Full text data of ALAD
ALAD
[Confidence: high (present in two of the MS resources)]
Delta-aminolevulinic acid dehydratase; ALADH; 4.2.1.24 (Porphobilinogen synthase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Delta-aminolevulinic acid dehydratase; ALADH; 4.2.1.24 (Porphobilinogen synthase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00010314
IPI00010314 Delta-aminolevulinic aciD DehyDratase isoform b Porphobilinogen synthase, platelet, Porphyrin and heme biosynthesis (2nd step), There are two common alleles of ALAD. Individuals heterozygous or homozygous for ALAD*2 Asn-59 have significantly higher blood lead levels than do ALAD*1 Lys-59 homozygotes when exposed to environmental lead, defect: acute liver porphyria. 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 not mentioned n/a found at its expected molecular weight found at molecular weight
IPI00010314 Delta-aminolevulinic aciD DehyDratase isoform b Porphobilinogen synthase, platelet, Porphyrin and heme biosynthesis (2nd step), There are two common alleles of ALAD. Individuals heterozygous or homozygous for ALAD*2 Asn-59 have significantly higher blood lead levels than do ALAD*1 Lys-59 homozygotes when exposed to environmental lead, defect: acute liver porphyria. 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 not mentioned n/a found at its expected molecular weight found at molecular weight
UniProt
P13716
ID HEM2_HUMAN Reviewed; 330 AA.
AC P13716; A8K375; B2R6F2; Q16870; Q16871; Q9BVQ9;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JAN-1990, sequence version 1.
DT 22-JAN-2014, entry version 158.
DE RecName: Full=Delta-aminolevulinic acid dehydratase;
DE Short=ALADH;
DE EC=4.2.1.24;
DE AltName: Full=Porphobilinogen synthase;
GN Name=ALAD;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=3463993; DOI=10.1073/pnas.83.20.7703;
RA Wetmur J.G., Bishop D.F., Cantelmo C., Desnick R.J.;
RT "Human delta-aminolevulinate dehydratase: nucleotide sequence of a
RT full-length cDNA clone.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:7703-7707(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Liver;
RX PubMed=1678509; DOI=10.1093/nar/19.15.4307-a;
RA Wetmur J.G.;
RT "RsaI polymorphism in the human delta-aminolevulinate dehydratase gene
RT at 9q34.";
RL Nucleic Acids Res. 19:4307-4307(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS AHEPP TRP-240 AND
RP THR-274.
RX PubMed=1569184; DOI=10.1172/JCI115732;
RA Ishida N., Fujita H., Fukuda Y., Noguchi T., Doss M., Kappas A.,
RA Sassa S.;
RT "Cloning and expression of the defective genes from a patient with
RT delta-aminolevulinate dehydratase porphyria.";
RL J. Clin. Invest. 89:1431-1437(1992).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain, 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 [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ASN-59.
RG NIEHS SNPs program;
RL Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (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 [8]
RP PROTEIN SEQUENCE OF 1-17.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [9]
RP ACTIVE SITE.
RX PubMed=3092810;
RA Gibbs P.N.B., Jordan P.M.;
RT "Identification of lysine at the active site of human 5-
RT aminolevulinate dehydratase.";
RL Biochem. J. 236:447-451(1986).
RN [10]
RP ENZYME REGULATION, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL
RP PROPERTIES, COFACTOR, MASS SPECTROMETRY, AND MUTAGENESIS OF CYS-122;
RP CYS-124; HIS-131; CYS-132 AND CYS-223.
RX PubMed=11032836; DOI=10.1074/jbc.M007663200;
RA Jaffe E.K., Martins J., Li J., Kervinen J., Dunbrack R.L. Jr.;
RT "The molecular mechanism of lead inhibition of human porphobilinogen
RT synthase.";
RL J. Biol. Chem. 276:1531-1537(2001).
RN [11]
RP FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, AND ENZYME REGULATION.
RX PubMed=19812033; DOI=10.1074/jbc.M109.026294;
RA Lawrence S.H., Ramirez U.D., Selwood T., Stith L., Jaffe E.K.;
RT "Allosteric inhibition of human porphobilinogen synthase.";
RL J. Biol. Chem. 284:35807-35817(2009).
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 X-RAY CRYSTALLOGRAPHY (2.83 ANGSTROMS) IN COMPLEX WITH PORPHOBILINOGEN
RP AND ZINC IONS.
RA Mills-Davies N.L., Thompson D., Cooper J.B., Shoolingin-Jordan P.M.;
RT "The crystal structure of human Ala-dehydratase.";
RL Submitted (OCT-1998) to the PDB data bank.
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF MUTANT LEU-12 IN COMPLEX WITH
RP SUBSTRATE ANALOG, SUBUNIT, MASS SPECTROMETRY, CATALYTIC ACTIVITY, AND
RP ENZYME REGULATION.
RX PubMed=12897770; DOI=10.1038/nsb963;
RA Breinig S., Kervinen J., Stith L., Wasson A.S., Fairman R.,
RA Wlodawer A., Zdanov A., Jaffe E.K.;
RT "Control of tetrapyrrole biosynthesis by alternate quaternary forms of
RT porphobilinogen synthase.";
RL Nat. Struct. Biol. 10:757-763(2003).
RN [15]
RP VARIANT ASN-59.
RX PubMed=1716854;
RA Wetmur J.G., Kaya A.H., Plewinska M., Desnick R.J.;
RT "Molecular characterization of the human delta-aminolevulinate
RT dehydratase 2 (ALAD2) allele: implications for molecular screening of
RT individuals for genetic susceptibility to lead poisoning.";
RL Am. J. Hum. Genet. 49:757-763(1991).
RN [16]
RP VARIANTS AHEPP ARG-133 AND MET-275.
RX PubMed=2063868;
RA Plewinska M., Thunell S., Holmberg L., Wetmur J.G., Desnick R.J.;
RT "Delta-aminolevulinate dehydratase deficient porphyria: identification
RT of the molecular lesions in a severely affected homozygote.";
RL Am. J. Hum. Genet. 49:167-174(1991).
RN [17]
RP VARIANTS AHEPP TRP-240 AND THR-274, AND CHARACTERIZATION OF VARIANTS
RP AHEPP TRP-240 AND THR-274.
RX PubMed=1309003;
RA Sassa S., Ishida N., Fujita H., Fukuda Y., Noguchi T., Doss M.,
RA Kappas A.;
RT "Cloning and expression of the defective genes in delta-
RT aminolevulinate dehydratase porphyria: compound heterozygosity in this
RT hereditary liver disease.";
RL Trans. Assoc. Am. Physicians 105:250-259(1992).
RN [18]
RP VARIANT LEU-12, AND CHARACTERIZATION OF VARIANT LEU-12.
RX PubMed=10519994; DOI=10.1046/j.1365-2141.1999.01647.x;
RA Akagi R., Yasui Y., Harper P., Sassa S.;
RT "A novel mutation of delta-aminolaevulinate dehydratase in a healthy
RT child with 12% erythrocyte enzyme activity.";
RL Br. J. Haematol. 106:931-937(1999).
RN [19]
RP VARIANT AHEPP MET-153, AND CHARACTERIZATION OF VARIANT AHEPP MET-153.
RX PubMed=10706561; DOI=10.1002/hep.510310321;
RA Akagi R., Shimizu R., Furuyama K., Doss M.O., Sassa S.;
RT "Novel molecular defects of the delta-aminolevulinate dehydratase gene
RT in a patient with inherited acute hepatic porphyria.";
RL Hepatology 31:704-708(2000).
RN [20]
RP VARIANT LEU-12.
RX PubMed=16398658; DOI=10.1111/j.1365-2141.2005.05852.x;
RA Akagi R., Inoue R., Muranaka S., Tahara T., Taketani S.,
RA Anderson K.E., Phillips J.D., Sassa S.;
RT "Dual gene defects involving delta-aminolaevulinate dehydratase and
RT coproporphyrinogen oxidase in a porphyria patient.";
RL Br. J. Haematol. 132:237-243(2006).
RN [21]
RP CHARACTERIZATION OF VARIANTS AHEPP ARG-133; MET-153; TRP-240; THR-274
RP AND MET-275, AND CHARACTERIZATION OF VARIANTS LEU-12 AND ASN-59.
RX PubMed=17236137; DOI=10.1086/511444;
RA Jaffe E.K., Stith L.;
RT "ALAD porphyria is a conformational disease.";
RL Am. J. Hum. Genet. 80:329-337(2007).
CC -!- FUNCTION: Catalyzes an early step in the biosynthesis of
CC tetrapyrroles. Binds two molecules of 5-aminolevulinate per
CC subunit, each at a distinct site, and catalyzes their condensation
CC to form porphobilinogen.
CC -!- CATALYTIC ACTIVITY: 2 5-aminolevulinate = porphobilinogen + 2
CC H(2)O.
CC -!- COFACTOR: Binds 8 zinc ions per octamer. Requires four zinc ions
CC per octamer for full catalytic activity. Can bind up to 2 zinc
CC ions per subunit.
CC -!- ENZYME REGULATION: Can alternate between a fully active
CC homooctamer and a low-activity homohexamer. A bound magnesium ion
CC may promote the assembly of the fully active homooctamer. The
CC magnesium-binding site is absent in the low-activity homohexamer.
CC Inhibited by compounds that favor the hexameric state. Inhibited
CC by divalent lead ions. The lead ions partially displace the zinc
CC cofactor.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.09 mM for 5-aminolevulinate at pH 7;
CC Vmax=43 umol/h/mg enzyme at pH 7;
CC pH dependence:
CC Optimum pH is 6.8-7.3;
CC -!- PATHWAY: Porphyrin-containing compound metabolism; protoporphyrin-
CC IX biosynthesis; coproporphyrinogen-III from 5-aminolevulinate:
CC step 1/4.
CC -!- SUBUNIT: Homooctamer; active form. Homohexamer; low activity form.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P13716-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P13716-2; Sequence=VSP_037866;
CC -!- POLYMORPHISM: There are two common alleles of ALAD. Individuals
CC heterozygous or homozygous for ALAD*2 Asn-59 have significantly
CC higher blood lead levels than do ALAD*1 Lys-59 homozygotes when
CC exposed to environmental lead.
CC -!- DISEASE: Acute hepatic porphyria (AHEPP) [MIM:612740]: A form of
CC porphyria. Porphyrias are inherited defects in the biosynthesis of
CC heme, resulting in the accumulation and increased excretion of
CC porphyrins or porphyrin precursors. They are classified as
CC erythropoietic or hepatic, depending on whether the enzyme
CC deficiency occurs in red blood cells or in the liver. AHP is
CC characterized by attacks of gastrointestinal disturbances,
CC abdominal colic, paralyses and peripheral neuropathy. Most attacks
CC are precipitated by drugs, alcohol, caloric deprivation,
CC infections, or endocrine factors. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the ALADH family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH00977.3; Type=Erroneous initiation;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ALAD";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/alad/";
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DR EMBL; M13928; AAA51687.1; -; mRNA.
DR EMBL; X64467; CAA45796.1; -; Genomic_DNA.
DR EMBL; S99468; AAC60581.1; -; mRNA.
DR EMBL; S99471; AAC60582.1; -; mRNA.
DR EMBL; AK290490; BAF83179.1; -; mRNA.
DR EMBL; AK312552; BAG35449.1; -; mRNA.
DR EMBL; AY319481; AAP72012.1; -; Genomic_DNA.
DR EMBL; AL137066; CAH70099.3; -; Genomic_DNA.
DR EMBL; BC000977; AAH00977.3; ALT_INIT; mRNA.
DR PIR; A26478; A26478.
DR RefSeq; NP_000022.3; NM_000031.5.
DR RefSeq; XP_005251856.1; XM_005251799.1.
DR UniGene; Hs.1227; -.
DR PDB; 1E51; X-ray; 2.83 A; A/B=1-330.
DR PDB; 1PV8; X-ray; 2.20 A; A/B=1-330.
DR PDBsum; 1E51; -.
DR PDBsum; 1PV8; -.
DR ProteinModelPortal; P13716; -.
DR SMR; P13716; 1-328.
DR STRING; 9606.ENSP00000386284; -.
DR ChEMBL; CHEMBL3126; -.
DR DrugBank; DB00855; Aminolevulinic acid.
DR PhosphoSite; P13716; -.
DR DMDM; 122833; -.
DR OGP; P13716; -.
DR REPRODUCTION-2DPAGE; P13716; -.
DR SWISS-2DPAGE; P13716; -.
DR PaxDb; P13716; -.
DR PRIDE; P13716; -.
DR Ensembl; ENST00000409155; ENSP00000386284; ENSG00000148218.
DR GeneID; 210; -.
DR KEGG; hsa:210; -.
DR UCSC; uc011lxf.2; human.
DR CTD; 210; -.
DR GeneCards; GC09M116148; -.
DR HGNC; HGNC:395; ALAD.
DR HPA; HPA021023; -.
DR HPA; HPA022124; -.
DR MIM; 125270; gene.
DR MIM; 612740; phenotype.
DR neXtProt; NX_P13716; -.
DR Orphanet; 100924; Porphyria due to ALA dehydratase deficiency.
DR PharmGKB; PA24687; -.
DR eggNOG; COG0113; -.
DR HOGENOM; HOG000020323; -.
DR HOVERGEN; HBG001222; -.
DR KO; K01698; -.
DR OMA; IITYFTP; -.
DR OrthoDB; EOG751NFP; -.
DR BioCyc; MetaCyc:HS07501-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00251; UER00318.
DR ChiTaRS; ALAD; human.
DR EvolutionaryTrace; P13716; -.
DR GeneWiki; ALAD; -.
DR GenomeRNAi; 210; -.
DR NextBio; 840; -.
DR PRO; PR:P13716; -.
DR ArrayExpress; P13716; -.
DR Bgee; P13716; -.
DR CleanEx; HS_ALAD; -.
DR Genevestigator; P13716; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0032791; F:lead ion binding; IDA:UniProtKB.
