDRLLI EKFIDNPRHI EIQVLGDKHG NALWLNEREC SIQRRNQKVV
EEAPSIFLDA ETRRAMGEQA VALARAVKYS SAGTVEFLVD SKKNFYFLEM NTRLQVEHPV
TECITGLDLV QEMIRVAKGY PLRHKQADIR INGWAVECRV YAEDPYKSFG LPSIGRLSQY
QEPLHLPGVR VDSGIQPGSD ISIYYDPMIS KLITYGSDRT EALKRMADAL DNYVIRGVTH
NIALLREVII NSRFVKGDIS TKFLSDVYPD GFKGHMLTKS EKNQLLAIAS SLFVAFQLRA
QHFQENSRMP VIKPDIANWE LSVKLHDKVH TVVASNNGSV FSVEVDGSKL NVTSTWNLAS
PLLSVSVDGT QRTVQCLSRE AGGNMSIQFL GTVYKVNILT RLAAELNKFM LEKVTEDTSS
VLRSPMPGVV VAVSVKPGDA VAEGQEICVI EAMKMQNSMT AGKTGTVKSV HCQAGDTVGE
GDLLVELE
//

MIM 232000
*RECORD*
*FIELD* NO
232000
*FIELD* TI
*232000 PROPIONYL-CoA CARBOXYLASE, ALPHA SUBUNIT; PCCA
;;pccA 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.
PCC is composed of 2 nonidentical subunits, alpha and beta. The alpha
subunit is encoded by the PCCA gene and the beta subunit (232050) by the
PCCB gene (232050). Cells from patients with propionic acidemia (606054)
with mutations in the PCCA gene fall into complementation group pccA
(Fenton et al., 2001).

CLONING

Lamhonwah et al. (1983) found that the alpha chain of PCC, which
contains the biotin ligand, has a molecular mass of 72 kD; the beta
chain, a molecular mass of 56 kD. They predicted that the beta chain is
unstable in the absence of the alpha chain. Lamhonwah et al. (1983)
presented evidence suggesting that the mutation in the pccA
complementation group resides in the alpha chain of PCC and that the
beta chain is mutant in the pccBC complementation group (which includes
subgroups pccB and pccC). Lamhonwah et al. (1985, 1986) reported that
alpha chain mRNA was missing in the pccA complementation group.

The family originally reported by Childs et al. (1961) had the pccA type
of propionic acidemia (Wolf, 1986). 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.

MAPPING

By Southern blot analysis of somatic cell hybrids, Lamhonwah et al.
(1983) mapped the PCCA gene to chromosome 13. By the study of dosage
effect in cell cultures obtained from patients with different deletions
of chromosome 13, Kennerknecht et al. (1990) assigned the PCCA locus to
13q32. By in situ hybridization, Kennerknecht et al. (1992) confirmed
the location of PCCA on 13q32. In the CEPH linkage map of human
chromosome 13 reported by Bowcock et al. (1993), PCCA was located
between D13S92 proximally and D13S60 distally. Using interspecific and
intersubspecific mapping panels, Koizumi et al. (1995) mapped the
homologous gene to the distal portion of mouse chromosome 14.

MOLECULAR GENETICS

To characterize PCCA gene mutations responsible for PCC deficiency,
Richard et al. (1997) analyzed RT-PCR products obtained from cultured
fibroblasts from Spanish PCCA-deficient patients. In 3 patients, smaller
than normal PCR products were observed, and sequence analysis revealed
deletion of a 54-bp exon in the cDNA. Sequencing of genomic DNA from
these 3 patients led to the identification of 3 novel mutations in the
PCCA gene, 2 short deletions and 1 small insertion, adjacent to short
direct repeats; all of the mutations affected the consensus splice sites
of the skipped exon. These mutations (232000.0001-232000.0003) caused
aberrant splicing of the PCCA pre-mRNA and resulted in an in-frame
deletion of 54 nucleotides in the cDNA, probably leading to an unstable
protein structure that was responsible for the lack of activity
resulting in PCC deficiency in these patients.

