RBCC

Full text data of HMBS

HMBS (PBGD, UPS) [Confidence: high (present in two of the MS resources)]
Porphobilinogen deaminase; PBG-D; 2.5.1.61 (Hydroxymethylbilane synthase; HMBS; Pre-uroporphyrinogen synthase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00028160
IPI00028160 Splice Isoform 2 Of Porphobilinogen deaminase Tetrapolymerization of the monopyrrole PBG into the hydroxymethylbilane pre-uroporphyrinogen in several discrete steps soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic isoform 1 or 2 found at its expected molecular weight found at molecular weight

UniProt P08397
ID HEM3_HUMAN Reviewed; 361 AA.
AC P08397; A8K2L0; G3V1P4; G5EA58; P08396; Q16012;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1995, sequence version 2.
DT 22-JAN-2014, entry version 170.
DE RecName: Full=Porphobilinogen deaminase;
DE Short=PBG-D;
DE EC=2.5.1.61;
DE AltName: Full=Hydroxymethylbilane synthase;
DE Short=HMBS;
DE AltName: Full=Pre-uroporphyrinogen synthase;
GN Name=HMBS; Synonyms=PBGD, UPS;
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 2).
RX PubMed=2875434; DOI=10.1093/nar/14.15.5955;
RA Raich N., Romeo P.-H., Dubart A., Beaupain D., Cohen-Solal M.,
RA Goossens M.;
RT "Molecular cloning and complete primary sequence of human erythrocyte
RT porphobilinogen deaminase.";
RL Nucleic Acids Res. 14:5955-5968(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=3816774; DOI=10.1111/j.1432-1033.1987.tb10548.x;
RA Grandchamp B., de Verneuil H., Beaumont C., Chretien S., Walter O.,
RA Nordmann Y.;
RT "Tissue-specific expression of porphobilinogen deaminase. Two
RT isoenzymes from a single gene.";
RL Eur. J. Biochem. 162:105-110(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=7916736; DOI=10.1006/geno.1993.1005;
RA Yoo H.-W., Warner C.A., Chen C.-H., Desnick R.J.;
RT "Hydroxymethylbilane synthase: complete genomic sequence and
RT amplifiable polymorphisms in the human gene.";
RL Genomics 15:21-29(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 3 AND 4).
RC TISSUE=Colon;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F.,
RA Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E.,
RA FitzGerald M.G., Jaffe D.B., LaButti K., Nicol R., Park H.-S.,
RA Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W.,
RA Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S.,
RA Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain, and Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 30-53, AND TISSUE SPECIFICITY.
RX PubMed=3422427; DOI=10.1073/pnas.85.1.6;
RA Chretien S., Dubart A., Beaupain D., Raich N., Grandchamp B., Rosa J.,
RA Goossens M., Romeo P.-H.;
RT "Alternative transcription and splicing of the human porphobilinogen
RT deaminase gene result either in tissue-specific or in housekeeping
RT expression.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:6-10(1988).
RN [9]
RP PROTEIN SEQUENCE OF 18-36 (ISOFORM 2).
RX PubMed=2609111;
RA Lannfelt L., Wetterberg L., Lilius L., Thunell S., Joernvall H.,
RA Pavlu B., Wielburski A., Gellerfors P.;
RT "Porphobilinogen deaminase in human erythrocytes: purification of two
RT forms with apparent molecular weights of 40 kDa and 42 kDa.";
RL Scand. J. Clin. Lab. Invest. 49:677-684(1989).
RN [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS).
RX PubMed=19207107; DOI=10.1042/BJ20082077;
RA Gill R., Kolstoe S.E., Mohammed F., Al D-Bass A., Mosely J.E.,
RA Sarwar M., Cooper J.B., Wood S.P., Shoolingin-Jordan P.M.;
RT "Structure of human porphobilinogen deaminase at 2.8 A: the molecular
RT basis of acute intermittent porphyria.";
RL Biochem. J. 420:17-25(2009).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.18 ANGSTROMS), AND
RP S-(DIPYRROLYLMETHANEMETHYL)CYSTEINE AT CYS-261.
RX PubMed=18936296; DOI=10.1096/fj.08-115469;
RA Song G., Li Y., Cheng C., Zhao Y., Gao A., Zhang R., Joachimiak A.,
RA Shaw N., Liu Z.J.;
RT "Structural insight into acute intermittent porphyria.";
RL FASEB J. 23:396-404(2009).
RN [15]
RP VARIANTS AIP GLN-167 AND GLN-173.
RX PubMed=2243128; DOI=10.1172/JCI114869;
RA Delfau M.H., Picat C., de Rooij F.W.M., Hamer K., Bogard M.,
RA Wilson J.H.P., Deybach J.-C., Nordmann Y., Grandchamp B.;
RT "Two different point G to A mutations in exon 10 of the
RT porphobilinogen deaminase gene are responsible for acute intermittent
RT porphyria.";
RL J. Clin. Invest. 86:1511-1516(1990).
RN [16]
RP VARIANTS AIP GLN-149 AND ARG-245.
RX PubMed=1714233;
RA Delfau M.H., Picat C., de Rooij F.W.M., Voortman G., Deybach J.-C.,
RA Nordmann Y., Grandchamp B.;
RT "Molecular heterogeneity of acute intermittent porphyria:
RT identification of four additional mutations resulting in the CRIM-
RT negative subtype of the disease.";
RL Am. J. Hum. Genet. 49:421-428(1991).
RN [17]
RP VARIANT AIP TRP-167.
RX PubMed=1496994;
RA Gu X.-F., de Rooij F.W.M., Voortman G., Te Velde K., Nordmann Y.,
RA Grandchamp B.;
RT "High frequency of mutations in exon 10 of the porphobilinogen
RT deaminase gene in patients with a CRIM-positive subtype of acute
RT intermittent porphyria.";
RL Am. J. Hum. Genet. 51:660-665(1992).
RN [18]
RP VARIANTS AIP LYS-34; GLN-167; ARG-177 AND ASN-256.
RX PubMed=1427766; DOI=10.1007/BF00210738;
RA Mgone C.S., Lanyon W.G., Moore M.R., Connor J.M.;
RT "Detection of seven point mutations in the porphobilinogen deaminase
RT gene in patients with acute intermittent porphyria, by direct
RT sequencing of in vitro amplified cDNA.";
RL Hum. Genet. 90:12-16(1992).
RN [19]
RP VARIANTS AIP TRP-167 AND GLN-173.
RX PubMed=1301948; DOI=10.1002/humu.1380010508;
RA Kauppinen R., Peltonen L., Pihlaja H., Mustajoki P.;
RT "CRIM-positive mutations of acute intermittent porphyria in Finland.";
RL Hum. Mutat. 1:392-396(1992).
RN [20]
RP VARIANTS AIP ARG-247; THR-252 AND VAL-252.
RX PubMed=8262523; DOI=10.1007/BF00420949;
RA Mgone C.S., Lanyon W.G., Moore M.R., Louie G.V., Connor J.M.;
RT "Detection of a high mutation frequency in exon 12 of the
RT porphobilinogen deaminase gene in patients with acute intermittent
RT porphyria.";
RL Hum. Genet. 92:619-622(1993).
RN [21]
RP VARIANT AIP HIS-26.
RX PubMed=8401516; DOI=10.1093/hmg/2.8.1315;
RA Llewellyn D.H., Whatley S.D., Elder G.H.;
RT "Acute intermittent porphyria caused by an arginine to histidine
RT substitution (R26H) in the cofactor-binding cleft of porphobilinogen
RT deaminase.";
RL Hum. Mol. Genet. 2:1315-1316(1993).
RN [22]
RP VARIANT AIP ARG-111.
RX PubMed=8268934; DOI=10.1093/hmg/2.10.1735;
RA Gu X.-F., de Rooij F.W.M., de Baar E., Bruyland M., Lissens W.,
RA Nordmann Y., Grandchamp B.;
RT "Two novel mutations of the porphobilinogen deaminase gene in acute
RT intermittent porphyria.";
RL Hum. Mol. Genet. 2:1735-1736(1993).
RN [23]
RP VARIANTS AIP THR-31; SER-55; LEU-149; LYS-223 AND LYS-250.
RX PubMed=8270254; DOI=10.1007/BF00218912;
RA Gu X.-F., de Rooij F.W.M., Voortman G., Te Velde K., Deybach J.-C.,
RA Nordmann Y., Grandchamp B.;
RT "Detection of eleven mutations causing acute intermittent porphyria
RT using denaturing gradient gel electrophoresis.";
RL Hum. Genet. 93:47-52(1994).
RN [24]
RP VARIANT AIP TRP-201.
RX PubMed=8270256; DOI=10.1007/BF00218914;
RA Lundin G., Wedell A., Thunell S., Anvret M.;
RT "Two new mutations in the porphobilinogen deaminase gene and a
RT screening method using PCR amplification of specific alleles.";
RL Hum. Genet. 93:59-62(1994).