DR GO; GO:0004655; F:porphobilinogen synthase activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0071353; P:cellular response to interleukin-4; IEA:Ensembl.
DR GO; GO:0006783; P:heme biosynthetic process; IDA:UniProtKB.
DR GO; GO:0051260; P:protein homooligomerization; IPI:UniProtKB.
DR GO; GO:0006782; P:protoporphyrinogen IX biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 3.20.20.70; -; 1.
DR InterPro; IPR013785; Aldolase_TIM.
DR InterPro; IPR001731; Porphobilinogen_synth.
DR PANTHER; PTHR11458; PTHR11458; 1.
DR Pfam; PF00490; ALAD; 1.
DR PIRSF; PIRSF001415; Porphbilin_synth; 1.
DR PRINTS; PR00144; DALDHYDRTASE.
DR SMART; SM01004; ALAD; 1.
DR PROSITE; PS00169; D_ALA_DEHYDRATASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Allosteric enzyme; Alternative splicing;
KW Complete proteome; Direct protein sequencing; Disease mutation;
KW Heme biosynthesis; Lyase; Metal-binding; Phosphoprotein; Polymorphism;
KW Porphyrin biosynthesis; Reference proteome; Zinc.
FT CHAIN 1 330 Delta-aminolevulinic acid dehydratase.
FT /FTId=PRO_0000140526.
FT ACT_SITE 199 199 Schiff-base intermediate with substrate.
FT ACT_SITE 252 252 Schiff-base intermediate with substrate.
FT METAL 122 122 Zinc 1; catalytic.
FT METAL 124 124 Zinc 1; catalytic.
FT METAL 131 131 Zinc 2.
FT METAL 132 132 Zinc 1; catalytic.
FT METAL 223 223 Zinc 2.
FT BINDING 209 209 Substrate 1.
FT BINDING 221 221 Substrate 1.
FT BINDING 279 279 Substrate 2.
FT BINDING 318 318 Substrate 2.
FT MOD_RES 215 215 Phosphoserine (By similarity).
FT VAR_SEQ 1 38 MQPQSVLHSGYFHPLLRAWQTATTTLNASNLIYPIFVT ->
FT MPPTSSTPSLSRPGLGQAGKPDTGSHPPPTISTSIFLSCFP
FT TIPLSRPRTTGPSHSYQSISHPRSCR (in isoform
FT 2).
FT /FTId=VSP_037866.
FT VARIANT 12 12 F -> L (in an asymptomatic patient with
FT ALAD deficiency; hexamer with almost no
FT residual activity; also found in a
FT hereditary coproporphyria patient
FT carrying the R-279 mutation in CPOX).
FT /FTId=VAR_020973.
FT VARIANT 59 59 K -> N (in allele ALAD*2; 10% of
FT population; fully active octamer;
FT dbSNP:rs1800435).
FT /FTId=VAR_003633.
FT VARIANT 133 133 G -> R (in AHEPP; mixture of about 50%
FT hexamer and 50% octamer; about 10%
FT residual activity).
FT /FTId=VAR_003634.
FT VARIANT 153 153 V -> M (in AHEPP; about 95% octamer;
FT about 40% residual activity).
FT /FTId=VAR_020974.
FT VARIANT 240 240 R -> W (in AHEPP; mixture of about 80%
FT hexamer and 20% octamer; about 4%
FT residual activity).
FT /FTId=VAR_003635.
FT VARIANT 274 274 A -> T (in AHEPP; mixture of about 14%
FT hexamer and 86% octamer; about 20% enzyme
FT residual activity).
FT /FTId=VAR_003636.
FT VARIANT 275 275 V -> M (in AHEPP; mainly octamer; reduced
FT activity).
FT /FTId=VAR_003637.
FT MUTAGEN 122 122 C->A: Reduces enzyme activity about
FT 1000000-fold; when associated with A-124
FT and A-132.
FT MUTAGEN 124 124 C->A: Reduces enzyme activity about
FT 1000000-fold; when associated with A-122
FT and A-132.
FT MUTAGEN 131 131 H->A: No effect on catalytic activity;
FT when associated with A-223.
FT MUTAGEN 132 132 C->A: Reduces enzyme activity about
FT 1000000-fold; when associated with A-122
FT and A-124.
FT MUTAGEN 223 223 C->A: No effect on catalytic activity;
FT when associated with A-131.
FT HELIX 8 10
FT HELIX 14 20
FT TURN 21 24
FT HELIX 28 30
FT STRAND 31 37
FT STRAND 44 46
FT STRAND 48 50
FT STRAND 54 56
FT HELIX 58 71
FT STRAND 75 80
FT STRAND 83 85
FT STRAND 94 98
FT HELIX 100 111
FT STRAND 115 121
FT STRAND 123 126
FT HELIX 141 160
FT STRAND 163 167
FT HELIX 174 184
FT TURN 188 190
FT STRAND 192 194
FT STRAND 198 200
FT HELIX 203 205
FT HELIX 206 210
FT HELIX 221 223
FT HELIX 231 243
FT STRAND 247 253
FT HELIX 255 257
FT HELIX 258 267
FT STRAND 273 277
FT HELIX 279 290
FT HELIX 296 310
FT STRAND 313 317
FT HELIX 320 326
FT TURN 327 329
SQ SEQUENCE 330 AA; 36295 MW; E005F3055F6D9403 CRC64;
MQPQSVLHSG YFHPLLRAWQ TATTTLNASN LIYPIFVTDV PDDIQPITSL PGVARYGVKR
LEEMLRPLVE EGLRCVLIFG VPSRVPKDER GSAADSEESP AIEAIHLLRK TFPNLLVACD
VCLCPYTSHG HCGLLSENGA FRAEESRQRL AEVALAYAKA GCQVVAPSDM MDGRVEAIKE
ALMAHGLGNR VSVMSYSAKF ASCFYGPFRD AAKSSPAFGD RRCYQLPPGA RGLALRAVDR
DVREGADMLM VKPGMPYLDI VREVKDKHPD LPLAVYHVSG EFAMLWHGAQ AGAFDLKAAV
LEAMTAFRRA GADIIITYYT PQLLQWLKEE
//
ID HEM2_HUMAN Reviewed; 330 AA.
AC P13716; A8K375; B2R6F2; Q16870; Q16871; Q9BVQ9;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JAN-1990, sequence version 1.
DT 22-JAN-2014, entry version 158.
DE RecName: Full=Delta-aminolevulinic acid dehydratase;
DE Short=ALADH;
DE EC=4.2.1.24;
DE AltName: Full=Porphobilinogen synthase;
GN Name=ALAD;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=3463993; DOI=10.1073/pnas.83.20.7703;
RA Wetmur J.G., Bishop D.F., Cantelmo C., Desnick R.J.;
RT "Human delta-aminolevulinate dehydratase: nucleotide sequence of a
RT full-length cDNA clone.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:7703-7707(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Liver;
RX PubMed=1678509; DOI=10.1093/nar/19.15.4307-a;
RA Wetmur J.G.;
RT "RsaI polymorphism in the human delta-aminolevulinate dehydratase gene
RT at 9q34.";
RL Nucleic Acids Res. 19:4307-4307(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS AHEPP TRP-240 AND
RP THR-274.
RX PubMed=1569184; DOI=10.1172/JCI115732;
RA Ishida N., Fujita H., Fukuda Y., Noguchi T., Doss M., Kappas A.,
RA Sassa S.;
RT "Cloning and expression of the defective genes from a patient with
RT delta-aminolevulinate dehydratase porphyria.";
RL J. Clin. Invest. 89:1431-1437(1992).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain, 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 [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ASN-59.
RG NIEHS SNPs program;
RL Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (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 [8]
RP PROTEIN SEQUENCE OF 1-17.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [9]
RP ACTIVE SITE.
RX PubMed=3092810;
RA Gibbs P.N.B., Jordan P.M.;
RT "Identification of lysine at the active site of human 5-
RT aminolevulinate dehydratase.";
RL Biochem. J. 236:447-451(1986).
RN [10]
RP ENZYME REGULATION, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL
RP PROPERTIES, COFACTOR, MASS SPECTROMETRY, AND MUTAGENESIS OF CYS-122;
RP CYS-124; HIS-131; CYS-132 AND CYS-223.
RX PubMed=11032836; DOI=10.1074/jbc.M007663200;
RA Jaffe E.K., Martins J., Li J., Kervinen J., Dunbrack R.L. Jr.;
RT "The molecular mechanism of lead inhibition of human porphobilinogen
RT synthase.";
RL J. Biol. Chem. 276:1531-1537(2001).
RN [11]
RP FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, AND ENZYME REGULATION.
RX PubMed=19812033; DOI=10.1074/jbc.M109.026294;
RA Lawrence S.H., Ramirez U.D., Selwood T., Stith L., Jaffe E.K.;
RT "Allosteric inhibition of human porphobilinogen synthase.";
RL J. Biol. Chem. 284:35807-35817(2009).
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 X-RAY CRYSTALLOGRAPHY (2.83 ANGSTROMS) IN COMPLEX WITH PORPHOBILINOGEN
RP AND ZINC IONS.
RA Mills-Davies N.L., Thompson D., Cooper J.B., Shoolingin-Jordan P.M.;
RT "The crystal structure of human Ala-dehydratase.";
RL Submitted (OCT-1998) to the PDB data bank.
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF MUTANT LEU-12 IN COMPLEX WITH
RP SUBSTRATE ANALOG, SUBUNIT, MASS SPECTROMETRY, CATALYTIC ACTIVITY, AND
RP ENZYME REGULATION.
RX PubMed=12897770; DOI=10.1038/nsb963;
RA Breinig S., Kervinen J., Stith L., Wasson A.S., Fairman R.,
RA Wlodawer A., Zdanov A., Jaffe E.K.;
RT "Control of tetrapyrrole biosynthesis by alternate quaternary forms of
RT porphobilinogen synthase.";
RL Nat. Struct. Biol. 10:757-763(2003).
RN [15]
RP VARIANT ASN-59.
RX PubMed=1716854;
RA Wetmur J.G., Kaya A.H., Plewinska M., Desnick R.J.;
RT "Molecular characterization of the human delta-aminolevulinate
RT dehydratase 2 (ALAD2) allele: implications for molecular screening of
RT individuals for genetic susceptibility to lead poisoning.";
RL Am. J. Hum. Genet. 49:757-763(1991).
RN [16]
RP VARIANTS AHEPP ARG-133 AND MET-275.
RX PubMed=2063868;
RA Plewinska M., Thunell S., Holmberg L., Wetmur J.G., Desnick R.J.;
RT "Delta-aminolevulinate dehydratase deficient porphyria: identification
RT of the molecular lesions in a severely affected homozygote.";
RL Am. J. Hum. Genet. 49:167-174(1991).
RN [17]
RP VARIANTS AHEPP TRP-240 AND THR-274, AND CHARACTERIZATION OF VARIANTS
RP AHEPP TRP-240 AND THR-274.
RX PubMed=1309003;
RA Sassa S., Ishida N., Fujita H., Fukuda Y., Noguchi T., Doss M.,
RA Kappas A.;
RT "Cloning and expression of the defective genes in delta-
RT aminolevulinate dehydratase porphyria: compound heterozygosity in this
RT hereditary liver disease.";
RL Trans. Assoc. Am. Physicians 105:250-259(1992).
RN [18]
RP VARIANT LEU-12, AND CHARACTERIZATION OF VARIANT LEU-12.
RX PubMed=10519994; DOI=10.1046/j.1365-2141.1999.01647.x;
RA Akagi R., Yasui Y., Harper P., Sassa S.;
RT "A novel mutation of delta-aminolaevulinate dehydratase in a healthy
RT child with 12% erythrocyte enzyme activity.";
RL Br. J. Haematol. 106:931-937(1999).
RN [19]
RP VARIANT AHEPP MET-153, AND CHARACTERIZATION OF VARIANT AHEPP MET-153.
RX PubMed=10706561; DOI=10.1002/hep.510310321;
RA Akagi R., Shimizu R., Furuyama K., Doss M.O., Sassa S.;
RT "Novel molecular defects of the delta-aminolevulinate dehydratase gene
RT in a patient with inherited acute hepatic porphyria.";
RL Hepatology 31:704-708(2000).
RN [20]
RP VARIANT LEU-12.
RX PubMed=16398658; DOI=10.1111/j.1365-2141.2005.05852.x;
RA Akagi R., Inoue R., Muranaka S., Tahara T., Taketani S.,
RA Anderson K.E., Phillips J.D., Sassa S.;
RT "Dual gene defects involving delta-aminolaevulinate dehydratase and
RT coproporphyrinogen oxidase in a porphyria patient.";
RL Br. J. Haematol. 132:237-243(2006).
RN [21]
RP CHARACTERIZATION OF VARIANTS AHEPP ARG-133; MET-153; TRP-240; THR-274
RP AND MET-275, AND CHARACTERIZATION OF VARIANTS LEU-12 AND ASN-59.
RX PubMed=17236137; DOI=10.1086/511444;
RA Jaffe E.K., Stith L.;
RT "ALAD porphyria is a conformational disease.";
RL Am. J. Hum. Genet. 80:329-337(2007).
CC -!- FUNCTION: Catalyzes an early step in the biosynthesis of
CC tetrapyrroles. Binds two molecules of 5-aminolevulinate per
CC subunit, each at a distinct site, and catalyzes their condensation
CC to form porphobilinogen.
CC -!- CATALYTIC ACTIVITY: 2 5-aminolevulinate = porphobilinogen + 2
CC H(2)O.
CC -!- COFACTOR: Binds 8 zinc ions per octamer. Requires four zinc ions
CC per octamer for full catalytic activity. Can bind up to 2 zinc
CC ions per subunit.
CC -!- ENZYME REGULATION: Can alternate between a fully active
CC homooctamer and a low-activity homohexamer. A bound magnesium ion
CC may promote the assembly of the fully active homooctamer. The
CC magnesium-binding site is absent in the low-activity homohexamer.
