RBCC Red Blood Cell Collection

HLCS [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Biotin--protein ligase; 6.3.4.- (Biotin apo-protein ligase; Biotin--[methylmalonyl-CoA-carboxytransferase] ligase; 6.3.4.9; Biotin--[propionyl-CoA-carboxylase [ATP-hydrolyzing]] ligase; 6.3.4.10; Holocarboxylase synthetase; HCS; Biotin--[methylcrotonoyl-CoA-carboxylase] ligase; 6.3.4.11; Biotin--[acetyl-CoA-carboxylase] ligase; 6.3.4.15)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00301907
IPI00301907 Biotin--protein ligase Posttranslational modification of specific protein by attachment of biotin, biotin-[propionyl-CoA-carboxylase (ATP-hydrolyzing)] ligase activity soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic and mitochondrial n/a expected molecular weight found in band at molecular weight

UniProt P50747
ID BPL1_HUMAN Reviewed; 726 AA.
AC P50747; D3DSG6; Q99451;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 1.
DT 22-JAN-2014, entry version 133.
DE RecName: Full=Biotin--protein ligase;
DE EC=6.3.4.-;
DE AltName: Full=Biotin apo-protein ligase;
DE Includes:
DE RecName: Full=Biotin--[methylmalonyl-CoA-carboxytransferase] ligase;
DE EC=6.3.4.9;
DE Includes:
DE RecName: Full=Biotin--[propionyl-CoA-carboxylase [ATP-hydrolyzing]] ligase;
DE EC=6.3.4.10;
DE AltName: Full=Holocarboxylase synthetase;
DE Short=HCS;
DE Includes:
DE RecName: Full=Biotin--[methylcrotonoyl-CoA-carboxylase] ligase;
DE EC=6.3.4.11;
DE Includes:
DE RecName: Full=Biotin--[acetyl-CoA-carboxylase] ligase;
DE EC=6.3.4.15;
GN Name=HLCS;
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], AND VARIANT HLCS DEFICIENCY PRO-237.
RC TISSUE=Liver;
RX PubMed=7842009; DOI=10.1038/ng1094-122;
RA Suzuki Y., Aoki Y., Ishida Y., Chiba Y., Iwamatsu A., Kishino T.,
RA Niikawa N., Matsubara Y., Narisawa K.;
RT "Isolation and characterization of mutations in the human
RT holocarboxylase synthetase cDNA.";
RL Nat. Genet. 8:122-128(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Bone marrow;
RA Ohira M., Seki N., Nagase T., Suzuki E., Nomura N., Ohara O.,
RA Hattori M., Sakaki Y., Eki T., Murakami Y., Saito T., Ichikawa H.,
RA Ohki M.;
RT "Gene identification in the 1.6 Mb of the Down syndrome region on
RT chromosome 21.";
RL Submitted (FEB-1997) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Shibuya K., Kudoh J., Minoshima S., Kawasaki K., Nakatoh E.,
RA Shintani A., Asakawa S., Shimizu N.;
RT "Genomic sequencing of 1.2-Mb region on human chromosome 21q22.2.";
RL Submitted (NOV-1999) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS HLCS DEFICIENCY ASP-42;
RP PRO-237; GLU-333; SER-360; CYS-456; SER-470; TRP-508; GLY-547;
RP MET-550; SER-581; THR-610 DEL AND TYR-634, AND CHARACTERIZATION OF
RP VARIANTS HLCS DEFICIENCY ASP-42; SER-360; CYS-456; SER-470; GLY-547
RP AND TYR-634.
RX PubMed=11735028; DOI=10.1007/s004390100603;
RA Yang X., Aoki Y., Li X., Sakamoto O., Hiratsuka M., Kure S.,
RA Taheri S., Christensen E., Inui K., Kubota M., Ohira M., Ohki M.,
RA Kudoh J., Kawasaki K., Shibuya K., Shintani A., Asakawa S.,
RA Minoshima S., Shimizu N., Narisawa K., Matsubara Y., Suzuki Y.;
RT "Structure of human holocarboxylase synthetase gene and mutation
RT spectrum of holocarboxylase synthetase deficiency.";
RL Hum. Genet. 109:526-534(2001).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10830953; DOI=10.1038/35012518;
RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T.,
RA Park H.-S., Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y.,
RA Soeda E., Ohki M., Takagi T., Sakaki Y., Taudien S., Blechschmidt K.,
RA Polley A., Menzel U., Delabar J., Kumpf K., Lehmann R., Patterson D.,
RA Reichwald K., Rump A., Schillhabel M., Schudy A., Zimmermann W.,
RA Rosenthal A., Kudoh J., Shibuya K., Kawasaki K., Asakawa S.,
RA Shintani A., Sasaki T., Nagamine K., Mitsuyama S., Antonarakis S.E.,
RA Minoshima S., Shimizu N., Nordsiek G., Hornischer K., Brandt P.,
RA Scharfe M., Schoen O., Desario A., Reichelt J., Kauer G., Bloecker H.,
RA Ramser J., Beck A., Klages S., Hennig S., Riesselmann L., Dagand E.,
RA Wehrmeyer S., Borzym K., Gardiner K., Nizetic D., Francis F.,
RA Lehrach H., Reinhardt R., Yaspo M.-L.;
RT "The DNA sequence of human chromosome 21.";
RL Nature 405:311-319(2000).
RN [6]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-92.
RC TISSUE=Brain;
RX PubMed=9503011; DOI=10.1006/geno.1997.5146;
RA Dahmane N., Ait-Ghezala G., Gosset P., Chamoun Z.,
RA Dufresne-Zacharia M.-C., Lopes C., Rabatel N., Gassanova-Maugenre S.,
RA Chettouh Z., Abramowski V., Fayet E., Yaspo M.-L., Korn B.,
RA Blouin J.-L., Lehrach H., Poustka A., Antonarakis S.E., Sinet P.-M.,
RA Creau N., Delabar J.-M.;
RT "Transcriptional map of the 2.5-Mb CBR-ERG region of chromosome 21
RT involved in Down syndrome.";
RL Genomics 48:12-23(1998).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-147, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [10]
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 [11]
RP VARIANT HLCS DEFICIENCY PRO-237.
RX PubMed=8541348; DOI=10.1016/0925-4439(95)00082-8;
RA Aoki Y., Suzuki Y., Sakamoto O., Li X., Takahashi K., Ohtake A.,
RA Sakuta R., Ohura T., Miyabayashi S., Narisawa K.;
RT "Molecular analysis of holocarboxylase synthetase deficiency: a
RT missense mutation and a single base deletion are predominant in
RT Japanese patients.";
RL Biochim. Biophys. Acta 1272:168-174(1995).
RN [12]
RP VARIANTS HLCS DEFICIENCY ARG-216; ASP-363; TRP-508; GLU-518; MET-550
RP AND ASN-571.
RX PubMed=8817339; DOI=10.1093/hmg/5.7.1011;
RA Dupuis L., Leon-Del-Rio A., Leclerc D., Campeau E., Sweetman L.,
RA Saudubray J.-M., Herman G., Gibson K.M., Gravel R.A.;
RT "Clustering of mutations in the biotin-binding region of
RT holocarboxylase synthetase in biotin-responsive multiple carboxylase
RT deficiency.";
RL Hum. Mol. Genet. 5:1011-1016(1996).
RN [13]
RP VARIANTS HLCS DEFICIENCY PRO-237 AND MET-550.
RX PubMed=9396568; DOI=10.1203/00006450-199712000-00021;
RA Aoki Y., Suzuki Y., Li X., Sakamoto O., Chikaoka H., Takita S.,
RA Narisawa K.;
RT "Characterization of mutant holocarboxylase synthetase (HCS): a Km for