RN [25]
RP VARIANTS AIP GLN-116; TRP-173; ARG-177; ILE-269 AND ARG-274.
RX PubMed=8081367; DOI=10.1093/hmg/3.5.809;
RA Mgone C.S., Lanyon W.G., Moore M.R., Louie G.V., Connor J.M.;
RT "Identification of five novel mutations in the porphobilinogen
RT deaminase gene.";
RL Hum. Mol. Genet. 3:809-811(1994).
RN [26]
RP REVIEW ON AIP VARIANTS.
RX PubMed=7866402; DOI=10.1002/humu.1380040403;
RA Astrin K.N., Desnick R.J.;
RT "Molecular basis of acute intermittent porphyria: mutations and
RT polymorphisms in the human hydroxymethylbilane synthase gene.";
RL Hum. Mutat. 4:243-252(1994).
RN [27]
RP VARIANTS AIP PHE-93; TRP-116; TRP-201 AND PHE-247.
RX PubMed=7962538; DOI=10.1172/JCI117543;
RA Chen C.-H., Astrin K.H., Lee G., Anderson K.E., Desnick R.J.;
RT "Acute intermittent porphyria: identification and expression of exonic
RT mutations in the hydroxymethylbilane synthase gene. An initiation
RT codon missense mutation in the housekeeping transcript causes 'variant
RT acute intermittent porphyria' with normal expression of the erythroid-
RT specific enzyme.";
RL J. Clin. Invest. 94:1927-1937(1994).
RN [28]
RP VARIANTS AIP.
RX PubMed=7757070; DOI=10.1093/hmg/4.2.215;
RA Kauppinen R., Mustajoki S., Pihlaja H., Peltonen L., Mustajoki P.;
RT "Acute intermittent porphyria in Finland: 19 mutations in the
RT porphobilinogen deaminase gene.";
RL Hum. Mol. Genet. 4:215-222(1995).
RN [29]
RP VARIANTS AIP LEU-119 AND ALA-250.
RX PubMed=8825929;
RA Lundin G., Hashemi J., Floderus Y., Thunell S., Sagen E., Laegreid A.,
RA Wassif W., Peters T., Anvret M.;
RT "Four mutations in the porphobilinogen deaminase gene in patients with
RT acute intermittent porphyria.";
RL J. Med. Genet. 32:979-981(1995).
RN [30]
RP VARIANTS AIP.
RX PubMed=9199558;
RA Puy H., Deybach J.-C., Lamoril J., Robreau A.-M., Da Silva V.,
RA Gouya L., Grandchamp B., Nordmann Y.;
RT "Molecular epidemiology and diagnosis of PBG deaminase gene defects in
RT acute intermittent porphyria.";
RL Am. J. Hum. Genet. 60:1373-1383(1997).
RN [31]
RP VARIANTS AIP TRP-116; LEU-119; GLN-167; TRP-167; TRP-173; TRP-201 AND
RP ASP-216.
RX PubMed=9225970; DOI=10.1007/s004390050466;
RA Lundin G., Lee J.-S., Thunell S., Anvret M.;
RT "Genetic investigation of the porphobilinogen deaminase gene in
RT Swedish acute intermittent porphyria families.";
RL Hum. Genet. 100:63-66(1997).
RN [32]
RP VARIANTS AIP MET-222 AND PRO-278.
RX PubMed=9654202; DOI=10.1007/s004390050737;
RA Mustajoki S., Pihlaja H., Ahola H., Petersen N.E., Mustajoki P.,
RA Kauppinen R.;
RT "Three splicing defects, an insertion, and two missense mutations
RT responsible for acute intermittent porphyria.";
RL Hum. Genet. 102:541-548(1998).
RN [33]
RP VARIANT AIP CYS-22.
RX PubMed=9463797; DOI=10.1159/000022777;
RA Ong P.M., Lanyon W.G., Hift R.J., Halkett J., Cramp C.E., Moore M.R.,
RA Connor J.M.;
RT "Identification of two novel mutations in the hydroxymethylbilane
RT synthase gene in three patients from two unrelated families with acute
RT intermittent porphyria.";
RL Hum. Hered. 48:24-29(1998).
RN [34]
RP VARIANTS AIP PRO-34; ARG-111; TRP-173; TRP-201; 329-LEU--GLN-332 DEL
RP AND SER-335.
RX PubMed=10494093;
RX DOI=10.1002/(SICI)1096-8628(19991008)86:4<366::AID-AJMG11>3.3.CO;2-R;
RA De Siervi A., Rossetti M.V., Parera V.E., Astrin K.H., Aizencang G.I.,
RA Glass I.A., Batlle A.M.C., Desnick R.J.;
RT "Identification and characterization of hydroxymethylbilane synthase
RT mutations causing acute intermittent porphyria: evidence for an
RT ancestral founder of the common G111R mutation.";
RL Am. J. Med. Genet. 86:366-375(1999).
RN [35]
RP VARIANTS AIP CYS-22; CYS-26; HIS-26; PRO-31; SER-42; ASN-61; ARG-85;
RP GLY-90; ARG-111; GLN-173; TRP-173; ARG-177; CYS-195; ASP-219; ARG-247
RP AND ILE-269.
RX PubMed=10453740; DOI=10.1007/s004390050995;
RA Whatley S.D., Woolf J.R., Elder G.H.;
RT "Comparison of complementary and genomic DNA sequencing for the
RT detection of mutations in the HMBS gene in British patients with acute
RT intermittent porphyria: identification of 25 novel mutations.";
RL Hum. Genet. 104:505-510(1999).
RN [36]
RP VARIANT AIP ALA-152 DEL.
RX PubMed=10502788;
RX DOI=10.1002/(SICI)1098-1004(199910)14:4<355::AID-HUMU19>3.0.CO;2-T;
RA De Siervi A., Mendez M., Parera V.E., Varela L., Batlle A.M.C.,
RA Rossetti M.V.;
RT "Acute intermittent porphyria: characterization of two novel mutations
RT in the porphobilinogen deaminase gene, one amino acid deletion (453-
RT 455delAGC) and one splicing acceptor site mutation (IVS8-1G>T).";
RL Hum. Mutat. 14:355-355(1999).
RN [37]
RP VARIANTS AIP CYS-26 AND LEU-202.
RX PubMed=10657149; DOI=10.1006/mcpr.1999.0276;
RA Gross U., Puy H., Doss M., Robreau A.-M., Nordmann Y., Doss M.O.,
RA Deybach J.-C.;
RT "New mutations of the hydroxymethylbilane synthase gene in German
RT patients with acute intermittent porphyria.";
RL Mol. Cell. Probes 13:443-447(1999).
RN [38]
RP VARIANTS AIP ARG-111; TRP-116; TRP-167; TRP-173 AND VAL-212, AND
RP CHARACTERIZATION OF VARIANT AIP VAL-212.
RX PubMed=10602775;
RA Solis C., Lopez-Echaniz I., Sefarty-Graneda D., Astrin K.H.,
RA Desnick R.J.;
RT "Identification and expression of mutations in the hydroxymethylbilane
RT synthase gene causing acute intermittent porphyria (AIP).";
RL Mol. Med. 5:664-671(1999).
RN [39]
RP VARIANTS AIP PRO-78; GLY-80; ARG-111 AND TRP-173.
RX PubMed=11399210; DOI=10.1097/00125817-200009000-00004;
RA Ramdall R.B., Cunha L., Astrin K.H., Katz D.R., Anderson K.E.,
RA Glucksman M., Bottomley S.S., Desnick R.J.;
RT "Acute intermittent porphyria: novel missense mutations in the human
RT hydroxymethylbilane synthase gene.";
RL Genet. Med. 2:290-295(2000).
RN [40]
RP VARIANTS AIP TRP-116 AND GLY-270.
RX PubMed=11030413; DOI=10.1007/s004390000323;
RA Robreau-Fraolini A.M., Puy H., Aquaron C., Bogard C., Traore M.,
RA Nordmann Y., Aquaron R., Deybach J.-C.;
RT "Porphobilinogen deaminase gene in African and Afro-Caribbean ethnic
RT groups: mutations causing acute intermittent porphyria and specific
RT intragenic polymorphisms.";
RL Hum. Genet. 107:150-159(2000).
RN [41]
RP VARIANT AIP LEU-217.
RX PubMed=10782018; DOI=10.1159/000022924;
RA Schneider-Yin X., Bogard C., Rufenacht U.B., Puy H., Nordmann Y.,
RA Minder E.I., Deybach J.-C.;
RT "Identification of a prevalent nonsense mutation (W283X) and two novel
RT mutations in the porphobilinogen deaminase gene of Swiss patients with
RT acute intermittent porphyria.";
RL Hum. Hered. 50:247-250(2000).
RN [42]
RP VARIANTS AIP MET-35; ARG-111 AND GLY-281 DEL.
RX PubMed=11013452;
RX DOI=10.1002/1098-1004(200010)16:4<373::AID-HUMU14>3.0.CO;2-A;
RA De Siervi A., Weiss Cadiz D.E., Parera V.E., Batlle A.M.C.,
RA Rossetti M.V.;
RT "Identification and characterization of two novel mutations that
RT produce acute intermittent porphyria: a 3-base deletion (841-
RT 843delGGA) and a missense mutation (T35M).";
RL Hum. Mutat. 16:373-373(2000).
RN [43]
RP ERRATUM, AND VARIANT AIP ASN-99.
RA Martinez di Montemuros F., Di Pierro E., Fiorelli G., Cappellini M.D.;
RL Hum. Genet. 109:241-241(2001).
RN [44]
RP VARIANTS AIP ILE-18; PHE-96; HIS-99; GLY-122; PRO-254 AND TYR-261.
RX PubMed=12406973;
RA Kauppinen R., von und zu Fraunberg M.;
RT "Molecular and biochemical studies of acute intermittent porphyria in
RT 196 patients and their families.";