CC Inhibited by compounds that favor the hexameric state. Inhibited
CC by divalent lead ions. The lead ions partially displace the zinc
CC cofactor.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.09 mM for 5-aminolevulinate at pH 7;
CC Vmax=43 umol/h/mg enzyme at pH 7;
CC pH dependence:
CC Optimum pH is 6.8-7.3;
CC -!- PATHWAY: Porphyrin-containing compound metabolism; protoporphyrin-
CC IX biosynthesis; coproporphyrinogen-III from 5-aminolevulinate:
CC step 1/4.
CC -!- SUBUNIT: Homooctamer; active form. Homohexamer; low activity form.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P13716-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P13716-2; Sequence=VSP_037866;
CC -!- POLYMORPHISM: There are two common alleles of ALAD. Individuals
CC heterozygous or homozygous for ALAD*2 Asn-59 have significantly
CC higher blood lead levels than do ALAD*1 Lys-59 homozygotes when
CC exposed to environmental lead.
CC -!- DISEASE: Acute hepatic porphyria (AHEPP) [MIM:612740]: A form of
CC porphyria. Porphyrias are inherited defects in the biosynthesis of
CC heme, resulting in the accumulation and increased excretion of
CC porphyrins or porphyrin precursors. They are classified as
CC erythropoietic or hepatic, depending on whether the enzyme
CC deficiency occurs in red blood cells or in the liver. AHP is
CC characterized by attacks of gastrointestinal disturbances,
CC abdominal colic, paralyses and peripheral neuropathy. Most attacks
CC are precipitated by drugs, alcohol, caloric deprivation,
CC infections, or endocrine factors. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the ALADH family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH00977.3; Type=Erroneous initiation;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ALAD";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/alad/";
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DR EMBL; M13928; AAA51687.1; -; mRNA.
DR EMBL; X64467; CAA45796.1; -; Genomic_DNA.
DR EMBL; S99468; AAC60581.1; -; mRNA.
DR EMBL; S99471; AAC60582.1; -; mRNA.
DR EMBL; AK290490; BAF83179.1; -; mRNA.
DR EMBL; AK312552; BAG35449.1; -; mRNA.
DR EMBL; AY319481; AAP72012.1; -; Genomic_DNA.
DR EMBL; AL137066; CAH70099.3; -; Genomic_DNA.
DR EMBL; BC000977; AAH00977.3; ALT_INIT; mRNA.
DR PIR; A26478; A26478.
DR RefSeq; NP_000022.3; NM_000031.5.
DR RefSeq; XP_005251856.1; XM_005251799.1.
DR UniGene; Hs.1227; -.
DR PDB; 1E51; X-ray; 2.83 A; A/B=1-330.
DR PDB; 1PV8; X-ray; 2.20 A; A/B=1-330.
DR PDBsum; 1E51; -.
DR PDBsum; 1PV8; -.
DR ProteinModelPortal; P13716; -.
DR SMR; P13716; 1-328.
DR STRING; 9606.ENSP00000386284; -.
DR ChEMBL; CHEMBL3126; -.
DR DrugBank; DB00855; Aminolevulinic acid.
DR PhosphoSite; P13716; -.
DR DMDM; 122833; -.
DR OGP; P13716; -.
DR REPRODUCTION-2DPAGE; P13716; -.
DR SWISS-2DPAGE; P13716; -.
DR PaxDb; P13716; -.
DR PRIDE; P13716; -.
DR Ensembl; ENST00000409155; ENSP00000386284; ENSG00000148218.
DR GeneID; 210; -.
DR KEGG; hsa:210; -.
DR UCSC; uc011lxf.2; human.
DR CTD; 210; -.
DR GeneCards; GC09M116148; -.
DR HGNC; HGNC:395; ALAD.
DR HPA; HPA021023; -.
DR HPA; HPA022124; -.
DR MIM; 125270; gene.
DR MIM; 612740; phenotype.
DR neXtProt; NX_P13716; -.
DR Orphanet; 100924; Porphyria due to ALA dehydratase deficiency.
DR PharmGKB; PA24687; -.
DR eggNOG; COG0113; -.
DR HOGENOM; HOG000020323; -.
DR HOVERGEN; HBG001222; -.
DR KO; K01698; -.
DR OMA; IITYFTP; -.
DR OrthoDB; EOG751NFP; -.
DR BioCyc; MetaCyc:HS07501-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00251; UER00318.
DR ChiTaRS; ALAD; human.
DR EvolutionaryTrace; P13716; -.
DR GeneWiki; ALAD; -.
DR GenomeRNAi; 210; -.
DR NextBio; 840; -.
DR PRO; PR:P13716; -.
DR ArrayExpress; P13716; -.
DR Bgee; P13716; -.
DR CleanEx; HS_ALAD; -.
DR Genevestigator; P13716; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0032791; F:lead ion binding; IDA:UniProtKB.
DR GO; GO:0004655; F:porphobilinogen synthase activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0071353; P:cellular response to interleukin-4; IEA:Ensembl.
DR GO; GO:0006783; P:heme biosynthetic process; IDA:UniProtKB.
DR GO; GO:0051260; P:protein homooligomerization; IPI:UniProtKB.
DR GO; GO:0006782; P:protoporphyrinogen IX biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 3.20.20.70; -; 1.
DR InterPro; IPR013785; Aldolase_TIM.
DR InterPro; IPR001731; Porphobilinogen_synth.
DR PANTHER; PTHR11458; PTHR11458; 1.
DR Pfam; PF00490; ALAD; 1.
DR PIRSF; PIRSF001415; Porphbilin_synth; 1.
DR PRINTS; PR00144; DALDHYDRTASE.
DR SMART; SM01004; ALAD; 1.
DR PROSITE; PS00169; D_ALA_DEHYDRATASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Allosteric enzyme; Alternative splicing;
KW Complete proteome; Direct protein sequencing; Disease mutation;
KW Heme biosynthesis; Lyase; Metal-binding; Phosphoprotein; Polymorphism;
KW Porphyrin biosynthesis; Reference proteome; Zinc.
FT CHAIN 1 330 Delta-aminolevulinic acid dehydratase.
FT /FTId=PRO_0000140526.
FT ACT_SITE 199 199 Schiff-base intermediate with substrate.
FT ACT_SITE 252 252 Schiff-base intermediate with substrate.
FT METAL 122 122 Zinc 1; catalytic.
FT METAL 124 124 Zinc 1; catalytic.
FT METAL 131 131 Zinc 2.
FT METAL 132 132 Zinc 1; catalytic.
FT METAL 223 223 Zinc 2.
FT BINDING 209 209 Substrate 1.
FT BINDING 221 221 Substrate 1.
FT BINDING 279 279 Substrate 2.
FT BINDING 318 318 Substrate 2.
FT MOD_RES 215 215 Phosphoserine (By similarity).
FT VAR_SEQ 1 38 MQPQSVLHSGYFHPLLRAWQTATTTLNASNLIYPIFVT ->
FT MPPTSSTPSLSRPGLGQAGKPDTGSHPPPTISTSIFLSCFP
FT TIPLSRPRTTGPSHSYQSISHPRSCR (in isoform
FT 2).
FT /FTId=VSP_037866.
FT VARIANT 12 12 F -> L (in an asymptomatic patient with
FT ALAD deficiency; hexamer with almost no
FT residual activity; also found in a
FT hereditary coproporphyria patient
FT carrying the R-279 mutation in CPOX).
FT /FTId=VAR_020973.
FT VARIANT 59 59 K -> N (in allele ALAD*2; 10% of
FT population; fully active octamer;
FT dbSNP:rs1800435).
FT /FTId=VAR_003633.
FT VARIANT 133 133 G -> R (in AHEPP; mixture of about 50%
FT hexamer and 50% octamer; about 10%
FT residual activity).
FT /FTId=VAR_003634.
FT VARIANT 153 153 V -> M (in AHEPP; about 95% octamer;
FT about 40% residual activity).
FT /FTId=VAR_020974.
FT VARIANT 240 240 R -> W (in AHEPP; mixture of about 80%
FT hexamer and 20% octamer; about 4%
FT residual activity).
FT /FTId=VAR_003635.
FT VARIANT 274 274 A -> T (in AHEPP; mixture of about 14%
FT hexamer and 86% octamer; about 20% enzyme
FT residual activity).
FT /FTId=VAR_003636.
FT VARIANT 275 275 V -> M (in AHEPP; mainly octamer; reduced
FT activity).
FT /FTId=VAR_003637.
FT MUTAGEN 122 122 C->A: Reduces enzyme activity about
FT 1000000-fold; when associated with A-124
FT and A-132.
FT MUTAGEN 124 124 C->A: Reduces enzyme activity about
FT 1000000-fold; when associated with A-122
FT and A-132.
FT MUTAGEN 131 131 H->A: No effect on catalytic activity;
FT when associated with A-223.
FT MUTAGEN 132 132 C->A: Reduces enzyme activity about
FT 1000000-fold; when associated with A-122
FT and A-124.
FT MUTAGEN 223 223 C->A: No effect on catalytic activity;
FT when associated with A-131.
FT HELIX 8 10
FT HELIX 14 20
FT TURN 21 24
FT HELIX 28 30
FT STRAND 31 37
FT STRAND 44 46
FT STRAND 48 50
FT STRAND 54 56
FT HELIX 58 71
FT STRAND 75 80
FT STRAND 83 85
FT STRAND 94 98
FT HELIX 100 111
FT STRAND 115 121
FT STRAND 123 126
FT HELIX 141 160
FT STRAND 163 167
FT HELIX 174 184
FT TURN 188 190
FT STRAND 192 194
FT STRAND 198 200
FT HELIX 203 205
FT HELIX 206 210
FT HELIX 221 223
FT HELIX 231 243
FT STRAND 247 253
FT HELIX 255 257
FT HELIX 258 267
FT STRAND 273 277
FT HELIX 279 290
FT HELIX 296 310
FT STRAND 313 317
FT HELIX 320 326
FT TURN 327 329
SQ SEQUENCE 330 AA; 36295 MW; E005F3055F6D9403 CRC64;
MQPQSVLHSG YFHPLLRAWQ TATTTLNASN LIYPIFVTDV PDDIQPITSL PGVARYGVKR
LEEMLRPLVE EGLRCVLIFG VPSRVPKDER GSAADSEESP AIEAIHLLRK TFPNLLVACD
VCLCPYTSHG HCGLLSENGA FRAEESRQRL AEVALAYAKA GCQVVAPSDM MDGRVEAIKE
ALMAHGLGNR VSVMSYSAKF ASCFYGPFRD AAKSSPAFGD RRCYQLPPGA RGLALRAVDR
DVREGADMLM VKPGMPYLDI VREVKDKHPD LPLAVYHVSG EFAMLWHGAQ AGAFDLKAAV
LEAMTAFRRA GADIIITYYT PQLLQWLKEE
//
MIM
125270
*RECORD*
*FIELD* NO
125270
*FIELD* TI
*125270 DELTA-AMINOLEVULINATE DEHYDRATASE; ALAD
;;ALADH;;
PORPHOBILINOGEN SYNTHASE; PBGS
read more*FIELD* TX
DESCRIPTION
The ALAD gene encodes delta-aminolevulinate dehydratase, also known as
porphobilinogen synthase (PBGS; EC 4.2.1.24), a cytosolic enzyme that
catalyzes the second step in the porphyrin and heme biosynthetic
pathway. It forms the monopyrrole ring porphobilinogen from 2 molecules
of delta-aminolevulinate (ALA) (Ishida et al., 1992).
CLONING
Wetmur et al. (1986) identified 2 cDNAs encoding ALAD which they claimed
represented the first report of a cDNA clone for a human heme
biosynthetic enzyme. They found that the nucleotide sequences of the 2
cDNA clones differed at either position 730 or 733 and encoded 2
different charged amino acids, which was likely the basis for the
polymorphic charged isozymes of human ALAD.
GENE STRUCTURE
Kaya et al. (1994) determined that the ALAD gene spans 15.9 kb and
contains 2 alternative noncoding exons, 1A and 1B, and 11 coding exons,
2 through 12. The housekeeping transcript, which includes exon 1A and
not 1B, was identified in a human adult liver cDNA library, while an
erythroid-specific transcript, which contains exon 1B and not 1A, was
detected in a human erythroleukemia cDNA library. The promoter region
upstream of housekeeping exon 1A was GC-rich and contained 3 potential
Sp1 elements and a CCAAT box. Further upstream, there were 3 potential
GATA-1 binding sites and an AP1 site. The promoter region upstream of
erythroid-specific exon 1B had several CACCC boxes and 2 potential
GATA-1 binding sites. Kaya et al. (1994) transduced HeLa and K562 cells
with chloramphenicol acetyltransferase (CAT) constructs containing
either exon 1A or 1B. Those containing exon 1A were expressed in HeLa
cells, whereas the erythroid-specific construct containing exon 1B was
not. In contrast, the housekeeping and erythroid constructs were both
expressed in erythroleukemia cells.
MAPPING
In linkage studies, Amorim et al. (1982) excluded linkage of the ALAD
gene with MNSs, Fy, Jk, Rh, HLA, ACP1, and PGM1. Close linkage (theta
0.05 or less) was also excluded for K, PI, GPT, PGP, PGM3, GLO, and BF.
Haptoglobin showed a lod score of 0.922 at theta of 0.20 or less.
Eiberg et al. (1983) demonstrated linkage of ALAD to the ABO-AK1-ORM
linkage group on chromosome 9q. The most likely sequence was judged to
be ABO-AK1-ALADH-ORM. The lod and recombination values were as follows:
ABO-AK1 (6.27, 0.13); ABO-ALADH (5.38, 0.21); ABO-ORM (5.06, 0.27);
AK1-ORM (1.63, 0.17); ALADH-ORM (7.05, 0.13) and AK1-ALADH (2.45, 0.11).