RT biotin was not elevated in a patient with HCS deficiency.";
RL Pediatr. Res. 42:849-854(1997).
RN [14]
RP VARIANTS HLCS DEFICIENCY GLU-333; ILE-462; ASN-571; SER-581 AND
RP THR-610 DEL.
RX PubMed=10190325; DOI=10.1007/s004390050927;
RA Aoki Y., Li X., Sakamoto O., Hiratsuka M., Akaishi H., Xu L.,
RA Briones P., Suormala T., Baumgartner E.R., Suzuki Y., Narisawa K.;
RT "Identification and characterization of mutations in patients with
RT holocarboxylase synthetase deficiency.";
RL Hum. Genet. 104:143-148(1999).
RN [15]
RP BIOPHYSICOCHEMICAL PROPERTIES, VARIANTS HLCS DEFICIENCY PRO-183;
RP ARG-216; PRO-237; GLU-333; ASP-363; SER-581 AND THR-610 DEL, AND
RP CHARACTERIZATION OF VARIANTS HLCS DEFICIENCY PRO-183; ARG-216;
RP PRO-237; GLU-333; ASP-363; SER-581 AND THR-610 DEL.
RX PubMed=10590022; DOI=10.1203/00006450-199912000-00006;
RA Sakamoto O., Suzuki Y., Li X., Aoki Y., Hiratsuka M., Suormala T.,
RA Baumgartner E.R., Gibson K.M., Narisawa K.;
RT "Relationship between kinetic properties of mutant enzyme and
RT biochemical and clinical responsiveness to biotin in holocarboxylase
RT synthetase deficiency.";
RL Pediatr. Res. 46:671-676(1999).
RN [16]
RP VARIANTS HLCS DEFICIENCY ARG-216; LYS-511; SER-581 AND ARG-582.
RX PubMed=12124727; DOI=10.1002/ajmg.10532;
RA Morrone A., Malvagia S., Donati M.A., Funghini S., Ciani F., Pela I.,
RA Boneh A., Peters H., Pasquini E., Zammarchi E.;
RT "Clinical findings and biochemical and molecular analysis of four
RT patients with holocarboxylase synthetase deficiency.";
RL Am. J. Med. Genet. 111:10-18(2002).
RN [17]
RP VARIANTS HLCS DEFICIENCY TRP-508; MET-550 AND ASN-634.
RX PubMed=12633764; DOI=10.1016/S0009-9120(02)00432-0;
RA Tang N.L.S., Hui J., Yong C.K.K., Wong L.T.K., Applegarth D.A.,
RA Vallance H.D., Law L.K., Fung S.L.M., Mak T.W.L., Sung Y.M.,
RA Cheung K.L., Fok T.F.;
RT "A genomic approach to mutation analysis of holocarboxylase synthetase
RT gene in three Chinese patients with late-onset holocarboxylase
RT synthetase deficiency.";
RL Clin. Biochem. 36:145-149(2003).
RN [18]
RP VARIANTS HLCS DEFICIENCY TYR-615 AND GLY-715.
RX PubMed=16134170; DOI=10.1002/humu.20204;
RA Suzuki Y., Yang X., Aoki Y., Kure S., Matsubara Y.;
RT "Mutations in the holocarboxylase synthetase gene HLCS.";
RL Hum. Mutat. 26:285-290(2005).
RN [19]
RP VARIANT [LARGE SCALE ANALYSIS] ASP-42.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [20]
RP CHARACTERIZATION OF VARIANT HLCS DEFICIENCY ARG-216.
RX PubMed=18429047; DOI=10.1002/humu.20766;
RA Bailey L.M., Ivanov R.A., Jitrapakdee S., Wilson C.J., Wallace J.C.,
RA Polyak S.W.;
RT "Reduced half-life of holocarboxylase synthetase from patients with
RT severe multiple carboxylase deficiency.";
RL Hum. Mutat. 29:E47-E57(2008).
CC -!- FUNCTION: Post-translational modification of specific protein by
CC attachment of biotin. Acts on various carboxylases such as acetyl-
CC CoA-carboxylase, pyruvate carboxylase, propionyl CoA carboxylase,
CC and 3-methylcrotonyl CoA carboxylase.
CC -!- CATALYTIC ACTIVITY: ATP + biotin + apo-[methylmalonyl-CoA:pyruvate
CC carboxytransferase] = AMP + diphosphate + [methylmalonyl-
CC CoA:pyruvate carboxytransferase].
CC -!- CATALYTIC ACTIVITY: ATP + biotin + apo-[propionyl-CoA:carbon-
CC dioxide ligase (ADP-forming)] = AMP + diphosphate + [propionyl-
CC CoA:carbon-dioxide ligase (ADP-forming)].
CC -!- CATALYTIC ACTIVITY: ATP + biotin + apo-[3-methylcrotonoyl-
CC CoA:carbon-dioxide ligase (ADP-forming)] = AMP + diphosphate + [3-
CC methylcrotonoyl-CoA:carbon-dioxide ligase (ADP-forming)].
CC -!- CATALYTIC ACTIVITY: ATP + biotin + apo-[acetyl-CoA:carbon-dioxide
CC ligase (ADP-forming)] = AMP + diphosphate + [acetyl-CoA:carbon-
CC dioxide ligase (ADP-forming)].
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=224 nM for biotin;
CC Vmax=143.9 pmol/min/mg enzyme;
CC -!- SUBUNIT: Monomer.
CC -!- INTERACTION:
CC O00763:ACACB; NbExp=4; IntAct=EBI-3915568, EBI-2211739;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Mitochondrion.
CC -!- TISSUE SPECIFICITY: Mostly expressed in muscle, placenta, in
CC lesser extent in the brain, kidney, pancreas, liver and lung.
CC -!- DISEASE: Holocarboxylase synthetase deficiency (HLCS deficiency)
CC [MIM:253270]: A neonatal form of multiple carboxylase deficiency,
CC an autosomal recessive disorder of biotin metabolism,
CC characterized by ketoacidosis, hyperammonemia, excretion of
CC abnormal organic acid metabolites, and dermatitis. In
CC holocarboxylase synthetase deficiency, clinical and biochemical
CC symptoms improve dramatically with administration of biotin.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the biotin--protein ligase family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/HLCS";
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DR EMBL; D23672; BAA04902.1; -; mRNA.
DR EMBL; D87328; BAA13332.1; -; mRNA.
DR EMBL; AP000697; BAA89434.1; -; Genomic_DNA.
DR EMBL; AP000703; BAA89434.1; JOINED; Genomic_DNA.
DR EMBL; AP000701; BAA89434.1; JOINED; Genomic_DNA.
DR EMBL; AP000698; BAA89434.1; JOINED; Genomic_DNA.
DR EMBL; AB063285; BAB68550.1; -; Genomic_DNA.
DR EMBL; AP001727; BAA95511.1; -; Genomic_DNA.
DR EMBL; AP001726; BAA95510.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09731.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09732.1; -; Genomic_DNA.
DR EMBL; BC060787; AAH60787.1; -; mRNA.
DR EMBL; AJ001864; CAA05056.1; -; mRNA.
DR PIR; S50833; S50833.
DR RefSeq; NP_000402.3; NM_000411.6.
DR RefSeq; NP_001229713.1; NM_001242784.1.
DR RefSeq; NP_001229714.1; NM_001242785.1.
DR RefSeq; XP_005261012.1; XM_005260955.1.
DR RefSeq; XP_005261013.1; XM_005260956.1.
DR UniGene; Hs.371350; -.
DR UniGene; Hs.732538; -.
DR ProteinModelPortal; P50747; -.
DR SMR; P50747; 460-707.
DR IntAct; P50747; 3.
DR MINT; MINT-3018588; -.
DR STRING; 9606.ENSP00000338387; -.
DR ChEMBL; CHEMBL2062354; -.
DR DrugBank; DB00121; Biotin.
DR PhosphoSite; P50747; -.
DR DMDM; 1705499; -.
DR PaxDb; P50747; -.
DR PRIDE; P50747; -.
DR Ensembl; ENST00000336648; ENSP00000338387; ENSG00000159267.