RL Clin. Chem. 48:1891-1900(2002).
RN [45]
RP VARIANTS AIP CYS-26; HIS-26; VAL-86; PRO-92; GLY-99; ARG-111; THR-113;
RP GLN-173; ASN-178; GLN-225; GLY-225; TYR-256; ASP-260 AND PRO-343.
RX PubMed=12372055; DOI=10.1034/j.1399-0004.2002.620406.x;
RA Floderus Y., Shoolingin-Jordan P.M., Harper P.;
RT "Acute intermittent porphyria in Sweden. Molecular, functional and
RT clinical consequences of some new mutations found in the
RT porphobilinogen deaminase gene.";
RL Clin. Genet. 62:288-297(2002).
RN [46]
RP VARIANTS AIP HIS-26; TYR-61; VAL-93 DEL; ARG-111; GLN-173 AND ASP-335.
RX PubMed=11857754; DOI=10.1002/humu.9020;
RA Gregor A., Schneider-Yin X., Szlendak U., Wettstein A., Lipniacka A.,
RA Ruefenacht U.B., Minder E.I.;
RT "Molecular study of the hydroxymethylbilane synthase gene (HMBS) among
RT Polish patients with acute intermittent porphyria.";
RL Hum. Mutat. 19:310-310(2002).
RN [47]
RP VARIANTS AIP ARG-34; SER-236 AND PRO-244.
RX PubMed=14669009; DOI=10.1007/s00439-003-1059-5;
RA Gouya L., Puy H., Robreau A.-M., Lyoumi S., Lamoril J., Da Silva V.,
RA Grandchamp B., Deybach J.-C.;
RT "Modulation of penetrance by the wild-type allele in dominantly
RT inherited erythropoietic protoporphyria and acute hepatic
RT porphyrias.";
RL Hum. Genet. 114:256-262(2004).
RN [48]
RP VARIANT AIP PRO-81.
RX PubMed=14970743; DOI=10.1023/B:BOLI.0000016613.75677.05;
RA Hessels J., Voortman G., van der Wagen A., van der Elzen C.,
RA Scheffer H., Zuijderhoudt F.M.J.;
RT "Homozygous acute intermittent porphyria in a 7-year-old boy with
RT massive excretions of porphyrins and porphyrin precursors.";
RL J. Inherit. Metab. Dis. 27:19-27(2004).
RN [49]
RP VARIANTS AIP ARG-111 AND GLN-173.
RX PubMed=15669678; DOI=10.1023/B:BOLI.0000042936.20691.ad;
RA Schneider-Yin X., Hergersberg M., Schuurmans M.M., Gregor A.,
RA Minder E.I.;
RT "Mutation hotspots in the human porphobilinogen deaminase gene:
RT recurrent mutations G111R and R173Q occurring at CpG motifs.";
RL J. Inherit. Metab. Dis. 27:625-631(2004).
CC -!- FUNCTION: Tetrapolymerization of the monopyrrole PBG into the
CC hydroxymethylbilane pre-uroporphyrinogen in several discrete
CC steps.
CC -!- CATALYTIC ACTIVITY: 4 porphobilinogen + H(2)O =
CC hydroxymethylbilane + 4 NH(3).
CC -!- COFACTOR: Binds 1 dipyrromethane group covalently.
CC -!- PATHWAY: Porphyrin-containing compound metabolism; protoporphyrin-
CC IX biosynthesis; coproporphyrinogen-III from 5-aminolevulinate:
CC step 2/4.
CC -!- SUBCELLULAR LOCATION: Cytoplasm (Probable).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=Non-erythropoietic;
CC IsoId=P08397-1; Sequence=Displayed;
CC Name=2; Synonyms=Erythrocyte;
CC IsoId=P08397-2; Sequence=VSP_002067;
CC Name=3;
CC IsoId=P08397-3; Sequence=VSP_047294;
CC Note=No experimental confirmation available;
CC Name=4;
CC IsoId=P08397-4; Sequence=VSP_002067, VSP_047294;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Isoform 1 is ubiquitously expressed. Isoform 2
CC is found only in erythroid cells.
CC -!- DISEASE: Acute intermittent porphyria (AIP) [MIM:176000]: A form
CC of porphyria. Porphyrias are inherited defects in the biosynthesis
CC of 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. AIP is an
CC autosomal dominant form of hepatic porphyria characterized by
CC attacks of gastrointestinal disturbances, abdominal colic, with
CC neurological dysfunctions, hypertension, tachycardia and
CC peripheral neuropathy. Most attacks are precipitated by drugs,
CC alcohol, caloric deprivation, infections, or endocrine factors.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- MISCELLANEOUS: The porphobilinogen subunits are added to the
CC dipyrromethane group.
CC -!- SIMILARITY: Belongs to the HMBS family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/HMBS";
CC -----------------------------------------------------------------------
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DR EMBL; X04217; CAA27801.1; -; mRNA.
DR EMBL; X04808; CAA28499.1; -; mRNA.
DR EMBL; M95623; AAA60029.1; -; Genomic_DNA.
DR EMBL; M95623; AAA60030.1; -; Genomic_DNA.
DR EMBL; AK000628; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AK131072; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AK290275; BAF82964.1; -; mRNA.
DR EMBL; AP003391; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP003392; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471065; EAW67447.1; -; Genomic_DNA.
DR EMBL; CH471065; EAW67449.1; -; Genomic_DNA.
DR EMBL; CH471065; EAW67450.1; -; Genomic_DNA.
DR EMBL; BC000520; AAH00520.1; -; mRNA.
DR EMBL; BC008149; AAH08149.1; -; mRNA.
DR EMBL; BC019323; AAH19323.1; -; mRNA.
DR EMBL; X68018; CAA48156.1; -; Genomic_DNA.
DR EMBL; S60381; AAC60602.1; -; Genomic_DNA.
DR PIR; A45012; IBHUN.
DR RefSeq; NP_000181.2; NM_000190.3.
DR RefSeq; NP_001019553.1; NM_001024382.1.
DR RefSeq; NP_001245137.1; NM_001258208.1.
DR RefSeq; NP_001245138.1; NM_001258209.1.
DR RefSeq; XP_005271588.1; XM_005271531.1.
DR RefSeq; XP_005271589.1; XM_005271532.1.
DR UniGene; Hs.82609; -.
DR PDB; 3ECR; X-ray; 2.18 A; A/B=1-361.
DR PDB; 3EQ1; X-ray; 2.80 A; A/B=1-361.
DR PDBsum; 3ECR; -.
DR PDBsum; 3EQ1; -.
DR ProteinModelPortal; P08397; -.
DR SMR; P08397; 18-356.
DR STRING; 9606.ENSP00000278715; -.
DR PhosphoSite; P08397; -.
DR DMDM; 1170217; -.
DR PaxDb; P08397; -.
DR PRIDE; P08397; -.
DR DNASU; 3145; -.
DR Ensembl; ENST00000278715; ENSP00000278715; ENSG00000256269.
DR Ensembl; ENST00000392841; ENSP00000376584; ENSG00000256269.
DR Ensembl; ENST00000442944; ENSP00000392041; ENSG00000256269.
DR Ensembl; ENST00000537841; ENSP00000444730; ENSG00000256269.
DR Ensembl; ENST00000542729; ENSP00000443058; ENSG00000256269.
DR Ensembl; ENST00000544387; ENSP00000438424; ENSG00000256269.
DR Ensembl; ENST00000570821; ENSP00000458163; ENSG00000261883.
DR Ensembl; ENST00000571030; ENSP00000461361; ENSG00000261883.
DR Ensembl; ENST00000571563; ENSP00000458765; ENSG00000261883.
DR Ensembl; ENST00000574152; ENSP00000458891; ENSG00000261883.
DR Ensembl; ENST00000575587; ENSP00000460754; ENSG00000261883.
DR Ensembl; ENST00000575888; ENSP00000461906; ENSG00000261883.
DR GeneID; 3145; -.
DR KEGG; hsa:3145; -.
DR UCSC; uc001puz.1; human.
DR CTD; 3145; -.
DR GeneCards; GC11P118955; -.
DR HGNC; HGNC:4982; HMBS.
DR HPA; HPA006114; -.
DR MIM; 176000; phenotype.
DR MIM; 609806; gene.
DR neXtProt; NX_P08397; -.
DR Orphanet; 79276; Acute intermittent porphyria.
DR PharmGKB; PA29317; -.
DR eggNOG; COG0181; -.
DR HOGENOM; HOG000228587; -.
DR HOVERGEN; HBG000967; -.
DR InParanoid; P08397; -.
DR KO; K01749; -.
DR OMA; PLRGNAN; -.
DR PhylomeDB; P08397; -.
DR BioCyc; MetaCyc:HS07607-MONOMER; -.
DR BRENDA; 2.5.1.61; 2681.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00251; UER00319.
DR EvolutionaryTrace; P08397; -.
DR GeneWiki; Porphobilinogen_deaminase; -.
DR GenomeRNAi; 3145; -.
DR NextBio; 12464; -.
DR PRO; PR:P08397; -.
DR ArrayExpress; P08397; -.
DR Bgee; P08397; -.
DR CleanEx; HS_HMBS; -.
DR Genevestigator; P08397; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0004418; F:hydroxymethylbilane synthase activity; IDA:UniProtKB.
DR GO; GO:0006783; P:heme biosynthetic process; IC:UniProtKB.
DR GO; GO:0018160; P:peptidyl-pyrromethane cofactor linkage; IEA:InterPro.
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; 3.30.160.40; -; 1.
DR InterPro; IPR000860; 4pyrrol_synth_OHMeBilane_synth.