Amorim et al. (1984) presented data supporting the chromosome 9
assignment in man. Beaumont et al. (1984) assigned ALAD to chromosome 9
by somatic cell hybrid studies. They used two enzyme assays: one
specific for the human enzyme and one indicative of both rodent and
human enzymes. The ratio of the values was used to discriminate between
positive and negative clones. Wang et al. (1984) assigned the ALAD gene
to 9q by study of human-mouse somatic cell hybrids with methods that
specifically distinguished the mouse and human enzymes. Potluri et al.
(1987) localized ALAD to 9q34 by in situ hybridization using a
radio-iodine-labeled human ALAD cDNA.
In connection with a pulsed field gel electrophoresis analysis of the
9q32-q34 region, which contains a gene for tuberous sclerosis-1
(191100), Harris et al. (1993) found that the ALAD locus was the most
proximal of the genes they studied.
ALADH is linked to ACO1 (100880) and GALT (606999) in the mouse (Nadeau
and Eicher, 1982).
MOLECULAR GENETICS
Battistuzzi et al. (1981) described electrophoretic polymorphisms of
aminolevulinate dehydratase, and showed that the enzyme is encoded by an
autosomal gene with 2 common codominant alleles (frequencies, 0.94 and
0.06). Petrucci et al. (1982) studied the polymorphism of ALADH in
Italy.
Kapotis et al. (1998) found that the frequencies of the ALADH1 and
ALADH2 alleles in Greece are 0.955 and 0.0455, respectively. Data on
gene frequencies of allelic variants were tabulated by Roychoudhury and
Nei (1988).
In a Swedish boy with severe infantile onset of acute hepatic porphyria
(612740), Plewinska et al. (1991) identified compound heterozygosity for
2 mutations in the ALAD gene (125270.0001 and 125270.0002). ALAD
activity in erythrocytes was less than 5% of control values.
ALAD porphyria is a rare autosomal recessive disorder documented, at the
time of the report of Jaffe and Stith (2007), in only 5 patients, all
compound heterozygotes for mutations in the ALAD gene. The human PBGS
enzyme exists as an equilibrium of functionally distinct quaternary
structure assemblies, known as 'morpheeins,' in which one functional
homo-oligomer can dissociate, change conformation, and reassociate into
a different oligomer. In the case of human PBGS, the 2 assemblies are a
high-activity octamer and a low-activity hexamer. Jaffe and Stith (2007)
quantified the morpheein forms of human PBGS for the common and
porphyria-associated variants. Heterologous expression in E. coli,
followed by separation of the octameric and hexameric assemblies on an
ion-exchange column, showed that the percentages of hexamers for F12L
(125270.0006) (100%), R240W (125270.0004) (80%), G133R (125270.0001)
(48%), A274T (125270.0005) (14%), and 2 other variants were appreciably
larger than for the wildtype proteins K59 and N59 (see 125270.0003) (0%
and 3%, respectively). All 8 porphyria-associated variants showed an
increased propensity to form the hexamer, according to a kinetic
analysis. Thus, all porphyria-associated human PBGS variants shift the
morpheein equilibrium for PBGS toward the less active hexamer. Jaffe and
Stith (2007) proposed that the disequilibrium of morpheein assemblies
broadens the definition of conformational diseases beyond the prion
disorders and that ALAD porphyria is the first example of a
morpheein-based conformational disease.
*FIELD* AV
.0001
PORPHYRIA, ACUTE HEPATIC
ALAD, GLY133ARG
In a Swedish boy with severe infantile-onset of acute hepatic porphyria
(612740) previously reported by Fujita et al. (1987), Plewinska et al.
(1991) identified compound heterozygosity for 2 mutations in the ALAD
gene: a 397G-A transition in exon 5 resulting in a gly133-to-arg (G133R)
substitution inherited from the mother, and an 823G-A transition in exon
11 resulting in a val275-to-met (V275M; 125270.0002) substitution
inherited from the father. Both mutations occurred at CpG dinucleotides.
The G133R substitution occurred at the carboxyl end of the highly
conserved zinc-binding site in the enzyme subunit. The mutations
resulted in markedly reduced enzyme activity at less than 5% of normal
values. The couple had experienced 4 successive spontaneous abortions
(Fujita et al., 1987).
.0002
PORPHYRIA, ACUTE HEPATIC
ALAD, VAL275MET
See 125270.0001 and Plewinska et al. (1991).
.0003
AMINOLEVULINATE DEHYDRATASE, ALAD*1/ALAD*2 POLYMORPHISM
ALAD, LYS59ASN
Expression of the 2 common alleles, ALAD*1 (p = 0.9) and ALAD*2 (q =
0.1), results in a polymorphic enzyme system with 3 isozymes of distinct
charge, designated 1-1, 1-2, and 2-2. Individuals heterozygous (2pq =
0.18) or homozygous (frequency = 0.01) for the ALAD*2 allele had
significantly higher blood lead levels than did ALAD*1 homozygotes, when
exposed to low or high levels of lead in the environment. Wetmur et al.
(1991) found that the only difference in the ALAD*2 cDNA as compared
with the ALAD*1 sequence was a G-to-C transversion of nucleotide 177 in
the coding region. The change created an MspI restriction site. This
base substitution predicted the replacement of a positively charged
lysine by a neutral asparagine (K59N), an amino acid change consistent
with the more electronegative charge of the ALAD-2 subunit. The rapid
and accurate determination of the ALAD genotype permits molecular-based
screening of populations to identify individuals who are genetically
more susceptible to lead poisoning.
.0004
PORPHYRIA, ACUTE HEPATIC
ALAD, ARG240TRP
In a patient with delta-aminolevulinate dehydratase porphyria (612740)
previously reported by Doss et al. (1979) and Sassa et al. (1991),
Ishida et al. (1992) identified compound heterozygosity for 2 mutations
in the ALAD gene: a 718C-T transition resulting in an arg240-to-trp
(R240W) substitution within the substrate-binding site, and an 820G-A
transition resulting in an ala274-to-thr (A274T; 125270.0005)
substitution. Functional expression studies in Chinese hamster ovary
cells showed that the R240W mutant enzyme had little activity, whereas
the A274T mutant enzyme had about 50% residual activity. Pulse-labeling
studies demonstrated that the R240W enzyme had a normal half-life,
whereas the other enzyme had a markedly decreased half-life. Although
the proband had severe porphyric symptoms, other members of the family
displayed no symptomatology even though ALAD activity was half-normal.
The fact that the patient survived may be due to the residual activity
contributed by the A274T enzyme. A more marked deficiency may not have
been compatible with life.
.0005
PORPHYRIA, ACUTE HEPATIC
ALAD, ALA274THR
See 125270.0004 and Ishida et al. (1992).
.0006
PORPHYRIA, ACUTE HEPATIC, DIGENIC
ALAD, PHE12LEU
In a 23-year-old Caucasian man with porphyria where both
coproporphyrinogen (121300) and ALAD deficiencies (612740) were
demonstrated at the molecular level, Akagi et al. (2006) detected a
heterozygous 36C-G transversion in exon 2 of the ALAD gene that caused a
substitution of leucine for phenylalanine at codon 12 (F12L). Akagi et
al. (1999) had described this mutation in heterozygosity in an
asymptomatic Swedish girl and showed it to result in an ALAD protein
with no enzyme activity. Nucleotide sequence analysis of CPOX cDNA
revealed a novel mutation resulting in a missense amino acid change
(612732.0013).
.0007
PORPHYRIA, ACUTE HEPATIC
ALAD, IVS3AS, C-A, -11
In a 17-year-old German boy with acute ALAD-deficient porphyria
(612740), Doss et al. (2004) identified compound heterozygosity for 2
mutations in intron 3 of the ALAD gene: a C-to-A transversion and a
C-to-T transition (125270.0008), both at -11 bp upstream of the exon 3
start site, and predicted to result in altered splicing. Each unaffected
parent was heterozygous for 1 of the mutations. The patient had
abdominal pain, polyneuropathy, and ALAD activity at about 10% of normal
control values.
.0008
PORPHYRIA, ACUTE HEPATIC
ALAD, IVS3AS, C-T, -11
See 125270.0007 and Doss et al. (2004).
*FIELD* SA
Benkmann et al. (1983); Doss et al. (1982); Doss et al. (1980); Wang
et al. (1985); Wetmur et al. (1986)
*FIELD* RF
1. Akagi, R.; Inoue, R.; Muranaka, S.; Tahara, T.; Taketani, S.; Anderson,
K. E.; Phillips, J. D.; Sussa, S.: Dual gene defects involving delta-aminolaevulinate
dehydratase and coproporphyrinogen oxidase in a porphyria patient. Brit.
J. Haemat. 132: 237-243, 2006. Note: Erratum: Brit. J. Haemat. 132:
662 only, 2006.
2. Akagi, R.; Yasui, Y.; Harper, P.; Sassa, S.: A novel mutation
of delta-aminolaevulinate dehydratase in a healthy child with 12%
erythrocyte enzyme activity. Brit. J. Haemat. 106: 931-937, 1999.
3. Amorim, A.; Kompf, J.; Schunter, F.; Ritter, H.: Aminolevulinate
dehydratase (E.C. 4.2.1.24): linkage analysis. Hum. Genet. 61: 48-49,
1982.
4. Amorim, A.; Schunter, F.; Ritter, H.; Kompf, J.: Linkage studies
on the ALADH polymorphism. (Abstract) Cytogenet. Cell Genet. 37:
400 only, 1984.
5. Battistuzzi, G.; Petrucci, R.; Silvagni, L.; Urbani, F. R.; Caiola,
S.: Delta aminolevulinate dehydrase: a new genetic polymorphism in
man. Ann. Hum. Genet. 45: 223-229, 1981.
6. Beaumont, C.; Foubert, C.; Grandchamp, B.; Weil, D.; Van Cong,
N. G.; Gross, M. S.; Nordmann, Y.: Assignment of the human gene for
delta-aminolevulinate dehydrase to chromosome 9 by somatic cell hybridization
and specific enzyme immunoassay. Ann. Hum. Genet. 48: 153-159, 1984.
7. Benkmann, H.-G.; Bogdanski, P.; Goedde, H. W.: Polymorphism of
delta-aminolevulinic acid dehydratase in various populations. Hum.
Hered. 33: 62-64, 1983.
8. Doss, M.; Schneider, J.; von Tiepermann, R.; Brandt, A.: New type
of acute porphyria with porphobilinogen synthase (delta-aminolevulinic
acid dehydratase) defect in the homozygous state. Clin. Biochem. 15:
52-55, 1982.
9. Doss, M.; von Tiepermann, R.; Schneider, J.: Acute hepatic porphyria
syndrome with porphobilinogen synthase defect. Int. J. Biochem. 12:
823-826, 1980.
10. Doss, M.; von Tiepermann, R.; Schneider, J.; Schmid, H.: New
type of hepatic porphyria with porphobilinogen synthase defect and
intermittent acute clinical manifestation. Klin. Wschr. 57: 1123-1127,
1979.
11. Doss, M. O.; Stauch, T.; Gross, U.; Renz, M.; Akagi, R.; Doss-Frank,
M.; Seelig, H. P.; Sassa, S.: The third case of Doss porphyria (delta-aminolevulinic
acid dehydratase deficiency) in Germany. J. Inherit. Metab. Dis. 27:
529-536, 2004.
12. Eiberg, H.; Mohr, J.; Staub-Nielsen, L.: Delta-aminolevulinatedehydratase:
synteny with ABO-AK1-ORM (and assignment to chromosome 9). Clin.
Genet. 23: 150-154, 1983.
13. Fujita, H.; Sassa, S.; Lundgren, J.; Holmberg, L.; Thunell, S.;
Kappas, A.: Enzymatic defect in a child with hereditary hepatic porphyria
due to homozygous delta-aminolevulinic acid dehydratase deficiency:
immunochemical studies. Pediatrics 80: 880-885, 1987.
14. Harris, R. M.; Carter, N. P.; Griffiths, B.; Goudie, D.; Hampson,
R. M.; Yates, J. R. W.; Affara, N. A.; Ferguson-Smith, M. A.: Physical
mapping within the tuberous sclerosis linkage group in region 9q32-q34. Genomics 15:
265-274, 1993.
15. Ishida, N.; Fujita, H.; Fukuda, Y.; Noguchi, T.; Doss, M.; Kappas,
A.; Sassa, S.: Cloning and expression of the defective genes from
a patient with delta-aminolevulinate dehydratase porphyria. J. Clin.
Invest. 89: 1431-1437, 1992.
16. Jaffe, E. K.; Stith, L.: ALAD porphyria is a conformational disease. Am.
J. Hum. Genet. 80: 329-337, 2007.
17. Kapotis, C.; Tsomi, A.; Babionitakis, A.; Grammenou, G.; Kosmaoglou,
E.; Pardalidis, N.; Troupis, T.; Fertakis, A.: The genetic polymorphism
of aminolevulinate dehydratase (ALADH) in Greece. Hum. Hered. 48:
155-157, 1998.
18. Kaya, A. H.; Plewinska, M.; Wong, D. M.; Desnick, R. J.; Wetmur,
J. G.: Human delta-aminolevulinate dehydratase (ALAD) gene: structure
and alternative splicing of the erythroid and housekeeping mRNAs. Genomics 19:
242-248, 1994.
19. Nadeau, J. H.; Eicher, E. M.: Conserved linkage of soluble aconitase
and galactose-1-phosphate uridyl transferase in mouse and man: assignment
of these genes to mouse chromosome 4. Cytogenet. Cell Genet. 34:
271-281, 1982.
20. Petrucci, R.; Leonardi, A.; Battistuzzi, G.: The genetic polymorphism
of delta-aminolevulinate dehydrase in Italy. Hum. Genet. 60: 289-290,
1982.
21. Plewinska, M.; Thunell, S.; Holmberg, L.; Wetmur, J. G.; Desnick,
R. J.: Delta-aminolevulinate dehydratase deficient porphyria: identification
of the molecular lesions in a severely affected homozygote. Am. J.