DR Ensembl; ENST00000399120; ENSP00000382071; ENSG00000159267.
DR Ensembl; ENST00000448340; ENSP00000392923; ENSG00000159267.
DR GeneID; 3141; -.
DR KEGG; hsa:3141; -.
DR UCSC; uc002yvs.3; human.
DR CTD; 3141; -.
DR GeneCards; GC21M038123; -.
DR HGNC; HGNC:4976; HLCS.
DR HPA; HPA017379; -.
DR MIM; 253270; phenotype.
DR MIM; 609018; gene.
DR neXtProt; NX_P50747; -.
DR Orphanet; 79242; Holocarboxylase synthetase deficiency.
DR PharmGKB; PA29310; -.
DR eggNOG; COG0340; -.
DR HOGENOM; HOG000095254; -.
DR HOVERGEN; HBG004872; -.
DR InParanoid; P50747; -.
DR KO; K01942; -.
DR OMA; NLQTKQL; -.
DR OrthoDB; EOG7SV0TT; -.
DR PhylomeDB; P50747; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR GenomeRNAi; 3141; -.
DR NextBio; 12456; -.
DR PRO; PR:P50747; -.
DR ArrayExpress; P50747; -.
DR Bgee; P50747; -.
DR CleanEx; HS_HLCS; -.
DR Genevestigator; P50747; -.
DR GO; GO:0000785; C:chromatin; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
DR GO; GO:0005652; C:nuclear lamina; IDA:UniProtKB.
DR GO; GO:0016363; C:nuclear matrix; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0009374; F:biotin binding; IDA:UniProtKB.
DR GO; GO:0004077; F:biotin-[acetyl-CoA-carboxylase] ligase activity; IEA:UniProtKB-EC.
DR GO; GO:0004078; F:biotin-[methylcrotonoyl-CoA-carboxylase] ligase activity; IEA:UniProtKB-EC.
DR GO; GO:0004079; F:biotin-[methylmalonyl-CoA-carboxytransferase] ligase activity; IEA:UniProtKB-EC.
DR GO; GO:0004080; F:biotin-[propionyl-CoA-carboxylase (ATP-hydrolyzing)] ligase activity; IDA:UniProtKB.
DR GO; GO:0006768; P:biotin metabolic process; TAS:Reactome.
DR GO; GO:0008283; P:cell proliferation; IMP:UniProtKB.
DR GO; GO:0071110; P:histone biotinylation; IDA:UniProtKB.
DR GO; GO:0070781; P:response to biotin; IDA:UniProtKB.
DR InterPro; IPR004408; Biotin_CoA_COase_ligase.
DR InterPro; IPR003142; BPL_C.
DR InterPro; IPR004143; BPL_LipA_LipB.
DR PANTHER; PTHR12835; PTHR12835; 1.
DR Pfam; PF02237; BPL_C; 1.
DR Pfam; PF03099; BPL_LplA_LipB; 1.
DR TIGRFAMs; TIGR00121; birA_ligase; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Complete proteome; Cytoplasm; Disease mutation; Ligase;
KW Mitochondrion; Multifunctional enzyme; Nucleotide-binding;
KW Phosphoprotein; Polymorphism; Reference proteome.
FT CHAIN 1 726 Biotin--protein ligase.
FT /FTId=PRO_0000064979.
FT MOD_RES 147 147 Phosphoserine.
FT VARIANT 42 42 E -> D (in HLCS deficiency and a breast
FT cancer sample; somatic mutation;
FT conserves enzymatic wild-type activity;
FT unknown pathological significance).
FT /FTId=VAR_035800.
FT VARIANT 183 183 R -> P (in HLCS deficiency; has normal or
FT low KM values for biotin (non-KM
FT mutant)).
FT /FTId=VAR_046507.
FT VARIANT 216 216 L -> R (in HLCS deficiency; has normal or
FT low KM values for biotin (non-KM mutant);
FT growth of patients' fibroblasts is
FT compromised compared with normal
FT fibroblasts; patients cells are not
FT sensitive to biotin-depletion from the
FT media; growth rates cannot be restored by
FT re-administration of biotin; enzyme
FT activity is severely compromised and
FT cannot be increased by additional biotin;
FT turn-over rate for the mutant protein is
FT double that of wild-type enzyme;
FT dbSNP:rs28934602).
FT /FTId=VAR_021218.
FT VARIANT 237 237 L -> P (in HLCS deficiency; has normal or
FT low KM values for biotin (non-KM
FT mutant)).
FT /FTId=VAR_005084.
FT VARIANT 333 333 V -> E (in HLCS deficiency; <10%
FT activity; has normal or low KM values for
FT biotin (non-KM mutant)).
FT /FTId=VAR_009196.
FT VARIANT 360 360 R -> S (in HLCS deficiency; 22% activity;
FT shows elevated KM values for biotin (KM
FT mutant) compared with that of the wild-
FT type form).
FT /FTId=VAR_046508.
FT VARIANT 363 363 V -> D (in HLCS deficiency; has normal or
FT low KM values for biotin (non-KM
FT mutant)).
FT /FTId=VAR_046509.
FT VARIANT 456 456 Y -> C (in HLCS deficiency; 0.2%
FT activity).
FT /FTId=VAR_046510.
FT VARIANT 462 462 T -> I (in HLCS deficiency; <10%
FT activity).
FT /FTId=VAR_009197.
FT VARIANT 470 470 L -> S (in HLCS deficiency; 4.3%
FT activity).
FT /FTId=VAR_046511.
FT VARIANT 508 508 R -> W (in HLCS deficiency).
FT /FTId=VAR_013009.
FT VARIANT 511 511 N -> K (in HLCS deficiency).
FT /FTId=VAR_021219.
FT VARIANT 518 518 G -> E (in HLCS deficiency).
FT /FTId=VAR_046512.
FT VARIANT 547 547 V -> G (in HLCS deficiency; 3.4%
FT activity).
FT /FTId=VAR_046513.
FT VARIANT 550 550 V -> M (in HLCS deficiency).
FT /FTId=VAR_009198.
FT VARIANT 571 571 D -> N (in HLCS deficiency; almost no
FT activity).
FT /FTId=VAR_009199.
FT VARIANT 581 581 G -> S (in HLCS deficiency; <10%
FT activity).
FT /FTId=VAR_009200.
FT VARIANT 582 582 G -> R (in HLCS deficiency).
FT /FTId=VAR_021220.
FT VARIANT 610 610 Missing (in HLCS deficiency; 14% of
FT activity; shows elevated KM values for
FT biotin (KM mutant) compared with that of
FT the wild-type form).
FT /FTId=VAR_009201.
FT VARIANT 615 615 D -> Y (in HLCS deficiency).
FT /FTId=VAR_046514.
FT VARIANT 634 634 D -> N (in HLCS deficiency).
FT /FTId=VAR_046515.
FT VARIANT 634 634 D -> Y (in HLCS deficiency; 12%
FT activity).
FT /FTId=VAR_046516.
FT VARIANT 715 715 D -> G (in HLCS deficiency).
FT /FTId=VAR_046517.
FT CONFLICT 558 558 E -> K (in Ref. 2; BAA13332).
SQ SEQUENCE 726 AA; 80760 MW; 855B8E52106D675F CRC64;
MEDRLHMDNG LVPQKIVSVH LQDSTLKEVK DQVSNKQAQI LEPKPEPSLE IKPEQDGMEH
VGRDDPKALG EEPKQRRGSA SGSEPAGDSD RGGGPVEHYH LHLSSCHECL ELENSTIESV
KFASAENIPD LPYDYSSSLE SVADETSPER EGRRVNLTGK APNILLYVGS DSQEALGRFH
EVRSVLADCV DIDSYILYHL LEDSALRDPW TDNCLLLVIA TRESIPEDLY QKFMAYLSQG
GKVLGLSSSF TFGGFQVTSK GALHKTVQNL VFSKADQSEV KLSVLSSGCR YQEGPVRLSP
GRLQGHLENE DKDRMIVHVP FGTRGGEAVL CQVHLELPPS SNIVQTPEDF NLLKSSNFRR
YEVLREILTT LGLSCDMKQV PALTPLYLLS AAEEIRDPLM QWLGKHVDSE GEIKSGQLSL
RFVSSYVSEV EITPSCIPVV TNMEAFSSEH FNLEIYRQNL QTKQLGKVIL FAEVTPTTMR
LLDGLMFQTP QEMGLIVIAA RQTEGKGRGG NVWLSPVGCA LSTLLISIPL RSQLGQRIPF
VQHLMSVAVV EAVRSIPEYQ DINLRVKWPN DIYYSDLMKI GGVLVNSTLM GETFYILIGC
GFNVTNSNPT ICINDLITEY NKQHKAELKP LRADYLIARV VTVLEKLIKE FQDKGPNSVL
PLYYRYWVHS GQQVHLGSAE GPKVSIVGLD DSGFLQVHQE GGEVVTVHPD GNSFDMLRNL
ILPKRR
//