DR InterPro; IPR022419; Porphobilin_deaminase_cofac_BS.
DR InterPro; IPR022417; Porphobilin_deaminase_N.
DR InterPro; IPR022418; Porphobilinogen_deaminase_C.
DR PANTHER; PTHR11557; PTHR11557; 1.
DR Pfam; PF01379; Porphobil_deam; 1.
DR Pfam; PF03900; Porphobil_deamC; 1.
DR PIRSF; PIRSF001438; 4pyrrol_synth_OHMeBilane_synth; 1.
DR PRINTS; PR00151; PORPHBDMNASE.
DR SUPFAM; SSF54782; SSF54782; 2.
DR TIGRFAMs; TIGR00212; hemC; 1.
DR PROSITE; PS00533; PORPHOBILINOGEN_DEAM; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Disease mutation;
KW Heme biosynthesis; Porphyrin biosynthesis; Reference proteome;
KW Transferase.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 361 Porphobilinogen deaminase.
FT /FTId=PRO_0000143034.
FT MOD_RES 2 2 N-acetylserine.
FT MOD_RES 261 261 S-(dipyrrolylmethanemethyl)cysteine.
FT VAR_SEQ 1 17 Missing (in isoform 2 and isoform 4).
FT /FTId=VSP_002067.
FT VAR_SEQ 218 257 Missing (in isoform 3 and isoform 4).
FT /FTId=VSP_047294.
FT VARIANT 18 18 M -> I (in AIP).
FT /FTId=VAR_025558.
FT VARIANT 22 22 R -> C (in AIP).
FT /FTId=VAR_003638.
FT VARIANT 24 24 G -> S (in AIP).
FT /FTId=VAR_011001.
FT VARIANT 26 26 R -> C (in AIP).
FT /FTId=VAR_011002.
FT VARIANT 26 26 R -> H (in AIP).
FT /FTId=VAR_003639.
FT VARIANT 28 28 S -> N (in AIP).
FT /FTId=VAR_011003.
FT VARIANT 31 31 A -> P (in AIP).
FT /FTId=VAR_011004.
FT VARIANT 31 31 A -> T (in AIP).
FT /FTId=VAR_003640.
FT VARIANT 34 34 Q -> K (in AIP).
FT /FTId=VAR_003641.
FT VARIANT 34 34 Q -> P (in AIP; less than 3% of
FT activity).
FT /FTId=VAR_011005.
FT VARIANT 34 34 Q -> R (in AIP).
FT /FTId=VAR_025559.
FT VARIANT 35 35 T -> M (in AIP).
FT /FTId=VAR_011006.
FT VARIANT 42 42 L -> S (in AIP).
FT /FTId=VAR_011007.
FT VARIANT 55 55 A -> S (in AIP).
FT /FTId=VAR_003642.
FT VARIANT 61 61 D -> N (in AIP).
FT /FTId=VAR_011008.
FT VARIANT 61 61 D -> Y (in AIP).
FT /FTId=VAR_025560.
FT VARIANT 78 78 T -> P (in AIP).
FT /FTId=VAR_025561.
FT VARIANT 80 80 E -> G (in AIP).
FT /FTId=VAR_025562.
FT VARIANT 81 81 L -> P (in AIP).
FT /FTId=VAR_025563.
FT VARIANT 85 85 L -> R (in AIP).
FT /FTId=VAR_011009.
FT VARIANT 86 86 E -> V (in AIP).
FT /FTId=VAR_025564.
FT VARIANT 90 90 V -> G (in AIP).
FT /FTId=VAR_011010.
FT VARIANT 92 92 L -> P (in AIP).
FT /FTId=VAR_025565.
FT VARIANT 93 93 V -> F (in AIP; loss of activity).
FT /FTId=VAR_003643.
FT VARIANT 93 93 Missing (in AIP).
FT /FTId=VAR_025566.
FT VARIANT 96 96 S -> F (in AIP).
FT /FTId=VAR_025567.
FT VARIANT 98 98 K -> R (in AIP).
FT /FTId=VAR_003644.
FT VARIANT 99 99 D -> G (in AIP).
FT /FTId=VAR_025568.
FT VARIANT 99 99 D -> H (in AIP).
FT /FTId=VAR_025569.
FT VARIANT 99 99 D -> N (in AIP).
FT /FTId=VAR_025570.
FT VARIANT 111 111 G -> R (in AIP).
FT /FTId=VAR_003645.
FT VARIANT 113 113 I -> T (in AIP).
FT /FTId=VAR_025571.
FT VARIANT 116 116 R -> Q (in AIP).
FT /FTId=VAR_003646.
FT VARIANT 116 116 R -> W (in AIP; loss of activity).
FT /FTId=VAR_003647.
FT VARIANT 119 119 P -> L (in AIP).
FT /FTId=VAR_003648.
FT VARIANT 122 122 A -> G (in AIP).
FT /FTId=VAR_025572.
FT VARIANT 124 124 V -> D (in AIP).
FT /FTId=VAR_011011.
FT VARIANT 149 149 R -> L (in AIP).
FT /FTId=VAR_003649.
FT VARIANT 149 149 R -> Q (in AIP).
FT /FTId=VAR_003650.
FT VARIANT 152 152 Missing (in AIP).
FT /FTId=VAR_009223.
FT VARIANT 167 167 R -> Q (in AIP).
FT /FTId=VAR_003651.
FT VARIANT 167 167 R -> W (in AIP).
FT /FTId=VAR_003652.
FT VARIANT 173 173 R -> Q (in AIP; 0.6% of wild-type
FT activity).
FT /FTId=VAR_003653.
FT VARIANT 173 173 R -> W (in AIP).
FT /FTId=VAR_003654.
FT VARIANT 177 177 L -> R (in AIP).
FT /FTId=VAR_003655.
FT VARIANT 178 178 D -> N (in AIP).
FT /FTId=VAR_011012.
FT VARIANT 195 195 R -> C (in AIP; dbSNP:rs34413634).
FT /FTId=VAR_003656.
FT VARIANT 201 201 R -> W (in AIP; residual activity).
FT /FTId=VAR_003657.
FT VARIANT 202 202 V -> L (in AIP).
FT /FTId=VAR_011013.
FT VARIANT 209 209 E -> K (in AIP).
FT /FTId=VAR_011014.
FT VARIANT 212 212 M -> V (in AIP; <2% residual activity).
FT /FTId=VAR_025573.
FT VARIANT 216 216 G -> D (in AIP).
FT /FTId=VAR_011015.
FT VARIANT 217 217 Q -> H (in AIP).
FT /FTId=VAR_011016.
FT VARIANT 217 217 Q -> L (in AIP).
FT /FTId=VAR_011017.
FT VARIANT 219 219 A -> D (in AIP).
FT /FTId=VAR_011018.
FT VARIANT 222 222 V -> M (in AIP).
FT /FTId=VAR_003658.
FT VARIANT 223 223 E -> K (in AIP).
FT /FTId=VAR_003659.
FT VARIANT 225 225 R -> G (in AIP).
FT /FTId=VAR_003660.
FT VARIANT 225 225 R -> Q (in AIP).
FT /FTId=VAR_025574.
FT VARIANT 236 236 G -> S (in AIP).
FT /FTId=VAR_025575.
FT VARIANT 238 238 L -> R (in AIP).
FT /FTId=VAR_003661.
FT VARIANT 244 244 L -> P (in AIP).
FT /FTId=VAR_025576.
FT VARIANT 245 245 L -> R (in AIP).
FT /FTId=VAR_003662.
FT VARIANT 247 247 C -> F (in AIP; residual activity).
FT /FTId=VAR_003663.
FT VARIANT 247 247 C -> R (in AIP).
FT /FTId=VAR_003664.
FT VARIANT 248 248 I -> IETLLRCI (in AIP).
FT /FTId=VAR_011019.
FT VARIANT 250 250 E -> A (in AIP).
FT /FTId=VAR_003665.
FT VARIANT 250 250 E -> K (in AIP).
FT /FTId=VAR_003666.
FT VARIANT 250 250 E -> Q (in AIP).
FT /FTId=VAR_011020.
FT VARIANT 250 250 E -> V (in AIP).
FT /FTId=VAR_011021.
FT VARIANT 252 252 A -> T (in AIP).
FT /FTId=VAR_003667.
FT VARIANT 252 252 A -> V (in AIP).
FT /FTId=VAR_003668.
FT VARIANT 254 254 L -> P (in AIP).
FT /FTId=VAR_025577.
FT VARIANT 256 256 H -> N (in AIP).
FT /FTId=VAR_003669.
FT VARIANT 256 256 H -> Y (in AIP).
FT /FTId=VAR_011022.
FT VARIANT 260 260 G -> D (in AIP).
FT /FTId=VAR_025578.
FT VARIANT 261 261 C -> Y (in AIP).
FT /FTId=VAR_025579.
FT VARIANT 267 267 V -> M (in AIP).
FT /FTId=VAR_011023.
FT VARIANT 269 269 T -> I (in AIP).
FT /FTId=VAR_003670.
FT VARIANT 270 270 A -> D (in AIP).
FT /FTId=VAR_011024.
FT VARIANT 270 270 A -> G (in AIP).
FT /FTId=VAR_011025.
FT VARIANT 274 274 G -> R (in AIP).
FT /FTId=VAR_003671.
FT VARIANT 278 278 L -> P (in AIP).
FT /FTId=VAR_003672.
FT VARIANT 280 280 G -> R (in AIP).
FT /FTId=VAR_003673.
FT VARIANT 281 281 Missing (in AIP).
FT /FTId=VAR_011026.
FT VARIANT 329 332 Missing (in AIP).
FT /FTId=VAR_011027.
FT VARIANT 335 335 G -> D (in AIP).
FT /FTId=VAR_011028.
FT VARIANT 335 335 G -> S (in AIP; less than 3% of
FT activity).
FT /FTId=VAR_011029.
FT VARIANT 343 343 L -> P (in AIP).
FT /FTId=VAR_025580.
FT CONFLICT 177 177 L -> M (in Ref. 3; AAA60029/AAA60030).
FT CONFLICT 210 210 E -> K (in Ref. 2; CAA28499).
FT CONFLICT 349 349 N -> T (in Ref. 1; CAA27801).
FT STRAND 20 28
FT HELIX 29 45
FT STRAND 49 56
FT HELIX 78 86
FT STRAND 91 96
FT HELIX 97 99
FT STRAND 108 113
FT STRAND 121 125
FT HELIX 127 129
FT TURN 134 136
FT STRAND 142 144
FT HELIX 148 157
FT STRAND 161 164
FT HELIX 170 179
FT STRAND 180 182
FT STRAND 184 189
FT HELIX 190 195
FT HELIX 199 201
FT TURN 208 210
FT TURN 215 218
FT STRAND 220 225
FT HELIX 229 236
FT HELIX 241 257
FT STRAND 263 272
FT STRAND 275 283
FT STRAND 289 298
FT HELIX 325 344
FT HELIX 347 353
SQ SEQUENCE 361 AA; 39330 MW; 8F2F6F4150F1AD7E CRC64;
MSGNGNAAAT AEENSPKMRV IRVGTRKSQL ARIQTDSVVA TLKASYPGLQ FEIIAMSTTG
DKILDTALSK IGEKSLFTKE LEHALEKNEV DLVVHSLKDL PTVLPPGFTI GAICKRENPH
DAVVFHPKFV GKTLETLPEK SVVGTSSLRR AAQLQRKFPH LEFRSIRGNL NTRLRKLDEQ
QEFSAIILAT AGLQRMGWHN RVGQILHPEE CMYAVGQGAL GVEVRAKDQD ILDLVGVLHD
PETLLRCIAE RAFLRHLEGG CSVPVAVHTA MKDGQLYLTG GVWSLDGSDS IQETMQATIH
VPAQHEDGPE DDPQLVGITA RNIPRGPQLA AQNLGISLAN LLLSKGAKNI LDVARQLNDA
H
//