Hum. Genet. 49: 167-174, 1991.
22. Potluri, V. R.; Astrin, K. H.; Wetmur, J. G.; Bishop, D. F.; Desnick,
R. J.: Human delta-aminolevulinate dehydratase: chromosomal localization
to 9q34 by in situ hybridization. Hum. Genet. 76: 236-239, 1987.
23. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution. New York: Oxford Univ. Press (pub.) 1988.
24. Sassa, S.; Fujita, H.; Doss, M.; Hassoun, A.; Verstraeten, L.;
Mercelis, R.; Kappas, A.: Hereditary hepatic porphyria due to homozygous
delta-aminolevulinic acid dehydratase deficiency: studies in lymphocytes
and erythrocytes. Europ. J. Clin. Invest. 21: 244-248, 1991.
25. Wang, A.-L.; Astrin, K. H.; Anderson, W. F.; Desnick, R. J.:
Delta-aminolevulinate dehydratase: induced expression and regional
assignment of the human gene to chromosome 9q13-qter. Hum. Genet. 70:
6-10, 1985.
26. Wang, A.-L.; Smith, M.; Astrin, K. H.; Desnick, R. J.: Assignment
of the structural gene for human delta-aminolevulinate dehydratase
(ALAD) to human chromosome 9 (9q11-qter). (Abstract) Am. J. Hum.
Genet. 36: 208S only, 1984.
27. Wetmur, J. G.; Bishop, D. F.; Cantelmo, C.; Desnick, R. J.: Human
delta-aminolevulinate dehydratase: nucleotide sequence of a full-length
cDNA clone. Proc. Nat. Acad. Sci. 83: 7703-7707, 1986.
28. Wetmur, J. G.; Bishop, D. F.; Ostasiewicz, L.; Desnick, R. J.
: Molecular cloning of a cDNA for human delta-aminolevulinate dehydratase. Gene 43:
123-130, 1986.
29. Wetmur, J. G.; Kaya, A. H.; Plewinska, M.; Desnick, R. J.: Molecular
characterization of the human delta-aminolevulinate dehydratase 2
(ALAD-2) allele: implications for molecular screening of individuals
for genetic susceptibility to lead poisoning. Am. J. Hum. Genet. 49:
757-763, 1991.
*FIELD* CN
Cassandra L. Kniffin - reorganized: 5/18/2009
Cassandra L. Kniffin - updated: 4/23/2009
Victor A. McKusick - updated: 1/19/2007
Victor A. McKusick - updated: 8/26/1998
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
terry: 12/21/2012
carol: 2/18/2010
carol: 5/18/2009
ckniffin: 4/23/2009
carol: 4/16/2009
alopez: 1/19/2007
terry: 1/19/2007
carol: 3/17/2004
carol: 6/7/2002
carol: 9/1/1998
terry: 8/26/1998
mark: 10/8/1997
mimadm: 6/25/1994
carol: 4/12/1994
warfield: 2/14/1994
carol: 7/22/1993
carol: 3/17/1993
carol: 3/12/1993
*RECORD*
*FIELD* NO
125270
*FIELD* TI
*125270 DELTA-AMINOLEVULINATE DEHYDRATASE; ALAD
;;ALADH;;
PORPHOBILINOGEN SYNTHASE; PBGS
read more*FIELD* TX
DESCRIPTION
The ALAD gene encodes delta-aminolevulinate dehydratase, also known as
porphobilinogen synthase (PBGS; EC 4.2.1.24), a cytosolic enzyme that
catalyzes the second step in the porphyrin and heme biosynthetic
pathway. It forms the monopyrrole ring porphobilinogen from 2 molecules
of delta-aminolevulinate (ALA) (Ishida et al., 1992).
CLONING
Wetmur et al. (1986) identified 2 cDNAs encoding ALAD which they claimed
represented the first report of a cDNA clone for a human heme
biosynthetic enzyme. They found that the nucleotide sequences of the 2
cDNA clones differed at either position 730 or 733 and encoded 2
different charged amino acids, which was likely the basis for the
polymorphic charged isozymes of human ALAD.
GENE STRUCTURE
Kaya et al. (1994) determined that the ALAD gene spans 15.9 kb and
contains 2 alternative noncoding exons, 1A and 1B, and 11 coding exons,
2 through 12. The housekeeping transcript, which includes exon 1A and
not 1B, was identified in a human adult liver cDNA library, while an
erythroid-specific transcript, which contains exon 1B and not 1A, was
detected in a human erythroleukemia cDNA library. The promoter region
upstream of housekeeping exon 1A was GC-rich and contained 3 potential
Sp1 elements and a CCAAT box. Further upstream, there were 3 potential
GATA-1 binding sites and an AP1 site. The promoter region upstream of
erythroid-specific exon 1B had several CACCC boxes and 2 potential
GATA-1 binding sites. Kaya et al. (1994) transduced HeLa and K562 cells
with chloramphenicol acetyltransferase (CAT) constructs containing
either exon 1A or 1B. Those containing exon 1A were expressed in HeLa
cells, whereas the erythroid-specific construct containing exon 1B was
not. In contrast, the housekeeping and erythroid constructs were both
expressed in erythroleukemia cells.
MAPPING
In linkage studies, Amorim et al. (1982) excluded linkage of the ALAD
gene with MNSs, Fy, Jk, Rh, HLA, ACP1, and PGM1. Close linkage (theta
0.05 or less) was also excluded for K, PI, GPT, PGP, PGM3, GLO, and BF.
Haptoglobin showed a lod score of 0.922 at theta of 0.20 or less.
Eiberg et al. (1983) demonstrated linkage of ALAD to the ABO-AK1-ORM
linkage group on chromosome 9q. The most likely sequence was judged to
be ABO-AK1-ALADH-ORM. The lod and recombination values were as follows:
ABO-AK1 (6.27, 0.13); ABO-ALADH (5.38, 0.21); ABO-ORM (5.06, 0.27);
AK1-ORM (1.63, 0.17); ALADH-ORM (7.05, 0.13) and AK1-ALADH (2.45, 0.11).
Amorim et al. (1984) presented data supporting the chromosome 9
assignment in man. Beaumont et al. (1984) assigned ALAD to chromosome 9
by somatic cell hybrid studies. They used two enzyme assays: one
specific for the human enzyme and one indicative of both rodent and
human enzymes. The ratio of the values was used to discriminate between
positive and negative clones. Wang et al. (1984) assigned the ALAD gene
to 9q by study of human-mouse somatic cell hybrids with methods that
specifically distinguished the mouse and human enzymes. Potluri et al.
(1987) localized ALAD to 9q34 by in situ hybridization using a
radio-iodine-labeled human ALAD cDNA.
In connection with a pulsed field gel electrophoresis analysis of the
9q32-q34 region, which contains a gene for tuberous sclerosis-1
(191100), Harris et al. (1993) found that the ALAD locus was the most
proximal of the genes they studied.
ALADH is linked to ACO1 (100880) and GALT (606999) in the mouse (Nadeau
and Eicher, 1982).
MOLECULAR GENETICS
Battistuzzi et al. (1981) described electrophoretic polymorphisms of
aminolevulinate dehydratase, and showed that the enzyme is encoded by an
autosomal gene with 2 common codominant alleles (frequencies, 0.94 and
0.06). Petrucci et al. (1982) studied the polymorphism of ALADH in
Italy.
Kapotis et al. (1998) found that the frequencies of the ALADH1 and
ALADH2 alleles in Greece are 0.955 and 0.0455, respectively. Data on
gene frequencies of allelic variants were tabulated by Roychoudhury and
Nei (1988).
In a Swedish boy with severe infantile onset of acute hepatic porphyria
(612740), Plewinska et al. (1991) identified compound heterozygosity for
2 mutations in the ALAD gene (125270.0001 and 125270.0002). ALAD
activity in erythrocytes was less than 5% of control values.
ALAD porphyria is a rare autosomal recessive disorder documented, at the
time of the report of Jaffe and Stith (2007), in only 5 patients, all
compound heterozygotes for mutations in the ALAD gene. The human PBGS
enzyme exists as an equilibrium of functionally distinct quaternary
structure assemblies, known as 'morpheeins,' in which one functional
homo-oligomer can dissociate, change conformation, and reassociate into
a different oligomer. In the case of human PBGS, the 2 assemblies are a
high-activity octamer and a low-activity hexamer. Jaffe and Stith (2007)
quantified the morpheein forms of human PBGS for the common and
porphyria-associated variants. Heterologous expression in E. coli,
followed by separation of the octameric and hexameric assemblies on an
ion-exchange column, showed that the percentages of hexamers for F12L
(125270.0006) (100%), R240W (125270.0004) (80%), G133R (125270.0001)
(48%), A274T (125270.0005) (14%), and 2 other variants were appreciably
larger than for the wildtype proteins K59 and N59 (see 125270.0003) (0%
and 3%, respectively). All 8 porphyria-associated variants showed an
increased propensity to form the hexamer, according to a kinetic
analysis. Thus, all porphyria-associated human PBGS variants shift the
morpheein equilibrium for PBGS toward the less active hexamer. Jaffe and
Stith (2007) proposed that the disequilibrium of morpheein assemblies
broadens the definition of conformational diseases beyond the prion
disorders and that ALAD porphyria is the first example of a
morpheein-based conformational disease.
*FIELD* AV
.0001
PORPHYRIA, ACUTE HEPATIC
ALAD, GLY133ARG
In a Swedish boy with severe infantile-onset of acute hepatic porphyria
(612740) previously reported by Fujita et al. (1987), Plewinska et al.
(1991) identified compound heterozygosity for 2 mutations in the ALAD
gene: a 397G-A transition in exon 5 resulting in a gly133-to-arg (G133R)
substitution inherited from the mother, and an 823G-A transition in exon
11 resulting in a val275-to-met (V275M; 125270.0002) substitution
inherited from the father. Both mutations occurred at CpG dinucleotides.
The G133R substitution occurred at the carboxyl end of the highly
conserved zinc-binding site in the enzyme subunit. The mutations
resulted in markedly reduced enzyme activity at less than 5% of normal
values. The couple had experienced 4 successive spontaneous abortions
(Fujita et al., 1987).
.0002
PORPHYRIA, ACUTE HEPATIC
ALAD, VAL275MET
See 125270.0001 and Plewinska et al. (1991).
.0003
AMINOLEVULINATE DEHYDRATASE, ALAD*1/ALAD*2 POLYMORPHISM
ALAD, LYS59ASN
Expression of the 2 common alleles, ALAD*1 (p = 0.9) and ALAD*2 (q =
0.1), results in a polymorphic enzyme system with 3 isozymes of distinct
charge, designated 1-1, 1-2, and 2-2. Individuals heterozygous (2pq =
0.18) or homozygous (frequency = 0.01) for the ALAD*2 allele had
significantly higher blood lead levels than did ALAD*1 homozygotes, when
exposed to low or high levels of lead in the environment. Wetmur et al.
(1991) found that the only difference in the ALAD*2 cDNA as compared
with the ALAD*1 sequence was a G-to-C transversion of nucleotide 177 in
the coding region. The change created an MspI restriction site. This
base substitution predicted the replacement of a positively charged
lysine by a neutral asparagine (K59N), an amino acid change consistent
with the more electronegative charge of the ALAD-2 subunit. The rapid
and accurate determination of the ALAD genotype permits molecular-based
screening of populations to identify individuals who are genetically
more susceptible to lead poisoning.
.0004
PORPHYRIA, ACUTE HEPATIC
ALAD, ARG240TRP
In a patient with delta-aminolevulinate dehydratase porphyria (612740)
previously reported by Doss et al. (1979) and Sassa et al. (1991),
Ishida et al. (1992) identified compound heterozygosity for 2 mutations
in the ALAD gene: a 718C-T transition resulting in an arg240-to-trp
(R240W) substitution within the substrate-binding site, and an 820G-A
transition resulting in an ala274-to-thr (A274T; 125270.0005)
substitution. Functional expression studies in Chinese hamster ovary
cells showed that the R240W mutant enzyme had little activity, whereas
the A274T mutant enzyme had about 50% residual activity. Pulse-labeling
studies demonstrated that the R240W enzyme had a normal half-life,
whereas the other enzyme had a markedly decreased half-life. Although
the proband had severe porphyric symptoms, other members of the family
displayed no symptomatology even though ALAD activity was half-normal.
The fact that the patient survived may be due to the residual activity
contributed by the A274T enzyme. A more marked deficiency may not have
been compatible with life.
.0005
PORPHYRIA, ACUTE HEPATIC
ALAD, ALA274THR
See 125270.0004 and Ishida et al. (1992).
.0006
PORPHYRIA, ACUTE HEPATIC, DIGENIC
ALAD, PHE12LEU
In a 23-year-old Caucasian man with porphyria where both
coproporphyrinogen (121300) and ALAD deficiencies (612740) were
demonstrated at the molecular level, Akagi et al. (2006) detected a
heterozygous 36C-G transversion in exon 2 of the ALAD gene that caused a
substitution of leucine for phenylalanine at codon 12 (F12L). Akagi et
al. (1999) had described this mutation in heterozygosity in an
asymptomatic Swedish girl and showed it to result in an ALAD protein
with no enzyme activity. Nucleotide sequence analysis of CPOX cDNA
revealed a novel mutation resulting in a missense amino acid change
(612732.0013).
.0007
PORPHYRIA, ACUTE HEPATIC
ALAD, IVS3AS, C-A, -11
In a 17-year-old German boy with acute ALAD-deficient porphyria
(612740), Doss et al. (2004) identified compound heterozygosity for 2
mutations in intron 3 of the ALAD gene: a C-to-A transversion and a
C-to-T transition (125270.0008), both at -11 bp upstream of the exon 3
start site, and predicted to result in altered splicing. Each unaffected
parent was heterozygous for 1 of the mutations. The patient had
abdominal pain, polyneuropathy, and ALAD activity at about 10% of normal
control values.