Campeau et al. (1999) searched for mutations of the PCCA gene using
fibroblasts from patients diagnosed with alpha-subunit deficiency. By
RT-PCR, 4 of 12 cell lines examined appeared to have a larger transcript
present at a level comparable with that of the expected normal species.
Sequencing of the larger transcript revealed an 84-bp insertion at
nucleotide 1209 of the coding sequence; its incorporation in the
transcript resulted in translation termination due to the presence of 2
in-frame stop codons. The 84-bp insertion was found to originate from
the intron between nucleotides 1209 and 1210. Consensus splice donor and
acceptor sites were found at the 3-prime and 5-prime ends of the
insertion, respectively. The insertion was also found in the remaining 8
cell lines as well as in normal cells, but at a much reduced level
compared with the normal length sequence. Mutation analysis of the 4
cell lines that showed seemingly elevated levels of the insertion
sequence revealed 1 nonsense mutation (arg288 to ter; 232000.0004), 2
frameshift deletions, and 1 splice mutation as expressed alleles.
Campeau et al. (1999) concluded that the common characteristic of the 4
cell lines was that they contained mRNA-destabilizing mutations that
reduced the mRNA level of the normal length sequence. Consequently, the
low levels of cryptic mRNAs became detectable at a level similar to that
of the residual level of the normal length mRNA. They suggested that
screening for an increased proportion of the 84-bp insertion by RT-PCR
could be used as a rapid assay for RNA-destabilizing mutations. The
results suggested caution in associating such mutations with aberrant
mRNA species, such as cryptic splice products, which may instead be part
of the 'background noise' of the splicing machinery.

Richard et al. (1999) studied the PCCA gene in 12 unrelated propionic
acidemia patients with alpha-subunit deficiency, 11 from Spain and 1
from Brazil. A total of 10 different mutations, none predominant, were
present in the sample of 24 mutant alleles studied; 5 of these were
reported for the first time. One of these mutations, M348K
(232000.0005), was found to encode an unstable protein, which was
probably the disease-causing mechanism.

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.

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). The 3 new point mutations described in deep intronic
regions increased the splicing scores of pseudoexons or generated
consensus binding motifs for splicing factors, such as SRp40 (600914),
which favor the intronic inclusions in MUT (1957ins76; 609058.0013),
PCCA (1284ins84; 232000.0006), or PCCB (654ins72; 232050.0009) mRNAs.
Experimental confirmation that the changes were pathogenic and caused
the activation of the pseudoexon was obtained by use of minigenes. AMOs
were targeted to the 5-prime or 3-prime cryptic splice sites to block
access of a splicing machinery to the pseudoexonic regions of the
pre-mRNA. In the PCCA-mutated and PCCB-mutated cell lines, 100% of PCC
activity was measured after 24 hours of AMO delivery, and the presence
of biotinylated PCCA protein was detected by Western blot in treated
PCCA-deficient cells. Rincon et al. (2007) concluded that this
therapeutic strategy would be potentially applicable to a large number
of cases with deep intronic changes that, at that time, remained
undetected by standard mutation-detection techniques.

*FIELD* AV
.0001
PROPIONIC ACIDEMIA
PCCA, 4-BP DEL, 1824IVS, +3

Richard et al. (1997) identified a 4-bp (AAGT) deletion in the intron
downstream from nucleotide 1824 in the PCCA gene in an 18-year-old
patient with a late-onset, relatively mild form of propionic acidemia
(606054) reported by Merinero et al. (1981). The diagnosis was made at
the age of 17 months. The patient demonstrated a favorable response to
restriction of dietary protein, and psychomotor development was
adequate. The mutation was present in homozygous form.

Clavero et al. (2004) performed mRNA analysis of a fibroblast cell line
from the patient reported by Richard et al. (1997) to test for the
presence of normally spliced transcripts which might explain the
patient's mild phenotype. Very low levels of normal-sized transcript
were detectable by ethidium bromide staining; quantitative RT-PCR
revealed 30-fold less correctly spliced PCCA mRNA in the patient's
fibroblasts than in normal control fibroblasts. Clavero et al. (2004)
suggested that very low levels of correctly spliced transcript are
sufficient to permit development of the mild phenotype.

.0002
PROPIONIC ACIDEMIA
PCCA, 9-BP DEL, 1771IVS, -2

Richard et al. (1997) identified a 9-bp (AGTGTCTTT) deletion in the
intron upstream of nucleotide 1771 in the PCCA gene in a 16-year-old
patient with a late-onset form of propionic acidemia (606054). The
diagnosis was made at 6 years of age. Response to restricted dietary
protein was favorable, and psychomotor development was adequate. The
9-bp deletion, which affected the invariant AG dinucleotide in the
3-prime splice acceptor site and the first 7 bases of the exon, was
present in heterozygous form.