MIM 176000
*RECORD*
*FIELD* NO
176000
*FIELD* TI
#176000 PORPHYRIA, ACUTE INTERMITTENT
;;AIP;;
PORPHYRIA, SWEDISH TYPE;;
PORPHOBILINOGEN DEAMINASE DEFICIENCY;;
read morePBGD DEFICIENCY;;
UROPORPHYRINOGEN SYNTHASE DEFICIENCY;;
UPS DEFICIENCY
PORPHYRIA, ACUTE INTERMITTENT, NONERYTHROID VARIANT, INCLUDED;;
PORPHYRIA, CHESTER TYPE, INCLUDED; PORC, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because acute intermittent
porphyria (AIP) is caused by mutation in the gene encoding
hydroxymethylbilane synthase (HMBS; 609806), also referred to as
porphobilinogen deaminase (PBGD).

DESCRIPTION

Porphyrias are inherited defects in the biosynthesis of heme. Acute
intermittent porphyria, the most common form of porphyria, is an
autosomal dominant disorder characterized by recurrent attacks of
abdominal pain, gastrointestinal dysfunction, and neurologic
disturbances. In the classic form of AIP, both the ubiquitous
'nonerythroid' housekeeping HMBS isoform and the 'erythroid' HMBS
isoform are deficient. However, about 5% of families have the
'nonerythroid variant' of AIP, with a defect only in the ubiquitous
nonerythroid HMBS isoform and normal levels of the erythroid HMBS
isoform. Clinical characteristics in the 2 forms are identical;
diagnostic methods based on the level of enzyme in erythrocytes is
ineffective (Puy et al., 1998; Petrides, 1998; Whatley et al., 2000).