.0008
PORPHYRIA, ACUTE HEPATIC
ALAD, IVS3AS, C-T, -11
See 125270.0007 and Doss et al. (2004).
*FIELD* SA
Benkmann et al. (1983); Doss et al. (1982); Doss et al. (1980); Wang
et al. (1985); Wetmur et al. (1986)
*FIELD* RF
1. Akagi, R.; Inoue, R.; Muranaka, S.; Tahara, T.; Taketani, S.; Anderson,
K. E.; Phillips, J. D.; Sussa, S.: Dual gene defects involving delta-aminolaevulinate
dehydratase and coproporphyrinogen oxidase in a porphyria patient. Brit.
J. Haemat. 132: 237-243, 2006. Note: Erratum: Brit. J. Haemat. 132:
662 only, 2006.
2. Akagi, R.; Yasui, Y.; Harper, P.; Sassa, S.: A novel mutation
of delta-aminolaevulinate dehydratase in a healthy child with 12%
erythrocyte enzyme activity. Brit. J. Haemat. 106: 931-937, 1999.
3. Amorim, A.; Kompf, J.; Schunter, F.; Ritter, H.: Aminolevulinate
dehydratase (E.C. 4.2.1.24): linkage analysis. Hum. Genet. 61: 48-49,
1982.
4. Amorim, A.; Schunter, F.; Ritter, H.; Kompf, J.: Linkage studies
on the ALADH polymorphism. (Abstract) Cytogenet. Cell Genet. 37:
400 only, 1984.
5. Battistuzzi, G.; Petrucci, R.; Silvagni, L.; Urbani, F. R.; Caiola,
S.: Delta aminolevulinate dehydrase: a new genetic polymorphism in
man. Ann. Hum. Genet. 45: 223-229, 1981.
6. Beaumont, C.; Foubert, C.; Grandchamp, B.; Weil, D.; Van Cong,
N. G.; Gross, M. S.; Nordmann, Y.: Assignment of the human gene for
delta-aminolevulinate dehydrase to chromosome 9 by somatic cell hybridization
and specific enzyme immunoassay. Ann. Hum. Genet. 48: 153-159, 1984.
7. Benkmann, H.-G.; Bogdanski, P.; Goedde, H. W.: Polymorphism of
delta-aminolevulinic acid dehydratase in various populations. Hum.
Hered. 33: 62-64, 1983.
8. Doss, M.; Schneider, J.; von Tiepermann, R.; Brandt, A.: New type
of acute porphyria with porphobilinogen synthase (delta-aminolevulinic
acid dehydratase) defect in the homozygous state. Clin. Biochem. 15:
52-55, 1982.
9. Doss, M.; von Tiepermann, R.; Schneider, J.: Acute hepatic porphyria
syndrome with porphobilinogen synthase defect. Int. J. Biochem. 12:
823-826, 1980.
10. Doss, M.; von Tiepermann, R.; Schneider, J.; Schmid, H.: New
type of hepatic porphyria with porphobilinogen synthase defect and
intermittent acute clinical manifestation. Klin. Wschr. 57: 1123-1127,
1979.
11. Doss, M. O.; Stauch, T.; Gross, U.; Renz, M.; Akagi, R.; Doss-Frank,
M.; Seelig, H. P.; Sassa, S.: The third case of Doss porphyria (delta-aminolevulinic
acid dehydratase deficiency) in Germany. J. Inherit. Metab. Dis. 27:
529-536, 2004.
12. Eiberg, H.; Mohr, J.; Staub-Nielsen, L.: Delta-aminolevulinatedehydratase:
synteny with ABO-AK1-ORM (and assignment to chromosome 9). Clin.
Genet. 23: 150-154, 1983.
13. Fujita, H.; Sassa, S.; Lundgren, J.; Holmberg, L.; Thunell, S.;
Kappas, A.: Enzymatic defect in a child with hereditary hepatic porphyria
due to homozygous delta-aminolevulinic acid dehydratase deficiency:
immunochemical studies. Pediatrics 80: 880-885, 1987.
14. Harris, R. M.; Carter, N. P.; Griffiths, B.; Goudie, D.; Hampson,
R. M.; Yates, J. R. W.; Affara, N. A.; Ferguson-Smith, M. A.: Physical
mapping within the tuberous sclerosis linkage group in region 9q32-q34. Genomics 15:
265-274, 1993.
15. Ishida, N.; Fujita, H.; Fukuda, Y.; Noguchi, T.; Doss, M.; Kappas,
A.; Sassa, S.: Cloning and expression of the defective genes from
a patient with delta-aminolevulinate dehydratase porphyria. J. Clin.
Invest. 89: 1431-1437, 1992.
16. Jaffe, E. K.; Stith, L.: ALAD porphyria is a conformational disease. Am.
J. Hum. Genet. 80: 329-337, 2007.
17. Kapotis, C.; Tsomi, A.; Babionitakis, A.; Grammenou, G.; Kosmaoglou,
E.; Pardalidis, N.; Troupis, T.; Fertakis, A.: The genetic polymorphism
of aminolevulinate dehydratase (ALADH) in Greece. Hum. Hered. 48:
155-157, 1998.
18. Kaya, A. H.; Plewinska, M.; Wong, D. M.; Desnick, R. J.; Wetmur,
J. G.: Human delta-aminolevulinate dehydratase (ALAD) gene: structure
and alternative splicing of the erythroid and housekeeping mRNAs. Genomics 19:
242-248, 1994.
19. Nadeau, J. H.; Eicher, E. M.: Conserved linkage of soluble aconitase
and galactose-1-phosphate uridyl transferase in mouse and man: assignment
of these genes to mouse chromosome 4. Cytogenet. Cell Genet. 34:
271-281, 1982.
20. Petrucci, R.; Leonardi, A.; Battistuzzi, G.: The genetic polymorphism
of delta-aminolevulinate dehydrase in Italy. Hum. Genet. 60: 289-290,
1982.
21. Plewinska, M.; Thunell, S.; Holmberg, L.; Wetmur, J. G.; Desnick,
R. J.: Delta-aminolevulinate dehydratase deficient porphyria: identification
of the molecular lesions in a severely affected homozygote. Am. J.
Hum. Genet. 49: 167-174, 1991.
22. Potluri, V. R.; Astrin, K. H.; Wetmur, J. G.; Bishop, D. F.; Desnick,
R. J.: Human delta-aminolevulinate dehydratase: chromosomal localization
to 9q34 by in situ hybridization. Hum. Genet. 76: 236-239, 1987.
23. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution. New York: Oxford Univ. Press (pub.) 1988.
24. Sassa, S.; Fujita, H.; Doss, M.; Hassoun, A.; Verstraeten, L.;
Mercelis, R.; Kappas, A.: Hereditary hepatic porphyria due to homozygous
delta-aminolevulinic acid dehydratase deficiency: studies in lymphocytes
and erythrocytes. Europ. J. Clin. Invest. 21: 244-248, 1991.
25. Wang, A.-L.; Astrin, K. H.; Anderson, W. F.; Desnick, R. J.:
Delta-aminolevulinate dehydratase: induced expression and regional
assignment of the human gene to chromosome 9q13-qter. Hum. Genet. 70:
6-10, 1985.
26. Wang, A.-L.; Smith, M.; Astrin, K. H.; Desnick, R. J.: Assignment
of the structural gene for human delta-aminolevulinate dehydratase
(ALAD) to human chromosome 9 (9q11-qter). (Abstract) Am. J. Hum.
Genet. 36: 208S only, 1984.
27. Wetmur, J. G.; Bishop, D. F.; Cantelmo, C.; Desnick, R. J.: Human
delta-aminolevulinate dehydratase: nucleotide sequence of a full-length
cDNA clone. Proc. Nat. Acad. Sci. 83: 7703-7707, 1986.
28. Wetmur, J. G.; Bishop, D. F.; Ostasiewicz, L.; Desnick, R. J.
: Molecular cloning of a cDNA for human delta-aminolevulinate dehydratase. Gene 43:
123-130, 1986.
29. Wetmur, J. G.; Kaya, A. H.; Plewinska, M.; Desnick, R. J.: Molecular
characterization of the human delta-aminolevulinate dehydratase 2
(ALAD-2) allele: implications for molecular screening of individuals
for genetic susceptibility to lead poisoning. Am. J. Hum. Genet. 49:
757-763, 1991.
*FIELD* CN
Cassandra L. Kniffin - reorganized: 5/18/2009
Cassandra L. Kniffin - updated: 4/23/2009
Victor A. McKusick - updated: 1/19/2007
Victor A. McKusick - updated: 8/26/1998
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
terry: 12/21/2012
carol: 2/18/2010
carol: 5/18/2009
ckniffin: 4/23/2009
carol: 4/16/2009
alopez: 1/19/2007
terry: 1/19/2007
carol: 3/17/2004
carol: 6/7/2002
carol: 9/1/1998
terry: 8/26/1998
mark: 10/8/1997
mimadm: 6/25/1994
carol: 4/12/1994
warfield: 2/14/1994
carol: 7/22/1993
carol: 3/17/1993
carol: 3/12/1993
MIM
612740
*RECORD*
*FIELD* NO
612740
*FIELD* TI
#612740 PORPHYRIA, ACUTE HEPATIC
;;DELTA-AMINOLEVULINATE DEHYDRATASE DEFICIENCY;;
ALAD DEFICIENCY;;
read morePORPHYRIA, ALAD;;
PORPHOBILINOGEN SYNTHASE DEFICIENCY;;
DOSS PORPHYRIA
LEAD POISONING, SUSCEPTIBILITY TO, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because Doss hepatic porphyria
is caused by mutation in the gene encoding delta-aminolevulinate
dehydratase (ALAD, PBGS; 125270).
DESCRIPTION
ALAD porphyria is a rare autosomal recessive disorder that has been
reported and confirmed by genetic analysis in only 5 patients (Jaffe and
Stith, 2007).
CLINICAL FEATURES
Bird et al. (1979) identified ALAD deficiency fortuitously during
accumulation of control data on red cell uroporphyrinogen synthase I
(HMBS; 609806). The screening assay measured conversion of ALA to
porphyrin and thus included both ALAD and HMBS; specific testing in the
individual with a defect revealed deficiency of ALAD. The individual was
an 18-year-old healthy college student with 22% of mean ALAD control
values. Subsequent examination of family members showed that many had
values ranging from 22 to 41%. Deficiency was traced through 3
generations, and by implication through a fourth, with 1 instance of
male-to-male transmission, consistent with autosomal dominant
inheritance. There were no clinical manifestations; however, Bird et al.
(1979) noted that ALAD activity is significantly inhibited by lead
(Haeger-Aronsen et al., 1971), and speculated that persons with low ALAD
activity may be especially sensitive to environmental lead exposure.
Doss et al. (1979) described 2 young boys with acute hepatic porphyria.
There was an excessive urinary excretion of delta-aminolevulinic acid
and porphyrins, and the activity of red cell ALAD was less than 1% of
normal values. The parents and a number of other unaffected relatives
exhibited an enzyme activity of about 50% of normal. Thus, the clinical
disorder in these particular patients was consistent with autosomal
recessive inheritance. Further studies in 1 of the patients reported by
Doss et al. (1979) suggested a structural mutation in the PBGS gene
(Brandt and Doss, 1981). Doss et al. (1983) presented further evidence
that the boys were homozygous for the enzyme deficiency, with less that
3% of control enzyme activity in bone marrow cells, and that all parents
and 'most of their brothers and sisters,' all asymptomatic, were
heterozygous carriers, with enzyme level about 50% of normal. They
pointed out that persons with PBGS deficiency are endangered by alcohol
ingestion or lead exposure because both agents inhibit PBGS. In the 2
males apparently homozygous for ALAD deficiency (Doss et al., 1979), de
Verneuil et al. (1985) demonstrated ALAD cross-reactive material,
further suggesting a mutation in this gene. Doss et al. (2004) reported
that the patients reported by Doss et al. (1979) were alive and well at
ages 45 and 47 years, respectively.
Thunell et al. (1987) reported ALAD-deficient porphyria in a 3-year-old
boy. He presented in the neonatal period and infancy with recurrent
attacks of pain, vomiting, hyponatremia, and symptoms of polyneuropathy
that compromised motor functions, including respiration. He excreted
large amounts of 5-aminolevulinic acid and coproporphyrin and minor
amounts of porphobilinogen in the urine. Diagnosis was established by
the finding of erythrocyte ALAD activity at less than 5% in the patient
and between 26 and 51% of normal in both parents, the grandfathers, and
a sib. Thunell et al. (1992) noted that the patient with severe
infantile onset of porphyria (Thunell et al., 1987) underwent liver
transplantation at age 7 years in the hopes that a new liver would
reduce the metabolic disturbance and thus avert the porphyric symptoms.
After transplant, the patient was able to withstand several
porphyrinogenic challenges without increasing the excretion of
porphyrin. However, he continued to have episodes of neurologic and
respiratory crises. Doss et al. (2004) reported that the patient
reported by Thunell et al. (1987, 1992) died at age 9 years.
Sassa et al. (1991) studied 2 patients with homozygous ALAD deficiency:
1 had teenage onset of acute hepatic porphyria (Doss et al., 1979); the
second was a patient with late onset of the disease, a man who was 63
years old at the time of diagnosis (Hassoun et al., 1989). Enzyme
activity was markedly decreased in lymphocytes from both patients and
moderately decreased in heterozygous members of the families.
Immunochemical quantitation of red cell ALAD suggested the presence of
cross-reactive material in the patient with late onset.
Doss et al. (2004) reported a 17-year-old German boy who had colicky
abdominal pain and severe polyneuropathy for 2 years. Urinary ALAD was
increased 32-fold, and coproporphyrin 76-fold compared to normal ranges.
ALAD activity in erythrocytes was decreased to 10% of normal in the
patient and about 50% in both parents. The patient was successfully
treated with heme arginate infusion. The clinical condition improved,
and urinary excretion of ALA and coproporphyrin fell to levels of
approximately 50% compared to pretreatment levels during acute relapses.