MIM 253270
*RECORD*
*FIELD* NO
253270
*FIELD* TI
#253270 HOLOCARBOXYLASE SYNTHETASE DEFICIENCY
;;HLCS DEFICIENCY;;
MULTIPLE CARBOXYLASE DEFICIENCY, NEONATAL FORM;;
read moreMULTIPLE CARBOXYLASE DEFICIENCY, EARLY ONSET
*FIELD* TX
A number sign (#) is used with this entry because neonatal multiple
carboxylase deficiency (MCD) is caused by mutation in the gene encoding
holocarboxylase synthetase (HLCS; 609018).

DESCRIPTION

Early-onset multiple carboxylase deficiency, or holocarboxylase
deficiency, is an autosomal recessive disorder of biotin metabolism. See
also late-onset or juvenile MCD (253260) caused by mutation in the
biotinidase gene (BTD; 609019). Sweetman (1981) recognized that multiple
carboxylase deficiency could be classified into early and late forms.
The early form showed higher urinary excretion of 3-hydroxyisovaleric
acid and 3-hydroxypropionic acid than the late form and was associated
with normal plasma biotin concentrations. Sweetman (1981) proposed a
defect in holocarboxylase synthetase and intestinal biotin absorption,
respectively.

Care must be taken to differentiate the inherited multiple carboxylase
deficiencies from acquired biotin deficiencies, such as those that
develop after excessive dietary intake of avidin, an egg-white
glycoprotein that binds specifically and essentially irreversibly to
biotin (Sweetman et al., 1981) or prolonged parenteral alimentation
without supplemental biotin (Mock et al., 1981).

CLINICAL FEATURES

Thoene et al. (1979) described a child with decreased activity of 3
biotin-dependent carboxylases: pyruvate carboxylase (PCC; 608786),
propionyl CoA carboxylase (PCCA; 232000), and alpha-methylcrotonyl CoA
carboxylase (MCCC1; 609010). The severe manifestations included lactic
acidosis, alopecia, keratoconjunctivitis, perioral erosions, and
seizures; all symptoms were completely reversed by biotin treatment.
Assays of lymphocyte carboxylase activities also rose with biotin.
Saunders et al. (1979) demonstrated failure of complementation with
other carboxylase mutants and suggested that the defect involved a
holocarboxylase synthetase necessary for linking the 3 apoenzymes with
biotin.

Feldman et al. (1981) studied cultured fibroblasts from 2 patients with
neonatal multiple carboxylase deficiency. Both cell lines were deficient
in the 3 biotin-dependent carboxylases and belonged to the 'bio'
complementation group. However, the activities of the 3 carboxylases
became normal when the cells of 1 line were incubated in medium
supplemented with biotin (1 mg per liter) for 24 hours, whereas in the
second line a longer time (4 to 6 days) was required to achieve maximal
activities at an intermediate level (29 to 57% of normal) with a higher
concentration of biotin (10 mg per liter).

Burri et al. (1981) showed deficiency in holocarboxylase synthetase
activity in a patient with early-onset MCD. Munnich et al. (1981)
presented evidence suggesting that defective absorption of biotin at the
level of the intestinal mucosa underlies some cases of this disorder.
Enzyme activities in the MCD patients' fibroblasts cultured in a
biotin-free medium were similar to those in controls.

Wolf and Feldman (1982) reviewed the differences between the neonatal
and late-onset forms of multiple carboxylase deficiency. Whereas the
neonatal form results from deficiency of holocarboxylase synthetase, the
findings of Munnich et al. (1981) suggested that biotin absorption or
transport may be defective in the form that has its onset at about 3
months of age. A primary or secondary defect in biotin absorption leads
to alopecia, an erythematous periorificial dermatitis, and ataxia in
babies with infantile-onset disease. The neonatal-onset form presents as
congenital lactic acidosis of variable severity with the underlying
biochemical lesion in some families identified as an abnormal
holocarboxylase synthetase with an elevated Km(biotin) and a decreased
Vmax. Packman et al. (1984) concluded, however, that age of onset or
severity of clinical presentation may not serve to classify accurately
all cases of MCD. They proposed that the patients be classified into 2
categories: type 1 patients have a decline in cytosolic carboxylase
activities with biotin deprivation; holocarboxylase synthetase
deficiency; and assignment to the 'bio' complementation group. Although
most patients in this class show congenital lactic acidosis, milder
cases occur. Type 2 patients are characterized by normal fibroblast
carboxylase activities at all biotin concentrations; a variable
infantile-onset syndrome resembling biotin deficiency states; and a
possible primary or secondary absorptive defect. A defect in biotinidase
activity has been demonstrated in such patients (Wolf et al., 1983).