There are several other forms of porphyria: see porphyria cutanea tarda
(176100), variegata porphyria (176200), coproporphyria (121300), acute
hepatic porphyria (125270), and congenital erythropoietic porphyria
(263700).

CLINICAL FEATURES

Acute intermittent porphyria is characterized clinically by acute
episodes of a variety of gastrointestinal and neuropathic symptoms;
between episodes, the patient is healthy. Abdominal pain is the most
common symptom, sometimes with constipation and urinary retention;
paraesthesias and paralysis also occur, and death may result from
respiratory paralysis (Goldberg, 1959; Stein and Tschudy, 1970; Becker
and Kramer, 1977). Many other phenomena, including seizures, psychotic
episodes, and hypertension, may occur in acute attacks.

Acute attacks rarely occur before puberty; they may be precipitated by
porphyrinogenic drugs such as barbiturates and sulfonamides (for list,
see Tschudy et al., 1975), some of which are known to induce the earlier
rate-controlling step in heme synthesis, delta-aminolevulinic acid (ALA)
synthesis. Other known precipitants are alcohol, infection, starvation,
and hormonal changes; attacks are more common in women. Only about 10 to
20% of AIP gene carriers become symptomatic during their lifetime
(Petrides, 1998).

From a survey of AIP cases in the west of Scotland, Yeung Laiwah et al.
(1983) observed an association with early-onset chronic renal failure.
Porphyria-induced hypertension was considered the most likely causal
factor, but enhanced susceptibility to analgesic nephropathy and
nephrotoxic effects of porphyrins and their precursors were mentioned as
possibilities.

Beukeveld et al. (1990) reported a rare case of a child with presumed
homozygous AIP who demonstrated porencephaly and severe developmental
retardation. The child consistently excreted excessive amounts of
delta-aminolevulinic acid, porphobilinogen, and uroporphyrin in her
urine from early childhood. She died at age 8 years. Her mother suffered
from AIP. Although the father never had attacks, blood and urine studies
showed that he too was affected. Using allele-specific oligonucleotides,
Picat et al. (1990) demonstrated that the proband reported by Beukeveld
et al. (1990) was compound heterozygous for 2 mutations in the HMBS gene
(609806.0005; 609806.0006). Each parent was heterozygous for 1 of the
mutations.

Hessels et al. (2004) described a 7-year-old boy with homozygous AIP who
demonstrated hepatosplenomegaly, mild anemia, mild mental retardation,
yellow-brown teeth, and dark red urine and who had excessively elevated
levels of urinary delta-aminolevulinic acid, porphobilinogen, and
uroporphyrin. Further hepta-, hexa-, penta- and copro(I)porphyrins were
highly increased in urine. This pattern of porphyrin precursor and
metabolite excretion is characteristic of acute intermittent porphyria.
The porphobilinogen deaminase activity in red cells was decreased to 2
to 4%. The parents were unaffected.

- Chester Type Porphyria

McColl et al. (1985) identified a form of acute porphyria in a large
family in Chester, U.K. Patients presented with attacks of neurovisceral
dysfunction; none had cutaneous photosensitivity. Biochemically, the
pattern of excretion of heme precursors varied between individuals. Some
had a pattern of acute intermittent porphyria, others showed that of
variegate porphyria, and some showed an intermediate pattern. A dual
enzyme deficiency was found in peripheral blood cells; reduced activity
was found in both PBGD, as in AIP, and protoporphyrinogen oxidase (PPOX;
600923), as in variegate porphyria. McColl et al. (1985) initially
thought that this was a new form of porphyria. In the family with
Chester type porphyria, Norton et al. (1991, 1993) identified a
multipoint maximum lod score of 7.33 at a distance less than 1 cM
proximal to D11S351.

In affected members of the original family reported by McColl et al.
(1985), Poblete-Gutierrez et al. (2006) identified a heterozygous
truncating mutation in the HMBS gene (609806.0046). No mutations were
found in the PPOX gene. These findings confirmed that Chester type
porphyria is a variant of AIP. Poblete-Gutierrez et al. (2006) suggested
that the original biochemical studies indicating PPOX deficiency may
have been erroneous or misinterpreted.

BIOCHEMICAL FEATURES

The essential biochemical finding in acute attacks of AIP is increased
urinary excretion of the HMBS precursors delta-aminolevulinic acid (ALA)
and porphobilinogen (PBG); this is the basis for the Watson-Schwartz
test (Watson and Bossenmaier, 1964). Many latent AIP subjects never have
acute attacks, but some intermittently excrete excess porphyrin
precursors in urine without having symptoms. Porphyrins may be formed in
the urine from the precursors (Waldenstrom, 1956).

Anderson et al. (1979) described abnormalities in steroid metabolism in
AIP patients.

Among 22 unrelated families with AIP, Anderson et al. (1981) found
differences in the pattern of the 5 stable enzyme-substrate
intermediates (A, B, C, D, E) of PBG-deaminase separated by
anion-exchange chromatography of erythrocyte lysates. In most patients,
the elution profile was similar to the normal with each intermediate
reduced about 50%. Some heterozygotes had a second profile in which the
C intermediate had disproportionately higher activity than the A or B
intermediates; this pattern was observed during an acute attack,
suggesting that induction of the enzyme depends on substrate
concentrations.

Verma et al. (1987) found that porphyrins are endogenous ligands for a
'peripheral-type' of benzodiazepine receptor, which is selectively
associated with the outer mitochondrial membrane. The anxiolytic effects
of benzodiazepines are mediated by a 'central' benzodiazepine receptor,
located primarily in the brain. The findings may have relevance to the
neuropsychiatric aspects of AIP.

Mustajoki and Desnick (1985) used biochemical and immunologic techniques
to characterize 4 mutant types of porphobilinogen deaminase in 68 AIP
patients from 33 unrelated families in Finland. About 80% of the mutant
enzymes were cross-reactive immunologic material (CRM)-negative and fell
into 2 types: those in which PBGD levels and enzyme activity were
half-normal in all tissues, and a large kindred with normal erythrocyte
PBGD levels. The remainder of the families had CRM-positive mutations,
including an unusual group that had increased levels of immunoreactive,
non-catalytic enzyme. Mustajoki and Desnick (1985) suggested that the
CRM-positive patients of the second type have milder disease.

Desnick et al. (1985) further characterized the 4 classes of mutations
in AIP by studying 165 AIP heterozygotes from 92 unrelated families. The
majority of patients had CRM-negative mutations with half-normal PBGD
activity; these were designated 'CRM-negative type 1.' In 3 families,
designated 'CRM-negative type 2,' symptomatic patients had increased
urinary delta-ALA and PBG with normal levels of erythrocyte PBGD
activity. Eleven families had CRM-positive, noncatalytic PBGD. Of these,
a subset of patients had increased levels of noncatalytic PBGD with
increased levels of substrate-bound intermediates, suggestive of
increased binding affinity. The findings indicated allelic heterogeneity
for mutations in the PBGD gene.

- Nonerythroid Variant of AIP

Mustajoki (1981) reported a large kindred in which 10 members had AIP
with normal erythrocyte PBG-deaminase activity. This form is referred to
as the 'nonerythroid-variant' of AIP. Forty-nine other Finnish patients
with AIP who were unrelated to this kindred had the usual low activity
of PBG-deaminase. Mustajoki (1981) suggested that the large kindred
represented a variant form of AIP in which the enzyme defect was not
expressed in erythrocytes.