.0003
PROPIONIC ACIDEMIA
PCCA, 2-BP INS, 1824IVS, +3

In a patient with a severe, neonatal form of propionic acidemia
(606054), which was diagnosed at 2 weeks of age and led to death shortly
thereafter, Richard et al. (1997) found a 2-bp (CT) insertion after
nucleotide 3 in the intron following coding nucleotide 1824. The
mutation was present in heterozygous form and led to an in-frame
deletion of 54 nucleotides in the cDNA. The 2-bp insertion in this
patient occurred at the same position as the 4-bp deletion (232000.0001)
that was associated with a late-onset, relatively mild form of the
disorder.

.0004
PROPIONIC ACIDEMIA
PCCA, ARG288TER

In cell lines from 2 patients with type I propionic acidemia (606054),
Campeau et al. (1999) identified an arg288-to-ter mutation leading to
truncation of the PCCA molecule. The underlying mutation, a C-to-T
transition at nucleotide 862, was present in homozygous form in 1
patient and in heterozygous form in the second.

.0005
PROPIONIC ACIDEMIA
PCCA, MET348LYS

Richard et al. (1999) found that 2 of 24 PCCA mutant alleles from 12
unrelated patients with propionic acidemia (606054) carried a
met348-to-lys mutation resulting from a 1043T-A transition. To examine
the effect of the mutation, which involved a highly conserved residue,
they carried out in vitro expression of normal and mutant PCCA cDNA.
They found that both wildtype and mutant proteins were imported into
mitochondria and processed into the mature form with similar efficiency,
but the mature mutant M348K protein decayed more rapidly than did the
wildtype, indicating a reduced stability, which was probably the
disease-causing mechanism.

.0006
PROPIONIC ACIDEMIA
PCCA, IVS14, A-G, -1416

In cultured cells from a patient with propionic acidemia (606054),
Rincon et al. (2007) found a homozygous 84-bp insertion between exons 14
and 15 of PCCA mRNA (1284ins84). The 84-bp insertion corresponded to a
pseudoexon in exon 14. The authors amplified the pseudoexon from genomic
DNA of the patient and found an A-G substitution (IVS14-1416A-G) in the
middle of the inserted sequence.

*FIELD* SA
Hsia et al. (1979); Kalousek et al. (1983); Kalousek et al. (1980);
Nyhan et al. (1961); Wolf et al. (1980)
*FIELD* RF
1. Bowcock, A. M.; Gerken, S. C.; Barnes, R. I.; Shiang, R.; Jabs,
E. W.; Warren, A. C.; Antonarakis, S.; Retief, A. E.; Vergnaud, G.;
Leppert, M.; Lalouel, J.-M.; White, R. L.; Cavalli-Sforza, L. L.:
The CEPH consortium linkage map of human chromosome 13. Genomics 16:
486-496, 1993.

2. Campeau, E.; Dupuis, L.; Leclerc, D.; Gravel, R. A.: Detection
of a normally rare transcript in propionic acidemia patients with
mRNA destabilizing mutations in the PCCA gene. Hum. Molec. Genet. 8:
107-113, 1999.

3. 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.

4. Clavero, S.; Perez, B.; Rincon, A.; Ugarte, M.; Desviat, L. R.
: Qualitative and quantitative analysis of the effect of splicing
mutations in propionic acidemia underlying non-severe phenotypes. Hum.
Genet. 115: 239-247, 2004.

5. 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.

6. 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.

7. Hsia, Y. E.; Scully, K. J.; Rosenberg, L. E.: Human propionyl
CoA carboxylase: some properties of the partially purified enzyme
in fibroblasts from controls and patients with propionic acidemia. Pediat.
Res. 13: 746-751, 1979.

8. Kalousek, F.; Orsulak, M. D.; Rosenberg, L. R.: Absence of cross-reacting
material in isolated propionyl CoA carboxylase deficiency: nature
of residual carboxylating activity. Am. J. Hum. Genet. 35: 409-420,
1983.

9. Kalousek, T.; Darigo, M. C.; Rosenberg, L. E.: Isolation and characterization
of propionyl-CoA carboxylase from normal human liver: evidence for
a protomeric tetramer of nonidentical subunits. J. Biol. Chem. 285:
60-65, 1980.