Burri et al. (1985) studied holocarboxylase synthetase from fibroblasts
of 7 patients with the neonatal form of biotin-responsive multiple
carboxylase deficiency. Differences among the values obtained for the Km
for biotin and the heat stability of holocarboxylase synthetase
suggested that the patients studied represented at least 4 distinct
variants at the holocarboxylase synthetase locus. See review of Sweetman
and Nyhan (1986).

Fuchshuber et al. (1993) reported a patient with early-onset MCD.
Symptoms appeared at day 2 of life, with lactic acidosis,
hyperammonemia, and urinary excretion of 3-hydroxyisovaleric acid,
3-methylcrotonylglycine, 3-hydroxypropionic acid, and methylcitric acid.
Biotin supplementation resulted in marked clinical and biochemical
improvement.

The age of onset (2 days to 6 years), as well as the severity of the
illness, varied considerably in the 5 patients with biotin-responsive
holocarboxylase synthesis reported by Suormala et al. (1997). In all
patients, diagnosis was established by the finding of organic aciduria
typical for multiple carboxylase deficiency in a catabolic state. In 3
patients, clinical symptoms disappeared with 10 to 20 mg biotin/d,
whereas normalization of the biochemical parameters required higher
doses (20 to 40 mg/d). A fourth patient required a dose of 100 mg/d
before her skin rash disappeared; however she remained mentally retarded
and showed slightly elevated urinary organic acid excretion. The results
of studies of cultured fibroblasts were in accordance with a primary
defect of holocarboxylase synthetase due to a decreased affinity for
biotin.

Yang et al. (2001) reported multiple Japanese and non-Japanese patients
with neonatal MCD. Three patients developed severe acidosis in the first
few days of life and died soon after. HLCS activity ranged from 0.7 to
8% of normal. Six patients had later onset of symptoms (1 month to 3
years), were treated with biotin, and showed normal development. HLCS
activity in 1 of these patients was 14% of normal.

MOLECULAR GENETICS

In sibs with HLCS deficiency reported by Narisawa et al. (1982), Suzuki
et al. (1994) demonstrated compound heterozygosity for 2 mutations in
the HLCS gene (609018.0001; 609018.0002).

In 9 patients with multiple carboxylase deficiency, Dupuis et al. (1996)
identified 6 novel point mutations in the HLCS gene (see, e.g.,
609018.0003). Two of the mutations were frequent. Aoki et al. (1999)
reported 7 mutations (3 missense, 2 single-bp deletions, a 3-base
in-frame deletion, and a 68-bp deletion) identified in the cDNA of 7
holocarboxylase synthetase deficiency patients from Europe and the
Middle East. One of the patients was reported by Fuchshuber et al.
(1993) (see 609018.0005).

Yang et al. (2001) identified multiple mutations in the HLCS gene in a
group of Japanese and non-Japanese patients with biotin-responsive MCD
(see, e.g., 609018.0001-609018.0002; 609018.0004-609018.0008). There
were no panethnically prevalent mutations.

Suzuki et al. (2005) reviewed the mutations and polymorphisms that have
been found in the HLCS gene and their clinical relevance.

*FIELD* SA
Bartlett et al. (1985); Packman et al. (1981); Packman et al. (1981);
Saunders et al. (1982); Thoene et al. (1981); Yang et al. (2000)
*FIELD* RF
1. Aoki, Y.; Li, X.; Sakamoto, O.; Hiratsuka, M.; Akaishi, H.; Xu,
L.; Briones, P.; Suormala, T.; Baumgartner, E. R.; Suzuki, Y.; Narisawa,
K.: Identification and characterization of mutations in patients
with holocarboxylase synthetase deficiency. Hum. Genet. 104: 143-148,
1999.

2. Bartlett, K.; Ghneim, H. K.; Stirk, H.-J.; Wastell, H.: Enzyme
studies in biotin-responsive disorders. J. Inherit. Metab. Dis. 8
(suppl. 1): 46-52, 1985.

3. Burri, B. J.; Sweetman, L.; Nyhan, W. L.: Mutant holocarboxylase
synthetase: evidence for the enzyme defect in early infantile biotin-responsive
multiple carboxylase deficiency. J. Clin. Invest. 68: 1491-1495,
1981.

4. Burri, B. J.; Sweetman, L.; Nyhan, W. L.: Heterogeneity of holocarboxylase
synthetase in patients with biotin-responsive multiple carboxylase
deficiency. Am. J. Hum. Genet. 37: 326-337, 1985.

5. Dupuis, L.; Leon-Del-Rio, A.; Leclerc, D.; Campeau, E.; Sweetman,
L.; Saudubray, J. M.; Herman, G.; Gibson, K. M.; Gravel, R. A.: Clustering
of mutations in the biotin-binding region of holocarboxylase synthetase
in biotin-responsive multiple carboxylase deficiency. Hum. Molec.
Genet. 5: 1011-1016, 1996.

6. Feldman, G. L.; Hsia, Y. E.; Wolf, B.: Biochemical characterization
of biotin-responsive multiple carboxylase deficiency: heterogeneity
within the bio genetic complementation group. Am. J. Hum. Genet. 33:
692-701, 1981.

7. Fuchshuber, A.; Suormala, T.; Roth, B.; Duran, M.; Michalk, D.;
Baumgartner, E. R.: Holocarboxylase synthetase deficiency: early
diagnosis and management of a new case. Europ. J. Pediat. 152: 446-449,
1993.

8. Mock, D. M.; deLorimer, A. A.; Liebman, W. M.; Sweetman, L.; Baker,
H.: Biotin deficiency: an unusual complication of parenteral alimentation. New
Eng. J. Med. 304: 820-822, 1981.

9. Munnich, A.; Saudubray, J. M.; Carre, G.; Coude, F. X.; Ogier,
H.; Charpentier, C.; Frezal, J.: Defective biotin absorption in multiple
carboxylase deficiency. (Letter) Lancet 318: 263 only, 1981. Note:
Originally Volume 2.

10. Narisawa, K.; Arai, N.; Igarashi, Y.; Satoh, T.; Tada, K.: Clinical
and biochemical findings on a child with multiple biotin-responsive
carboxylase deficiencies. J. Inherit. Metab. Dis. 5: 67-68, 1982.

11. Packman, S.; Caswell, N.; Gonzalez-Rios, M. C.; Kadlecek, T.;
Cann, H.; Rassin, D.; McKay, C.: Acetyl CoA carboxylase in cultured
fibroblasts: differential biotin dependence in the two types of biotin-responsive
multiple carboxylase deficiency. Am. J. Hum. Genet. 36: 80-92, 1984.

12. Packman, S.; Sweetman, L.; Baker, H.; Wall, S.: The neonatal
form of biotin-responsive multiple carboxylase deficiency. J. Pediat. 99:
418-420, 1981.