In a study of affected members from 22 unrelated families with AIP,
Anderson et al. (1981) demonstrated heterogeneity of the erythrocyte
porphobilinogen deaminase defect. Although affected members from 21
families had absent CRM to the PBGD protein, all 7 AIP heterozygotes
from 1 family of Basque origin had positive CRM results detected in red
cell lysates. Further studies showed that this family had a
noncatalytic, immunoreactive protein.

Mustajoki and Desnick (1985) and Desnick et al. (1985) also identified
patients with AIP who had normal levels and activity of erythrocyte
PBG-deaminase.

INHERITANCE

Acute intermittent porphyria, and several other genetic porphyrias, are
unusual among enzyme deficiency states in that symptoms are manifest in
the heterozygous state, consistent with autosomal dominant inheritance
(Meyer and Schmid, 1978).

Although AIP is almost always inherited as an autosomal dominant trait,
there have been rare cases of patients with homozygous mutations,
consistent with autosomal recessive inheritance. These patients have
severe disease and early death (Beukeveld et al., 1990; Llewellyn et
al., 1992; Solis et al., 2004).

Doss (1989) described 4 unrelated individuals with coexistent AIP,
caused by deficiency of PBGD, and porphyria cutanea tarda (176100),
caused by deficiency of uroporphyrinogen decarboxylase (UROD; 613521).
The patients manifested clinical courses of both diseases. Family
studies showed that in 1 case the dually affected father transmitted
both deficiencies to 1 son and only 1 deficiency to a second son. The
findings were consistent with the nonlinkage and nonallelism of the 2
genes underlying the disorders.

PATHOGENESIS

Mustajoki and Desnick (1985) provided a useful illustration of the
putative mutation sites in the heme-synthesis pathway in each of 6 forms
of porphyria.

In patients with AIP, porphobilinogen deaminase activity reduced to
approximately half the normal level was demonstrated first in liver
(Strand et al., 1970), and subsequently in cultured fibroblasts and red
blood cells (Meyer et al., 1972; Strand et al., 1972; Sassa et al.,
1974; Kreimer-Birnbaum, 1975). In family studies, most individuals can
be characterized as having either clearly normal or 50% decreased levels
of PBGD activity, but intermediate values are sometimes found (Sassa et
al., 1974; Astrup, 1978; Kreimer-Birnbaum et al., 1980).

Goldberg (1985) wrote that allelic heterogeneity in AIP may be a factor
'among others, such as drugs, diet, and endogenous hormones, which
determine whether the latent state in one patient may continue without
incident or, in another, may be shattered by a painful and crippling
attack.'

The acute attacks in AIP are precipitated by metabolic, hormonal, and
environmental factors that induce hepatic 5-aminolevulinate synthase
(ALAS1; 125290) activity. With increased ALAS1 activity, porphyrin
precursors ALA and PBG increase, and the half-normal hepatic HMBS
activity in heterozygous AIP patients is insufficient to prevent
pathologic accumulation of the precursors, which are most likely
responsible for the symptoms (Strand et al., 1970; Solis et al., 2004).

Solis et al. (2004) reported a Spanish child with homozygous AIP and a
severe clinical course with developmental retardation and early death.
Neurologic and neuroradiologic findings suggested a primary process
affecting deep cerebral white matter myelination, with relative
preservation of the corpus callosum, anterior limb of the internal
capsule, cerebral gray matter, brainstem, and cerebellum. Thus, the
process affected tracts that myelinate in the later postnatal period,
but spared the many tracts that myelinate prenatally or shortly after
birth. The selective white matter damage was associated with arrest of
myelin maturation at the 8- to 10-month milestones, and later with
progressive vacuolation/caviation in the periventricular white matter.
The findings were consistent with ALA-mediated neurotoxicity which is
manifest postnatally. Solis et al. (2004) noted that if heme deficiency
was important in pathogenesis, then it would be expected to cause
earlier neuropathologic features. Solis et al. (2004) concluded that the
neuropathologic features in this case resulted from postnatal toxic
injury, presumably due to the persistent elevation of ALA, PBG, and/or
other porphyrin precursors. The findings indicated that the toxic
accumulation of porphyrin precursors, rather than heme deficiency, is
primarily responsible for acute neurologic attacks in heterozygous AIP.

In their patient, a 7-year-old boy with excessively elevated levels of
urinary delta-aminolevulinic acid, porphobilinogen, and uroporphyrin,
Hessels et al. (2004) found a novel homozygous leu81-to-pro (L81P)
mutation in exon 6 of the porphobilinogen deaminase gene (609806.0045).
The father and mother, shown to be gene carriers of the same mutation,
are asymptomatic and have normal urinary porphyrin precursor metabolite
excretion.

MAPPING

In 33 unrelated patients with acute intermittent porphyria, Llewellyn et
al. (1987) found linkage to a common 2-allele MspI RFLP of the PBGD gene
(maximum lod score of 3.14 with no recombinants). In 30 patients, no
cross-reacting immunologic material was produced by the mutant allele. A
major gene deletion was excluded as the cause of the CRM-negative
mutation in 18 heterozygous families.

By PCR, Lee et al. (1990) amplified polymorphic sites in the PBGD gene
that could be used for linkage analysis in AIP families.

Scobie et al. (1990) identified three 2-allele RFLPs in the PBGD gene,
each with allele frequencies close to 0.50. Marked linkage
disequilibrium limited the number of observed haplotypes to 4, of which
1 was uncommon. No common haplotype was observed among 47 unrelated AIP
patients.

In 3 Finnish families, each with a different subtype of AIP
(CRM-negative with low red cell enzyme activity; CRM-positive with low
enzyme activity; CRM-negative with normal enzyme activity), Kauppinen et
al. (1990) found evidence of tight linkage to PBGD RFLPs. Among 62
family members tested, 30 had a familial disease-associated haplotype;
in 5 of them, conventional tests for AIP were normal, and in 1,
uncertain. The authors concluded that RFLP analysis could be used to
detect gene carriers and to help in the diagnosis of persons with
uncertain results in other tests.

MOLECULAR GENETICS

In a large Dutch family with the nonerythroid variant of AIP, Grandchamp
et al. (1989) identified a heterozygous splice site mutation in intron 1
of the PBGD gene (609806.0001). The mutation interrupted the sequence
coding for the nonerythroid isoform of PBGD; thus, expression of the
erythroid isoform was unaffected. In a patient with CRM-positive AIP,
Grandchamp et al. (1989) identified a mutation in the HMBS gene,
resulting in the skipping of exon 12 (609806.0002).

In affected members of 11 different families with either CRM-negative or
CRM-positive AIP, Grandchamp et al. (1990) identified 7 different point
mutations in the PBGD gene.

Astrin and Desnick (1994) reviewed the 26 mutations in the HMBS
identified to that time.

Puy et al. (1997) performed molecular analysis of the PBGD gene by
denaturing gradient gel electrophoresis followed by direct sequencing in
405 subjects from 121 unrelated French-Caucasian AIP families. PBGD
mutations were identified in 109 families, but only 78 were of different
type, and each of these had a prevalence rate of less than 5%. Among
these mutations, 33 had not previously been published. Sixty percent of
the 78 mutations were located in 3 exons (exons 10, 12, and 14); 44%
were missense, 18% were splice defect, 19% were frameshift, and 16% were
nonsense.

Whatley et al. (1999) reported a prospective comparison of direct
automated sequencing of cDNA (in 29 patients) or genomic DNA (in 28
patients) to identify HMBS mutations in 57 patients referred
consecutively for mutation analysis; 39 different mutations were
identified in 54 patients. The sensitivity of the cDNA and genomic DNA
methods was 69% and 95%, respectively, indicating that analysis of
genomic DNA provides a higher mutation detection rate. The mutations
included 6 missense, 8 splice defects, 10 frameshifts, and 1 nonsense;
25 had not previously been reported. The results defined the extent of
allelic heterogeneity and the types (41% missense, 59% truncating) and
distribution (35% in exons 10, 12, and 14) of HMBS mutations for AIP in
the United Kingdom.

DIAGNOSIS

Sassa et al. (1975) noted that the enzyme defect in AIP is expressed in
cultured fibroblasts and amniotic cells, so that prenatal diagnosis is
possible. The enzyme can be induced and the defect demonstrated in
mitogen-stimulated lymphocytes (Sassa et al., 1978).