10. Kennerknecht, I.; Klett, C.; Hameister, H.: Assignment of the
human gene propionyl coenzyme A carboxylase, alpha-chain, (PCCA) to
chromosome 13q32 by in situ hybridization. Genomics 14: 550-551,
1992.

11. Kennerknecht, I.; Suormala, T.; Barbi, G.; Baumgartner, E. R.
: The gene coding for the alpha-chain of human propionyl-CoA carboxylase
maps to chromosome band 13q32. Hum. Genet. 86: 238-240, 1990.

12. Koizumi, T.; Hendel, E.; Lalley, P. A.; Tchetgen, M.-B. N.; Nadeau,
J. H.: Homologs of genes and anonymous loci on human chromosome 13
map to mouse chromosomes 8 and 14. Mammalian Genome 6: 263-268,
1995.

13. 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.

14. 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.

15. Lamhonwah, A. M.; Barankiewicz, T.; Willard, H. F.; Mahuran, D.;
Quan, F.; Gravel, R. A.: Propionicacidemia: absence of alpha chain
mRNA in pccA complementation group. (Abstract) Am. J. Hum. Genet. 37:
A164 only, 1985.

16. Lamhonwah, A. M.; Lam, K. F.; Tsui, F.; Robinson, B.; Saunders,
M. E.; Gravel, R. A.: Assignment of the alpha and beta chains of
human propionyl-CoA carboxylase to genetic complementation groups. Am.
J. Hum. Genet. 35: 889-899, 1983.

17. Merinero, B.; DelValle, J. A.; Jimenez, A.; Garcia, M. J.; Ugarte,
M.; Solaguren, R.; Lopez, O.; Condado, I.: Late onset type of propionic
acidaemia: case report and biochemical studies. J. Inherit. Metab.
Dis. 4: 71-72, 1981.

18. 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.

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. Richard, E.; Desviat, L. R.; Perez, B.; Perez-Cerda, C.; Ugarte,
M.: Three novel splice mutations in the PCCA gene causing identical
exon skipping in propionic acidemia patients. Hum. Genet. 101: 93-96,
1997.

22. Richard, E.; Desviat, L. R.; Perez, B.; Perez-Cerda, C.; Ugarte,
M.: Genetic heterogeneity in propionic acidemia patients with alpha-subunit
defects: identification of five novel mutations, one of them causing
instability of the protein. Biochim. Biophys. Acta 1453: 351-358,
1999.

23. 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.

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. Genet. 14: 275-282, 1999.

25. Wolf, B.: Personal Communication. Richmond, Va. 1/2/1986.

26. 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* CN
Victor A. McKusick - updated: 11/28/2007
Cassandra L. Kniffin - updated: 3/16/2007
Marla J. F. O'Neill - updated: 4/18/2005
Ada Hamosh - reorganized: 6/22/2001
Victor A. McKusick - updated: 9/5/2000
Wilson H. Y. Lo - updated: 11/17/1999
Victor A. McKusick - updated: 6/3/1999
Victor A. McKusick - updated: 2/18/1999
Victor A. McKusick - updated: 9/11/1998
Victor A. McKusick - updated: 9/2/1998

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

*FIELD* ED
alopez: 12/11/2007
terry: 11/28/2007
wwang: 4/2/2007
ckniffin: 3/16/2007
wwang: 4/27/2005
wwang: 4/19/2005
terry: 4/18/2005
terry: 4/6/2005
carol: 9/10/2001
carol: 6/22/2001
mcapotos: 9/27/2000
mcapotos: 9/19/2000
terry: 9/5/2000
carol: 4/17/2000
carol: 11/22/1999
carol: 11/17/1999
jlewis: 6/15/1999
jlewis: 6/14/1999
terry: 6/3/1999
mgross: 3/10/1999
carol: 2/25/1999
mgross: 2/25/1999
mgross: 2/22/1999
mgross: 2/19/1999
terry: 2/18/1999
carol: 9/16/1998
terry: 9/11/1998
alopez: 9/8/1998
terry: 9/2/1998
mark: 6/15/1995
davew: 8/26/1994
mimadm: 2/19/1994
carol: 9/13/1993
carol: 5/26/1993
carol: 5/21/1993

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