13. Packman, S.; Sweetman, L.; Yoshino, M.; Baker, H.; Cowan, M.:
Biotin-responsive multiple carboxylase deficiency of infantile onset. J.
Pediat. 99: 421-423, 1981.

14. Saunders, M.; Sweetman, L.; Robinson, B.; Roth, K.; Kohn, S.;
Sherwood, G.; Gravel, R.: Multiple carboxylase defects and complementation
studies in biotin responsive organicaciduria. (Abstract) Am. J. Hum.
Genet. 31: 61A, 1979.

15. Saunders, M. E.; Sherwood, W. G.; Duthie, M.; Surh, L.; Gravel,
R. A.: Evidence for a defect of holocarboxylase synthetase activity
in cultured lymphoblasts from a patient with biotin-responsive multiple
carboxylase deficiency. Am. J. Hum. Genet. 34: 590-601, 1982.

16. Suormala, T.; Fowler, B.; Duran, M.; Burtscher, A.; Fuchshuber,
A.; Tratzmuller, R.; Lenze, M. J.; Raab, K.; Baur, B.; Wick, H.; Baumgartner,
R.: Five patients with a biotin-responsive defect in holocarboxylase
formation: evaluation of responsiveness to biotin therapy in vivo
and comparative biochemical studies in vitro. Pediat. Res. 41: 666-673,
1997.

17. Suzuki, Y.; Aoki, Y.; Ishida, Y.; Chiba, Y.; Iwamatsu, A.; Kishino,
T.; Niikawa, N.; Matsubara, Y.; Narisawa, K.: Isolation and characterization
of mutations in the human holocarboxylase synthetase cDNA. Nature
Genet. 8: 122-128, 1994.

18. Suzuki, Y.; Yang, X.; Aoki, Y.; Kure, S.; Matsubara, Y.: Mutations
in the holocarboxylase synthetase gene HLCS. Hum. Mutat. 26: 285-290,
2005.

19. Sweetman, L.: Two forms of biotin-responsive multiple carboxylase
deficiency. J. Inherit. Metab. Dis. 4: 53-54, 1981.

20. Sweetman, L.; Nyhan, W. L.: Inheritable biotin-treatable disorders
and associated phenomena. Ann. Rev. Nutr. 6: 317-343, 1986.

21. Sweetman, L.; Surh, L.; Baker, H.; Peterson, R. M.; Nyhan, W.
L.: Clinical and metabolic abnormalities in a boy with dietary deficiency
of biotin. Pediatrics 68: 553-558, 1981.

22. Thoene, J.; Baker, H.; Yoshino, M.; Sweetman, L.: Biotin-responsive
carboxylase deficiency associated with subnormal plasma and urinary
biotin. New Eng. J. Med. 304: 817-820, 1981.

23. Thoene, J.; Sweetman, L.; Yoshino, M.: Biotin-responsive multiple
carboxylase deficiency. (Abstract) Am. J. Hum. Genet. 31: 64A, 1979.

24. Wolf, B.; Feldman, G. L.: The biotin-dependent carboxylase deficiencies. Am.
J. Hum. Genet. 34: 699-716, 1982.

25. Wolf, B.; Grier, R. E.; Parker, W. D.; Goodman, S. I.; Allen,
R. J.: Deficient biotinidase activity in late-onset multiple carboxylase
deficiency. (Letter) New Eng. J. Med. 308: 161, 1983.

26. Yang, X.; Aoki, Y.; Li, X.; Sakamoto, O.; Hiratsuka, M.; Gibson,
K. M.; Kure, S.; Narisawa, K.; Matsubara, Y.; Suzuki, Y.: Haplotype
analysis suggests that the two predominant mutations in Japanese patients
with holocarboxylase synthetase deficiency are founder mutations. J.
Hum. Genet. 45: 358-362, 2000.

27. Yang, X.; Aoki, Y.; Li, X.; Sakamoto, O.; Hiratsuka, M.; Kure,
S.; Taheri, S.; Christensen, E.; Inui, K.; Kubota, M.; Ohira, M.;
Ohki, M.; and 10 others: Structure of human holocarboxylase synthetase
gene and mutation spectrum of holocarboxylase synthetase deficiency. Hum.
Genet. 109: 526-534, 2001.

*FIELD* CS
INHERITANCE:
Autosomal recessive

RESPIRATORY:
Tachypnea;
Hyperventilation

ABDOMEN:
[Gastrointestinal];
Feeding problems;
Vomiting

SKIN, NAILS, HAIR:
[Skin];
Skin rash;
[Hair];
Alopecia

NEUROLOGIC:
[Central nervous system];
Irritability;
Hypotonia;
Seizures;
Lethargy;
Developmental delay;
Coma;
Hypertonia

METABOLIC FEATURES:
Metabolic acidosis;
Organic aciduria

HEMATOLOGY:
Thrombocytopenia

LABORATORY ABNORMALITIES:
Organic aciduria (elevated beta-hydroxyisovalerate, beta-methylcrotonylglycine,
beta-hydroxypropionate, methylcitrate, lactate, tiglylglycine);
Mild-moderate hyperammonemia;
Holocarboxylase synthetase deficiency;
Normal serum biotin concentration

MISCELLANEOUS:
Age of onset - birth to 15 months

MOLECULAR BASIS:
Caused by mutations in the holocarbyoxylase synthetase gene (HLCS,
253270.0001)

*FIELD* CN
Kelly A. Przylepa - revised: 08/14/2001

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

*FIELD* ED
joanna: 08/14/2001

*FIELD* CN
Marla J. F. O'Neill - updated: 11/4/2005
Cassandra L. Kniffin - reorganized: 11/29/2004
Cassandra L. Kniffin - updated: 11/10/2004
Victor A. McKusick - updated: 8/8/2002
Victor A. McKusick - updated: 12/6/2001
Victor A. McKusick - updated: 12/5/2000
Ada Hamosh - updated: 3/18/1999
Victor A. McKusick - updated: 7/14/1997
Victor A. McKusick - updated: 6/21/1997
Moyra Smith - updated: 11/8/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 04/28/2011
joanna: 5/7/2009
terry: 4/9/2009
wwang: 11/4/2005
carol: 11/29/2004
ckniffin: 11/11/2004
ckniffin: 11/10/2004
alopez: 3/17/2004
carol: 11/18/2002
tkritzer: 8/13/2002
tkritzer: 8/9/2002
terry: 8/8/2002
carol: 1/2/2002
mcapotos: 12/14/2001
terry: 12/6/2001
carol: 12/5/2000
terry: 12/5/2000
terry: 5/20/1999
alopez: 3/19/1999
alopez: 3/18/1999
terry: 6/4/1998
terry: 7/17/1997
terry: 7/14/1997
terry: 6/24/1997
terry: 6/21/1997
mark: 11/8/1996
mimman: 2/8/1996
mark: 6/12/1995
carol: 12/14/1994
terry: 10/26/1994
supermim: 3/17/1992
supermim: 3/20/1990
ddp: 10/26/1989

MIM 609018
*RECORD*
*FIELD* NO
609018
*FIELD* TI
*609018 HOLOCARBOXYLASE SYNTHETASE; HLCS
;;HCS
*FIELD* TX

DESCRIPTION

Holocarboxylase synthetase (EC 6.3.4.10) covalently links biotin to
read morepropionyl-CoA carboxylase (PCCA; 232000), pyruvate carboxylase (PC;
608786), alpha-methylcrotonyl-CoA carboxylase (MCCC1; 609010), and
acetyl-CoA carboxylase (ACACA; 200350).