The heme therapy was continued once weekly for 1 year. At the end of 1
year, urinary ALA and porphyrin levels were significantly lowered, and
the proband was almost free of clinical symptoms.
- Susceptibility to Lead Poisoning
Doss and Muller (1982) reported the case of a 48-year-old man who was
likely vulnerable to acute lead intoxication because of heterozygous
PBGS deficiency. He developed an acute abdominal syndrome, anemia, and a
grave toxic disorder of porphyrin metabolism, which was diagnosed as
acute lead intoxication. Although the hematologic findings and
porphyrins in the blood, as well as porphyrin precursors and porphyrin
excretion in the urine, returned to normal within 5 months after
exacerbation of the acute symptoms, PBGS activity was about 50% of
normal controls 6 years later.
Doss et al. (1984) reported a 30-year-old painter with an acute
abdominal-neurologic syndrome and anemia due to lead poisoning, despite
only moderate levels of blood lead. During the illness, red cell ALAD
levels were reduced to 8% of controls. Four years later the level
remained diminished at 30% of controls, and the mother was found also to
have ALAD levels in the heterozygous range.
Dyer et al. (1993) reported a lead worker who developed bilateral wrist
drop characteristic of lead neuropathy but whose screening tests for
blood and urine levels had been within the accepted safety limit during
employment. Further investigation showed, however, that he had
lead-associated porphyria (plumboporphyria) due to heterozygous ALAD
deficiency which had been symptom-free until he was exposed to lead.
CLINICAL MANAGEMENT
Goetsch and Bissell (1986) found that the instability of hematin
solutions was responsible for the failure of therapeutic benefit of this
agent in patients with ALAD deficiency. In addition, the decayed
material had anticoagulant effects, thus explaining one of the
complications of hematin therapy.
Doss et al. (2004) reported successful treatment of ALAD porphyria with
heme arginate infusion.
MOLECULAR GENETICS
In a Swedish boy with severe infantile onset of acute hepatic porphyria,
Plewinska et al. (1991) identified compound heterozygosity for 2
mutations in the ALAD gene (125270.0001 and 125270.0002). ALAD activity
in erythrocytes were less than 5% of control values.
In a patient with hepatic porphyria previously reported by Doss et al.
(1979) and Sassa et al. (1991), Ishida et al. (1992) identified compound
heterozygosity for 2 mutations in the ALAD gene (125270.0004 and
125240.0005).
In a 17-year-old German patient with hepatic porphyria, Doss et al.
(2004) identified compound heterozygosity for 2 mutations in the ALAD
gene (125270.0007 and 125270.0008).
PATHOGENESIS
Jaffe and Stith (2007) noted that the human PBGS enzyme exists as an
equilibrium of functionally distinct quaternary structure assemblies,
known as 'morpheeins,' in which one functional homo-oligomer can
dissociate, change conformation, and reassociate into a different
oligomer. In the case of human PBGS, the 2 assemblies are a
high-activity octamer and a low-activity hexamer. Jaffe and Stith (2007)
quantified the morpheein forms of human PBGS for the common and
porphyria-associated variants. Heterologous expression in E. coli,
followed by separation of the octameric and hexameric assemblies on an
ion-exchange column, showed that the percentages of hexamers for F12L
(125270.0006) (100%), R240W (125270.0004) (80%), G133R (125270.0001)
(48%), A274T (125270.0005) (14%), and 2 other variants were appreciably
larger than for the wildtype proteins K59 and N59 (see 125270.0003) (0%
and 3%, respectively). All 8 porphyria-associated variants showed an
increased propensity to form the hexamer, according to a kinetic
analysis. Thus, all porphyria-associated human PBGS variants shift the
morpheein equilibrium for PBGS toward the less active hexamer. Jaffe and
Stith (2007) proposed that the disequilibrium of morpheein assemblies
broadens the definition of conformational diseases beyond the prion
disorders and that ALAD porphyria is the first example of a
morpheein-based conformational disease.
*FIELD* SA
Doss et al. (1986); Doss et al. (1982); Doss et al. (1980); Fujita
et al. (1987)
*FIELD* RF
1. Bird, T. D.; Hamernyik, P.; Nutter, J. Y.; Labbe, R. F.: Inherited
deficiency of delta-aminolevulinic acid dehydratase. Am. J. Hum.
Genet. 31: 662-668, 1979.
2. Brandt, A.; Doss, M.: Hereditary porphobilinogen synthase deficiency
in human associated with acute hepatic porphyria. Hum. Genet. 58:
194-197, 1981.
3. de Verneuil, H.; Doss, M.; Brusco, N.; Beaumont, C.; Nordmann,
Y.: Hereditary hepatic porphyria with delta aminolevulinate dehydrase
deficiency: immunologic characterization of the non-catalytic enzyme. Hum.
Genet. 69: 174-177, 1985.
4. Doss, M.; Benkmann, H.-G.; Goedde, H.-W.: Delta-aminolevulinic
acid dehydrase (porphobilinogen synthase) in two families with inherited
enzyme deficiency. Clin. Genet. 30: 191-198, 1986.
5. Doss, M.; Laubenthal, F.; Stoeppler, M.: Lead poisoning in inherited
delta-aminolevulinic acid dehydratase deficiency. Int. Arch. Occup.
Environ. Health 54: 55-63, 1984.
6. Doss, M.; Muller, W. A.: Acute lead poisoning in inherited porphobilinogen
synthase (delta-aminolevulinic acid dehydrase) deficiency. Blut 45:
131-139, 1982.
7. Doss, M.; Schneider, J.; von Tiepermann, R.; Brandt, A.: New type
of acute porphyria with porphobilinogen synthase (delta-aminolevulinic
acid dehydratase) defect in the homozygous state. Clin. Biochem. 15:
52-55, 1982.
8. Doss, M.; von Tiepermann, R.; Schneider, J.: Porphobilinogen-synthase
(delta-aminolevulinic acid dehydratase) deficiency in bone marrow
cells of two patients with porphobilinogen-synthase defect acute porphyria. Klin.
Wschr. 61: 699-702, 1983.
9. Doss, M.; von Tiepermann, R.; Schneider, J.: Acute hepatic porphyria
syndrome with porphobilinogen synthase defect. Int. J. Biochem. 12:
823-826, 1980.
10. Doss, M.; von Tiepermann, R.; Schneider, J.; Schmid, H.: New
type of hepatic porphyria with porphobilinogen synthase defect and
intermittent acute clinical manifestation. Klin. Wschr. 57: 1123-1127,
1979.
11. Doss, M. O.; Stauch, T.; Gross, U.; Renz, M.; Akagi, R.; Doss-Frank,
M.; Seelig, H. P.; Sassa, S.: The third case of Doss porphyria (delta-aminolevulinic
acid dehydratase deficiency) in Germany. J. Inherit. Metab. Dis. 27:
529-536, 2004.
12. Dyer, J.; Garrick, D. P.; Inglis, A.; Pye, I. F.: Plumboporphyria
(ALAD deficiency) in a lead worker: a scenario for potential diagnostic
confusion. Brit. J. Indust. Med. 50: 1119-1121, 1993.
13. Fujita, H.; Sassa, S.; Lundgren, J.; Holmberg, L.; Thunell, S.;
Kappas, A.: Enzymatic defect in a child with hereditary hepatic porphyria
due to homozygous delta-aminolevulinic acid dehydratase deficiency:
immunochemical studies. Pediatrics 80: 880-885, 1987.
14. Goetsch, C. A.; Bissell, D. M.: Instability of hematin used in
the treatment of acute hepatic porphyria. New Eng. J. Med. 315:
235-238, 1986.
15. Haeger-Aronsen, B.; Abdulla, M.; Fristedt, B. I.: Effect of lead
on delta-aminolevulinic acid dehydrase activity in red blood cells. Arch.
Environ. Health 23: 440-445, 1971.
16. Hassoun, A.; Verstraeten, L.; Mercelis, R.; Martin, J. J.: Biochemical
diagnosis of an hereditary aminolaevulinate dehydratase deficiency
in a 63-year-old man. J. Clin. Chem. Clin. Biochem. 27: 781-786,
1989.
17. Ishida, N.; Fujita, H.; Fukuda, Y.; Noguchi, T.; Doss, M.; Kappas,
A.; Sassa, S.: Cloning and expression of the defective genes from
a patient with delta-aminolevulinate dehydratase porphyria. J. Clin.
Invest. 89: 1431-1437, 1992.
18. Jaffe, E. K.; Stith, L.: ALAD porphyria is a conformational disease. Am.
J. Hum. Genet. 80: 329-337, 2007.
19. Plewinska, M.; Thunell, S.; Holmberg, L.; Wetmur, J. G.; Desnick,
R. J.: Delta-aminolevulinate dehydratase deficient porphyria: identification
of the molecular lesions in a severely affected homozygote. Am. J.
Hum. Genet. 49: 167-174, 1991.
20. Sassa, S.; Fujita, H.; Doss, M.; Hassoun, A.; Verstraeten, L.;
Mercelis, R.; Kappas, A.: Hereditary hepatic porphyria due to homozygous
delta-aminolevulinic acid dehydratase deficiency: studies in lymphocytes
and erythrocytes. Europ. J. Clin. Invest. 21: 244-248, 1991.
21. Thunell, S.; Henrichson, A.; Floderus, Y.; Groth, C. G.; Eriksson,
B.-G.; Barkholt, L.; Nemeth, A.; Strandvik, B.; Eleborg, L.; Holmberg,
L.; Lundgren, J.: Liver transplantation in a boy with acute porphyria
due to aminolaevulinate dehydratase deficiency. Europ. J. Clin. Chem.
Clin. Biochem. 30: 599-606, 1992.
22. Thunell, S.; Holmberg, L.; Lundgren, J.: Aminolevulinate dehydratase
porphyria in infancy: a clinical and biochemical study. J. Clin.
Chem. Clin. Biochem. 25: 5-14, 1987.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
RESPIRATORY:
[Lung];
Respiratory paralysis
ABDOMEN:
[Gastrointestinal];
Vomiting;
Abdominal colic
MUSCLE, SOFT TISSUE:
Hypotonia;
Muscle weakness
NEUROLOGIC:
[Peripheral nervous system];
Neuropathy (motor and sensory);
Paresthesia;
Paralysis
HEMATOLOGY:
Hemolytic anemia;
Porphyria
LABORATORY ABNORMALITIES:
Erythrocyte delta-aminolevulinate dehydratase (ALAD) deficiency;
Elevated urinary delta-aminolevulinic acid and porphyrins
MISCELLANEOUS:
Very rare;
Asymptomatic heterozygotes susceptible to lead toxicity;
Exacerbation following stress, decreased food intake, or alcohol use
MOLECULAR BASIS:
Caused by mutation in the delta-aminolevulinate dehydratase gene (ALAD,
125270.0001)
*FIELD* CN
Kelly A. Przylepa - revised: 3/13/2000
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 02/07/2011
joanna: 6/11/2009
ckniffin: 4/23/2009
joanna: 10/27/2000
kayiaros: 3/13/2000
*FIELD* CN
Cassandra L. Kniffin - updated: 4/23/2009
*FIELD* CD
Cassandra L. Kniffin: 4/21/2009
*FIELD* ED
carol: 02/27/2012
carol: 6/23/2011
carol: 1/5/2010
terry: 6/19/2009
carol: 5/20/2009
carol: 5/18/2009
ckniffin: 4/23/2009
*RECORD*
*FIELD* NO
612740
*FIELD* TI
#612740 PORPHYRIA, ACUTE HEPATIC
;;DELTA-AMINOLEVULINATE DEHYDRATASE DEFICIENCY;;
ALAD DEFICIENCY;;
read morePORPHYRIA, ALAD;;
PORPHOBILINOGEN SYNTHASE DEFICIENCY;;
DOSS PORPHYRIA
LEAD POISONING, SUSCEPTIBILITY TO, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because Doss hepatic porphyria
is caused by mutation in the gene encoding delta-aminolevulinate
dehydratase (ALAD, PBGS; 125270).
DESCRIPTION
ALAD porphyria is a rare autosomal recessive disorder that has been
reported and confirmed by genetic analysis in only 5 patients (Jaffe and
Stith, 2007).
CLINICAL FEATURES
Bird et al. (1979) identified ALAD deficiency fortuitously during
accumulation of control data on red cell uroporphyrinogen synthase I
(HMBS; 609806). The screening assay measured conversion of ALA to
porphyrin and thus included both ALAD and HMBS; specific testing in the
individual with a defect revealed deficiency of ALAD. The individual was
an 18-year-old healthy college student with 22% of mean ALAD control
values. Subsequent examination of family members showed that many had
values ranging from 22 to 41%. Deficiency was traced through 3
generations, and by implication through a fourth, with 1 instance of
male-to-male transmission, consistent with autosomal dominant
inheritance. There were no clinical manifestations; however, Bird et al.
(1979) noted that ALAD activity is significantly inhibited by lead
(Haeger-Aronsen et al., 1971), and speculated that persons with low ALAD
activity may be especially sensitive to environmental lead exposure.
Doss et al. (1979) described 2 young boys with acute hepatic porphyria.
There was an excessive urinary excretion of delta-aminolevulinic acid
and porphyrins, and the activity of red cell ALAD was less than 1% of
normal values. The parents and a number of other unaffected relatives
exhibited an enzyme activity of about 50% of normal. Thus, the clinical
disorder in these particular patients was consistent with autosomal
recessive inheritance. Further studies in 1 of the patients reported by
Doss et al. (1979) suggested a structural mutation in the PBGS gene
(Brandt and Doss, 1981). Doss et al. (1983) presented further evidence
that the boys were homozygous for the enzyme deficiency, with less that
3% of control enzyme activity in bone marrow cells, and that all parents
and 'most of their brothers and sisters,' all asymptomatic, were
heterozygous carriers, with enzyme level about 50% of normal. They
pointed out that persons with PBGS deficiency are endangered by alcohol
ingestion or lead exposure because both agents inhibit PBGS. In the 2
males apparently homozygous for ALAD deficiency (Doss et al., 1979), de
Verneuil et al. (1985) demonstrated ALAD cross-reactive material,
further suggesting a mutation in this gene. Doss et al. (2004) reported
that the patients reported by Doss et al. (1979) were alive and well at
ages 45 and 47 years, respectively.