CLONING

Suzuki et al. (1994) cloned a human holocarboxylase synthetase cDNA and
showed that antiserum against the recombinant protein immunoprecipitated
the enzyme. Human HLCS shows homology with E. coli BirA, which acts as
both a biotin-(acetyl-CoA-carboxylase) ligase and a biotin repressor in
E. coli, suggesting a functional relationship between the 2 proteins.

Leon-Del-Rio et al. (1995) isolated a cDNA encoding human HLCS by
complementation of the E. coli BirA mutant defective in biotin ligase.
The predicted 726-amino acid protein has a molecular mass of
approximately 81 kD. Northern blot analysis detected a 5.8-kb major
transcript in all human tissues tested, with highest expression in
skeletal muscle, kidney, and pancreas. Several minor transcripts were
also detected. Several forms of the mRNA are generated by alternative
splicing, and as a result, 2 mRNA molecules bear different putative
translation initiation sites. A sequence upstream of the first
translation initiation site encoded a peptide structurally similar to
mitochondrial presequences, but it lacked an in-frame ATG codon to
direct its translation. Leon-Del-Rio et al. (1995) anticipated that
alternative splicing most likely mediates the mitochondrial versus
cytoplasmic expression, although the elements required for directing the
enzyme to the mitochondria remained to be confirmed.

GENE FUNCTION

Narang et al. (2004) showed that the majority of HCS localized to the
nucleus rather than to cytoplasm, based on immunofluorescence studies
with antibodies to peptides and full-length HCS and based on expression
of recombinant HCS. Subnuclear fractionation indicated that HCS was
associated with chromatin and the nuclear lamina, the latter in a
discontinuous distribution in high salt-extracted nuclear membranes.
During mitosis, HCS resolved into ring-like particles, which colocalized
with lamin B (LMNB1; 150340). Nuclear HCS retained its biotinylating
activity and was shown to biotinylate purified histones in vitro.
Fibroblasts from patients with HCS deficiency were severely deficient in
histone biotinylation in addition to being deficient in carboxylase
activity. Narang et al. (2004) proposed that the role of HCS in histone
modification may be linked to participation of biotin in the regulation
of gene expression or cell division, and that affected patients may have
additional disease beyond that due to the effect on carboxylases.

MAPPING

By fluorescence in situ hybridization, Suzuki et al. (1994) mapped the
HLCS gene to chromosome 21q22.1. The assignment to chromosome 21 was
confirmed by PCR analysis of a DNA panel of human/hamster hybrid somatic
cells. By fluorescence in situ hybridization, Zhang et al. (1997) also
mapped the HLCS gene to 21q22.1 in human and to chromosome 16 in the
mouse.

MOLECULAR GENETICS

In sibs with HLCS deficiency, Suzuki et al. (1994) demonstrated compound
heterozygosity for 2 mutations in the HLCS gene (609018.0001;
609018.0002).

In 9 patients with multiple carboxylase deficiency, Dupuis et al. (1996)
identified 6 novel point mutations in the HLCS gene (see, e.g.,
609018.0003). Two of the mutations were frequent. Aoki et al. (1999)
reported 7 mutations (3 missense, 2 single-bp deletions, a 3-base
in-frame deletion, and a 68-bp deletion) identified in the cDNA of 7
holocarboxylase synthetase deficiency patients from Europe and the
Middle East.

In a large-scale analysis of mutations in the HLCS gene in patients with
biotin-responsive multiple carboxylase deficiency, Yang et al. (2001)
found no panethnically prevalent mutations; the arg508-to-trp
(609018.0004), gly581-to-ser (609018.0005), and val550-to-met
(609018.0006) mutations were found in both Japanese and non-Japanese
populations; the IVS10+5G-A mutation (609018.0007) was predominant and
probably a founder mutation in European patients; and the 780delG
(609018.0001), leu237-to-pro (609018.0002), and 665insA (609018.0008)
mutations were unique in Japanese patients. Mutations found
predominantly among Japanese patients severely affected enzyme activity,
whereas most of the mutations found in the non-Japanese patients
retained residual HLCS activity.

In 4 patients with HLCS deficiency (2 Italian, 1 Iranian, and 1
Australian/Maori), Morrone et al. (2002) identified 6 mutations in the
HLCS gene, including 2 novel mutations. Five of the mutations were
localized within the HLCS biotin-binding domain, whereas one (L216R;
609018.0009) was located in the N-terminal region outside of the
putative biotin-binding domain. This mutation, previously reported in
heterozygous state, was detected for the first time in a patient with
homozygous status. The patient's severe clinical phenotype and partial
responsiveness to biotin supported a genotype-phenotype correlation
through the involvement of residues of the N-terminal region involved in
substrate specificity recognition or regulation of the HLCS enzyme.

Suzuki et al. (2005) reviewed the mutations and polymorphisms that have
been found in the HLCS gene and their clinical relevance.

*FIELD* AV
.0001
HOLOCARBOXYLASE SYNTHETASE DEFICIENCY
HLCS, 1-BP DEL, 780G

In a cell line from a patient with HLCS deficiency (253270) previously
reported by Narisawa et al. (1982), Suzuki et al. (1994) identified a
1-bp deletion (1067G, now designated 780delG) in the HLCS gene,
resulting in a frameshift and premature stop codon at amino acid
position 280. The patient was a compound heterozygote for the 1-bp
deletion and a 997C-T transition, resulting in a leu237-to-pro amino
acid substitution (L237P; 253270.0002). Allele-specific oligonucleotide
hybridization analysis of the patient and her affected sister showed
that both were heterozygous for these mutations.

In 10 Japanese families with deficiency of holocarboxylase synthetase,
Yang et al. (2000) found that the 780delG mutation accounted for 5 of 20
alleles and the L237P mutation for 7 of 20 alleles. All examples of
these 2 alleles were associated with haplotype 2-2. The authors
suggested that these are founder mutations in the Japanese population.

.0002
HOLOCARBOXYLASE SYNTHETASE DEFICIENCY
HLCS, LEU237PRO

See 609018.0001, Suzuki et al. (1994), and Yang et al. (2001).

.0003
HOLOCARBOXYLASE SYNTHETASE DEFICIENCY
HLCS, ASP571ASN

In a patient with multiple carboxylase deficiency (253270), Dupuis et
al. (1996) identified a 1998G-A transition in the HLCS gene, resulting
in an asp571-to-asn (D571N) substitution. Aoki et al. (1999) performed
transient transfection studies in patient fibroblasts, which revealed
that the D571N mutant protein had 0.1% of wildtype activity, suggesting
that asp571 is crucial for catalytic activity.

.0004
HOLOCARBOXYLASE SYNTHETASE DEFICIENCY
HLCS, ARG508TRP

In a large survey of HLCS mutations in patients with biotin-responsive
MCD (253270), Yang et al. (2001) identified a 1522C-t transition in the
HLCS gene, resulting in an arg508-to-trp (R508W) substitution. The
mutation was present in both Japanese and European patients .