Thunell et al. (1987) reported ALAD-deficient porphyria in a 3-year-old
boy. He presented in the neonatal period and infancy with recurrent
attacks of pain, vomiting, hyponatremia, and symptoms of polyneuropathy
that compromised motor functions, including respiration. He excreted
large amounts of 5-aminolevulinic acid and coproporphyrin and minor
amounts of porphobilinogen in the urine. Diagnosis was established by
the finding of erythrocyte ALAD activity at less than 5% in the patient
and between 26 and 51% of normal in both parents, the grandfathers, and
a sib. Thunell et al. (1992) noted that the patient with severe
infantile onset of porphyria (Thunell et al., 1987) underwent liver
transplantation at age 7 years in the hopes that a new liver would
reduce the metabolic disturbance and thus avert the porphyric symptoms.
After transplant, the patient was able to withstand several
porphyrinogenic challenges without increasing the excretion of
porphyrin. However, he continued to have episodes of neurologic and
respiratory crises. Doss et al. (2004) reported that the patient
reported by Thunell et al. (1987, 1992) died at age 9 years.
Sassa et al. (1991) studied 2 patients with homozygous ALAD deficiency:
1 had teenage onset of acute hepatic porphyria (Doss et al., 1979); the
second was a patient with late onset of the disease, a man who was 63
years old at the time of diagnosis (Hassoun et al., 1989). Enzyme
activity was markedly decreased in lymphocytes from both patients and
moderately decreased in heterozygous members of the families.
Immunochemical quantitation of red cell ALAD suggested the presence of
cross-reactive material in the patient with late onset.
Doss et al. (2004) reported a 17-year-old German boy who had colicky
abdominal pain and severe polyneuropathy for 2 years. Urinary ALAD was
increased 32-fold, and coproporphyrin 76-fold compared to normal ranges.
ALAD activity in erythrocytes was decreased to 10% of normal in the
patient and about 50% in both parents. The patient was successfully
treated with heme arginate infusion. The clinical condition improved,
and urinary excretion of ALA and coproporphyrin fell to levels of
approximately 50% compared to pretreatment levels during acute relapses.
The heme therapy was continued once weekly for 1 year. At the end of 1
year, urinary ALA and porphyrin levels were significantly lowered, and
the proband was almost free of clinical symptoms.
- Susceptibility to Lead Poisoning
Doss and Muller (1982) reported the case of a 48-year-old man who was
likely vulnerable to acute lead intoxication because of heterozygous
PBGS deficiency. He developed an acute abdominal syndrome, anemia, and a
grave toxic disorder of porphyrin metabolism, which was diagnosed as
acute lead intoxication. Although the hematologic findings and
porphyrins in the blood, as well as porphyrin precursors and porphyrin
excretion in the urine, returned to normal within 5 months after
exacerbation of the acute symptoms, PBGS activity was about 50% of
normal controls 6 years later.
Doss et al. (1984) reported a 30-year-old painter with an acute
abdominal-neurologic syndrome and anemia due to lead poisoning, despite
only moderate levels of blood lead. During the illness, red cell ALAD
levels were reduced to 8% of controls. Four years later the level
remained diminished at 30% of controls, and the mother was found also to
have ALAD levels in the heterozygous range.
Dyer et al. (1993) reported a lead worker who developed bilateral wrist
drop characteristic of lead neuropathy but whose screening tests for
blood and urine levels had been within the accepted safety limit during
employment. Further investigation showed, however, that he had
lead-associated porphyria (plumboporphyria) due to heterozygous ALAD
deficiency which had been symptom-free until he was exposed to lead.
CLINICAL MANAGEMENT
Goetsch and Bissell (1986) found that the instability of hematin
solutions was responsible for the failure of therapeutic benefit of this
agent in patients with ALAD deficiency. In addition, the decayed
material had anticoagulant effects, thus explaining one of the
complications of hematin therapy.
Doss et al. (2004) reported successful treatment of ALAD porphyria with
heme arginate infusion.
MOLECULAR GENETICS
In a Swedish boy with severe infantile onset of acute hepatic porphyria,
Plewinska et al. (1991) identified compound heterozygosity for 2
mutations in the ALAD gene (125270.0001 and 125270.0002). ALAD activity
in erythrocytes were less than 5% of control values.
In a patient with hepatic porphyria previously reported by Doss et al.
(1979) and Sassa et al. (1991), Ishida et al. (1992) identified compound
heterozygosity for 2 mutations in the ALAD gene (125270.0004 and
125240.0005).
In a 17-year-old German patient with hepatic porphyria, Doss et al.
(2004) identified compound heterozygosity for 2 mutations in the ALAD
gene (125270.0007 and 125270.0008).
PATHOGENESIS
Jaffe and Stith (2007) noted that the human PBGS enzyme exists as an
equilibrium of functionally distinct quaternary structure assemblies,
known as 'morpheeins,' in which one functional homo-oligomer can
dissociate, change conformation, and reassociate into a different
oligomer. In the case of human PBGS, the 2 assemblies are a
high-activity octamer and a low-activity hexamer. Jaffe and Stith (2007)
quantified the morpheein forms of human PBGS for the common and
porphyria-associated variants. Heterologous expression in E. coli,
followed by separation of the octameric and hexameric assemblies on an
ion-exchange column, showed that the percentages of hexamers for F12L
(125270.0006) (100%), R240W (125270.0004) (80%), G133R (125270.0001)
(48%), A274T (125270.0005) (14%), and 2 other variants were appreciably
larger than for the wildtype proteins K59 and N59 (see 125270.0003) (0%
and 3%, respectively). All 8 porphyria-associated variants showed an
increased propensity to form the hexamer, according to a kinetic
analysis. Thus, all porphyria-associated human PBGS variants shift the
morpheein equilibrium for PBGS toward the less active hexamer. Jaffe and
Stith (2007) proposed that the disequilibrium of morpheein assemblies
broadens the definition of conformational diseases beyond the prion
disorders and that ALAD porphyria is the first example of a
morpheein-based conformational disease.
*FIELD* SA
Doss et al. (1986); Doss et al. (1982); Doss et al. (1980); Fujita
et al. (1987)
*FIELD* RF
1. Bird, T. D.; Hamernyik, P.; Nutter, J. Y.; Labbe, R. F.: Inherited
deficiency of delta-aminolevulinic acid dehydratase. Am. J. Hum.
Genet. 31: 662-668, 1979.
2. Brandt, A.; Doss, M.: Hereditary porphobilinogen synthase deficiency
in human associated with acute hepatic porphyria. Hum. Genet. 58:
194-197, 1981.
3. de Verneuil, H.; Doss, M.; Brusco, N.; Beaumont, C.; Nordmann,
Y.: Hereditary hepatic porphyria with delta aminolevulinate dehydrase
deficiency: immunologic characterization of the non-catalytic enzyme. Hum.
Genet. 69: 174-177, 1985.
4. Doss, M.; Benkmann, H.-G.; Goedde, H.-W.: Delta-aminolevulinic
acid dehydrase (porphobilinogen synthase) in two families with inherited
enzyme deficiency. Clin. Genet. 30: 191-198, 1986.
5. Doss, M.; Laubenthal, F.; Stoeppler, M.: Lead poisoning in inherited
delta-aminolevulinic acid dehydratase deficiency. Int. Arch. Occup.
Environ. Health 54: 55-63, 1984.
6. Doss, M.; Muller, W. A.: Acute lead poisoning in inherited porphobilinogen
synthase (delta-aminolevulinic acid dehydrase) deficiency. Blut 45:
131-139, 1982.
7. Doss, M.; Schneider, J.; von Tiepermann, R.; Brandt, A.: New type
of acute porphyria with porphobilinogen synthase (delta-aminolevulinic
acid dehydratase) defect in the homozygous state. Clin. Biochem. 15:
52-55, 1982.
8. Doss, M.; von Tiepermann, R.; Schneider, J.: Porphobilinogen-synthase
(delta-aminolevulinic acid dehydratase) deficiency in bone marrow
cells of two patients with porphobilinogen-synthase defect acute porphyria. Klin.
Wschr. 61: 699-702, 1983.
9. Doss, M.; von Tiepermann, R.; Schneider, J.: Acute hepatic porphyria
syndrome with porphobilinogen synthase defect. Int. J. Biochem. 12:
823-826, 1980.
10. Doss, M.; von Tiepermann, R.; Schneider, J.; Schmid, H.: New
type of hepatic porphyria with porphobilinogen synthase defect and
intermittent acute clinical manifestation. Klin. Wschr. 57: 1123-1127,
1979.
11. Doss, M. O.; Stauch, T.; Gross, U.; Renz, M.; Akagi, R.; Doss-Frank,
M.; Seelig, H. P.; Sassa, S.: The third case of Doss porphyria (delta-aminolevulinic
acid dehydratase deficiency) in Germany. J. Inherit. Metab. Dis. 27:
529-536, 2004.
12. Dyer, J.; Garrick, D. P.; Inglis, A.; Pye, I. F.: Plumboporphyria
(ALAD deficiency) in a lead worker: a scenario for potential diagnostic
confusion. Brit. J. Indust. Med. 50: 1119-1121, 1993.
13. Fujita, H.; Sassa, S.; Lundgren, J.; Holmberg, L.; Thunell, S.;
Kappas, A.: Enzymatic defect in a child with hereditary hepatic porphyria
due to homozygous delta-aminolevulinic acid dehydratase deficiency:
immunochemical studies. Pediatrics 80: 880-885, 1987.
14. Goetsch, C. A.; Bissell, D. M.: Instability of hematin used in
the treatment of acute hepatic porphyria. New Eng. J. Med. 315:
235-238, 1986.
15. Haeger-Aronsen, B.; Abdulla, M.; Fristedt, B. I.: Effect of lead
on delta-aminolevulinic acid dehydrase activity in red blood cells. Arch.
Environ. Health 23: 440-445, 1971.
16. Hassoun, A.; Verstraeten, L.; Mercelis, R.; Martin, J. J.: Biochemical
diagnosis of an hereditary aminolaevulinate dehydratase deficiency
in a 63-year-old man. J. Clin. Chem. Clin. Biochem. 27: 781-786,
1989.
17. Ishida, N.; Fujita, H.; Fukuda, Y.; Noguchi, T.; Doss, M.; Kappas,
A.; Sassa, S.: Cloning and expression of the defective genes from
a patient with delta-aminolevulinate dehydratase porphyria. J. Clin.
Invest. 89: 1431-1437, 1992.
18. Jaffe, E. K.; Stith, L.: ALAD porphyria is a conformational disease. Am.
J. Hum. Genet. 80: 329-337, 2007.
19. Plewinska, M.; Thunell, S.; Holmberg, L.; Wetmur, J. G.; Desnick,
R. J.: Delta-aminolevulinate dehydratase deficient porphyria: identification
of the molecular lesions in a severely affected homozygote. Am. J.
Hum. Genet. 49: 167-174, 1991.
20. Sassa, S.; Fujita, H.; Doss, M.; Hassoun, A.; Verstraeten, L.;
Mercelis, R.; Kappas, A.: Hereditary hepatic porphyria due to homozygous
delta-aminolevulinic acid dehydratase deficiency: studies in lymphocytes
and erythrocytes. Europ. J. Clin. Invest. 21: 244-248, 1991.
21. Thunell, S.; Henrichson, A.; Floderus, Y.; Groth, C. G.; Eriksson,
B.-G.; Barkholt, L.; Nemeth, A.; Strandvik, B.; Eleborg, L.; Holmberg,
L.; Lundgren, J.: Liver transplantation in a boy with acute porphyria
due to aminolaevulinate dehydratase deficiency. Europ. J. Clin. Chem.
Clin. Biochem. 30: 599-606, 1992.
22. Thunell, S.; Holmberg, L.; Lundgren, J.: Aminolevulinate dehydratase
porphyria in infancy: a clinical and biochemical study. J. Clin.
Chem. Clin. Biochem. 25: 5-14, 1987.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
RESPIRATORY:
[Lung];
Respiratory paralysis
ABDOMEN:
[Gastrointestinal];
Vomiting;
Abdominal colic
MUSCLE, SOFT TISSUE:
Hypotonia;
Muscle weakness
NEUROLOGIC:
[Peripheral nervous system];
Neuropathy (motor and sensory);
Paresthesia;
Paralysis
HEMATOLOGY:
Hemolytic anemia;
Porphyria
LABORATORY ABNORMALITIES:
Erythrocyte delta-aminolevulinate dehydratase (ALAD) deficiency;
Elevated urinary delta-aminolevulinic acid and porphyrins
MISCELLANEOUS:
Very rare;
Asymptomatic heterozygotes susceptible to lead toxicity;
Exacerbation following stress, decreased food intake, or alcohol use
MOLECULAR BASIS:
Caused by mutation in the delta-aminolevulinate dehydratase gene (ALAD,
125270.0001)
*FIELD* CN
Kelly A. Przylepa - revised: 3/13/2000
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 02/07/2011
joanna: 6/11/2009
ckniffin: 4/23/2009
joanna: 10/27/2000
kayiaros: 3/13/2000
*FIELD* CN
Cassandra L. Kniffin - updated: 4/23/2009
*FIELD* CD
Cassandra L. Kniffin: 4/21/2009
*FIELD* ED
carol: 02/27/2012
carol: 6/23/2011
carol: 1/5/2010
terry: 6/19/2009
carol: 5/20/2009
carol: 5/18/2009
ckniffin: 4/23/2009