.0005
HOLOCARBOXYLASE SYNTHETASE DEFICIENCY
HLCS, GLY581SER

In a large survey of HLCS mutations in patients with biotin-responsive
MCD (253270), Yang et al. (2001) found the 1741G-A transition in the
HLCS gene, resulting in a gly581-to-ser (G581S) substitution. The
mutation was present in both Japanese and European patients. This
mutation had previously been identified by Aoki et al. (1999) in a
patient reported by Fuchshuber et al. (1993).

.0006
HOLOCARBOXYLASE SYNTHETASE DEFICIENCY
HLCS, VAL550MET

In a large survey of HLCS mutations in patients with biotin-responsive
MCD (253270), Yang et al. (2001) identified a 1648G-A transition in the
HLCS gene, resulting in a val550-to-met (V550M) substitution. The
mutation was found in both Japanese and European patients. The V550M
mutation was previously reported by Aoki et al. (1997) who determined
that it is within the putative biotin-binding site of the protein. Aoki
et al. (1997) reported the mutation as 1935G-A.

.0007
HOLOCARBOXYLASE SYNTHETASE DEFICIENCY
HLCS, IVS10, G-A, +5

In a large survey of HLCS mutations in patients with biotin-responsive
MCD (253270), Yang et al. (2001) identified an IVS10+5G-A mutation in 6
patients: 2 patients from the Faroe Islands and a Spanish and a Danish
patient were homozygous for the mutation; and a French and a German
patient were heterozygous. The haplotype of the HLCS gene in all 6
patients was identical, suggesting a founder mutation.

.0008
HOLOCARBOXYLASE SYNTHETASE DEFICIENCY
HLCS, 1-BP INS, 655A

In a large survey of HLCS mutations in Japanese patients with
biotin-responsive MCD (253270), Yang et al. (2001) identified a 1-bp
insertion (655insA) in the HLCS gene.

.0009
HOLOCARBOXYLASE SYNTHETASE DEFICIENCY
HLCS, LEU216ARG

In an Australian/Maori patient with HLCS deficiency (253270) who had a
severe clinical and biotin-unresponsive phenotype, Morrone et al. (2002)
identified a homozygous 674T-G transversion in the HLCS gene, resulting
in a leu216-to-arg (L216R) substitution. The mutation was located
outside of the biotin-binding domain and completely abolished the enzyme
activity.

*FIELD* RF
1. Aoki, Y.; Li, X.; Sakamoto, O.; Hiratsuka, M.; Akaishi, H.; Xu,
L.; Briones, P.; Suormala, T.; Baumgartner, E. R.; Suzuki, Y.; Narisawa,
K.: Identification and characterization of mutations in patients
with holocarboxylase synthetase deficiency. Hum. Genet. 104: 143-148,
1999.

2. Aoki, Y.; Suzuki, Y.; Li, X.; Sakamoto, O.; Chikaoka, H.; Takita,
S.; Narisawa, K.: Characterization of mutant holocarboxylase synthetase
(HCS): a Km for biotin was not elevated in a patient with HCS deficiency. Pediat.
Res. 42: 849-854, 1997.

3. Dupuis, L.; Leon-Del-Rio, A.; Leclerc, D.; Campeau, E.; Sweetman,
L.; Saudubray, J. M.; Herman, G.; Gibson, K. M.; Gravel, R. A.: Clustering
of mutations in the biotin-binding region of holocarboxylase synthetase
in biotin-responsive multiple carboxylase deficiency. Hum. Molec.
Genet. 5: 1011-1016, 1996.

4. Fuchshuber, A.; Suormala, T.; Roth, B.; Duran, M.; Michalk, D.;
Baumgartner, E. R.: Holocarboxylase synthetase deficiency: early
diagnosis and management of a new case. Europ. J. Pediat. 152: 446-449,
1993.

5. Leon-Del-Rio, A.; Leclerc, D.; Akerman, B.; Wakamatsu, N.; Gravel,
R. A.: Isolation of a cDNA encoding human holocarboxylase synthetase
by functional complementation of a biotin auxotroph of Escherichia
coli. Proc. Nat. Acad. Sci. 92: 4626-4630, 1995.

6. Morrone, A.; Malvagia, S.; Donati, M. A.; Funghini, S.; Ciani,
F.; Pela, I.; Boneh, A.; Peters, H.; Pasquini, E.; Zammarchi, E.:
Clinical findings and biochemical and molecular analysis of four patients
with holocarboxylase synthetase deficiency. Am. J. Med. Genet. 111:
10-18, 2002.

7. Narang, M. A.; Dumas, R.; Ayer, L. M.; Gravel, R. A.: Reduced
histone biotinylation in multiple carboxylase deficiency patients:
a nuclear role for holocarboxylase synthetase. Hum. Molec. Genet. 13:
15-23, 2004.

8. Narisawa, K.; Arai, N.; Igarashi, Y.; Satoh, T.; Tada, K.: Clinical
and biochemical findings on a child with multiple biotin-responsive
carboxylase deficiencies. J. Inherit. Metab. Dis. 5: 67-68, 1982.

9. Suzuki, Y.; Aoki, Y.; Ishida, Y.; Chiba, Y.; Iwamatsu, A.; Kishino,
T.; Niikawa, N.; Matsubara, Y.; Narisawa, K.: Isolation and characterization
of mutations in the human holocarboxylase synthetase cDNA. Nature
Genet. 8: 122-128, 1994.

10. Suzuki, Y.; Yang, X.; Aoki, Y.; Kure, S.; Matsubara, Y.: Mutations
in the holocarboxylase synthetase gene HLCS. Hum. Mutat. 26: 285-290,
2005.

11. Yang, X.; Aoki, Y.; Li, X.; Sakamoto, O.; Hiratsuka, M.; Gibson,
K. M.; Kure, S.; Narisawa, K.; Matsubara, Y.; Suzuki, Y.: Haplotype
analysis suggests that the two predominant mutations in Japanese patients
with holocarboxylase synthetase deficiency are founder mutations. J.
Hum. Genet. 45: 358-362, 2000.

12. Yang, X.; Aoki, Y.; Li, X.; Sakamoto, O.; Hiratsuka, M.; Kure,
S.; Taheri, S.; Christensen, E.; Inui, K.; Kubota, M.; Ohira, M.;
Ohki, M.; and 10 others: Structure of human holocarboxylase synthetase
gene and mutation spectrum of holocarboxylase synthetase deficiency. Hum.
Genet. 109: 526-534, 2001.

13. Zhang, X. X.; Leon-Del-Rio, A.; Gravel, R. A.; Eydoux, P.: Assignment
of holocarboxylase synthetase gene (HLCS) to human chromosome band
21q22.1 and to mouse chromosome band 16C4 by in situ hybridization. Cytogenet.
Cell Genet. 76: 179 only, 1997.

*FIELD* CN
George E. Tiller - updated: 2/17/2006
Marla J. F. O'Neill - updated: 11/4/2005
Cassandra L. Kniffin - updated: 11/10/2004

*FIELD* CD
Cassandra L. Kniffin: 11/8/2004

*FIELD* ED
wwang: 03/03/2006
terry: 2/17/2006
wwang: 11/4/2005
carol: 11/29/2004
ckniffin: 11/10/2004