Puy et al. (1997) found that the standard PBGD enzymatic screening
method for gene-carrier detection had 95% concordancy with the
molecular-based diagnosis.

CLINICAL MANAGEMENT

Most acute attacks, if correctly recognized, settle with supportive
treatment; dextrose infusion and high carbohydrate intake may be helpful
(Stein and Tschudy, 1970). Successful treatment by infusion of hematin,
which is a specific feedback inhibitor of heme synthesis, has repeatedly
been reported (McColl et al., 1978; Lamon et al., 1979), but hematin is
neither readily available nor very soluble and its use may carry a risk
of renal damage (Dhar et al., 1978).

Goetsch and Bissell (1986) described a 22-year-old woman who had had
more than 15 acute attacks requiring hospitalization. Hematin was the
mainstay of the patient's therapy, eliciting a well-defined clinical and
biochemical response after more than 200 infusions. On one occasion,
however, the patient did not respond to a batch of hematin that, in
retrospect, was found to have deteriorated. Goetsch and Bissell (1986)
quantified the instability of hematin and showed that the decay
product(s) is ineffective in regulating porphyrin production. The
decayed material, furthermore, was found to have anticoagulant effects,
thus explaining one of the complications of hematin therapy.

An experience reported by Anderson et al. (1984) suggests that in women
with premenstrual exacerbation of AIP, a long-acting agonist of
luteinizing hormone-releasing hormone may be an effective preventive
measure. Srugo et al. (1987) described acute intermittent porphyria as
the cause of 'surgical abdomen' in a 15-year-old boy. Because
hypertension, tachycardia, and paralytic ileus were present, suggesting
sympathetic overactivity, the beta-adrenergic blocking agent propranolol
was administered in high doses with apparent dramatic improvement.

In 9 members of a German kindred in which the proband had nonerythroid
variant of AIP resulting in a life-threatening coma, Petrides (1998)
identified a mutation in the HMBS gene (609806.0001). The newly
identified family members were informed of the disease and taught how to
prevent porphyric attacks. They were also given medical alert
information certificates. Petrides (1998) emphasized the importance of
identifying gene carriers as part of the clinical management of AIP.

Soonawalla et al. (2004) reported a 19-year-old woman with severe AIP
who underwent successful treatment with liver transplantation. After the
transplant, concentrations of heme precursors in the patient's urine
returned to normal and 1.5 years later, her quality of life was good.

POPULATION GENETICS

High prevalence of AIP is known in northern Sweden where Waldenstrom's
classic observations were made (Waldenstrom, 1956).

AIP occurs with very low prevalence, perhaps 1 in 50,000, probably in
all ethnic groups (Tschudy et al., 1975), including blacks
(Kreimer-Birnbaum et al., 1980), but figures for prevalence based on
manifest AIP, i.e., acute attacks, greatly underestimate the number of
persons with latent AIP.

Lee et al. (1991) stated that the prevalence of AIP in Lappland,
northern Sweden was 1 in 1,500. They identified 3 different disease
haplotypes among 28 Swedish AIP families. The haplotype designated
2/1/1/2 was the most frequent, segregating with AIP in 10 of 28
families. Lee and Anvret (1991) identified a mutation in the HMBS gene
(W198X; 609806.0012) in 15 of 33 AIP families from Lappland, Sweden.
Genealogic data showed that 12 of the 15 were related, suggesting a
founder effect.

In 28 Finnish families representing 72% of all AIP families in the
Finnish population of 5 million, Kauppinen et al. (1995) found 19
separate mutations in HMBS: 13 novel mutations, including 1 de novo
event, and 6 previously characterized mutations.

Floderus et al. (2002) stated that the prevalence of AIP in Sweden is
about 1 in 10,000. Among Swedish AIP kindreds, they identified 27 novel
HMBS mutations, bringing the total number of known mutations in Sweden
to 39.

HISTORY

Loftus and Arnold (1991) suggested that Vincent van Gogh had suffered
from attacks of acute intermittent porphyria, exacerbated by
malnutrition and absinthe abuse. They suggested that this would best
explain the abruptness of the onset and recovery from attacks. It has
been suggested that George III had porphyria variegata (176200).

ANIMAL MODEL

During study of the pathogenesis of the neurologic symptoms of AIP,
Lindberg et al. (1996) generated Pbgd (HMBS; 609806)-deficient mice by
gene targeting. These mice exhibited typical biochemical characteristics
of human AIP, including decreased hepatic Pbgd activity, increased
delta-aminolevulinic acid synthase activity, and massively increased
urinary excretion of the heme precursor delta-aminolevulinic acid after
treatment with drugs such as phenobarbital. Behavioral tests revealed
decreased motor function and histopathologic findings, including axonal
neuropathy and neurologic muscle atrophy.

Puy et al. (1996) noted that a porphyric rat model showed increased
plasma concentration and brain uptake of tryptophan and increased
synthesis of serotonin in the nervous system. The increased
concentration of tryptophan and serotonin may be partly due to the
hepatic heme deficiency decreasing the activity of the liver cytosolic
enzyme heme-dependent tryptophan pyrrolase. Injection of heme lowered
heme precursors, tryptophan, and serotonin to normal levels, but did not
increase melatonin, which is produced from tryptophan. Puy et al. (1996)
noted that women with AIP demonstrate a rise in serotonin and plasma
tryptophan during the attacks, whereas both daytime and nighttime
melatonin concentrations are dramatically decreased. From the animal
experiments, Puy et al. (1996) suggested that delta-aminolevulinic acid
is responsible for decreased production of melatonin by the pineal
gland.

Clavero et al. (2010) described a naturally occurring feline model of
AIP in 4 unrelated cat lines that presented phenotypically as congenital
erythropoietic porphyria (CEP; 263700). Affected cats had erythrodontia,
brownish urine, fluorescent bones, and markedly elevated urinary
uroporphyrin and coproporphyrin, consistent with CEP. However, their
uroporphyrinogen-III synthase (UROS; 606938) activities (deficient in
CEP) were normal. Notably, affected cats had half-normal Hmbs activities
and elevated urinary 5-aminolevulinic acid and porphobilinogen.
Sequencing the feline Hmbs gene revealed different mutations in each
line, including a duplication, an in-frame 3-bp deletion (842delGAG),
and 2 missense (A84T and R149W) mutations. The 842delGAG and R149W
mutations were identical to mutations reported in human. Prokaryotic
expression of the 842delGAG and R149W mutations resulted in mutant
enzymes with less than 1% wildtype activity, whereas the A84T mutation
expressed a stable enzyme with approximately 35% of wildtype activity.
The discolored teeth from the affected cats contained markedly elevated
URO I and III, accounting for the CEP-like phenocopy. In 3 lines, the
phenotype was an autosomal dominant trait, while affected cats with the
A84T mutation were homozygous, a unique recessive form of AIP.

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40. Mustajoki, P.: Normal erythrocyte uroporphyrinogen I synthase
in a kindred with acute intermittent porphyria. Ann. Intern. Med. 95:
162-166, 1981.

41. Mustajoki, P.; Desnick, R. J.: Genetic heterogeneity in acute
intermittent porphyria: characterisation and frequency of porphobilinogen
deaminase mutations in Finland. Brit. Med. J. 291: 505-509, 1985.

42. Norton, B.; Lanyon, W. G.; Moore, M. R.; Porteous, M.; Youngs,
G. R.; Connor, J. M.: Evidence for involvement of a second genetic
locus on chromosome 11q in porphyrin metabolism. Hum. Genet. 91:
576-578, 1993.

43. Norton, B.; Lanyon, W. G.; Moore, M. R.; Youngs, G. R.; Tomlinson,
J. E. M.; Aitken, D. A.; Connor, J. M.: Evidence for a second genetic
locus for porphyrin metabolism on chromosome 11q. (Abstract) J. Med.
Genet. 28: 551-552, 1991.

44. Petrides, P. E.: Acute intermittent porphyria: mutation analysis
and identification of gene carriers in a German kindred by PCR-DGGE
analysis. Skin Pharmacol. Appl. Skin Physiol. 11: 374-380, 1998.

45. Picat, C.; Delfau, M. H.; de Rooij, F. W. M.; Beukeveld, G. J.
J.; Wolthers, B. G.; Wadman, S. K.; Nordmann, Y.; Grandchamp, B.:
Identification of the mutations in the parents of a patient with a
putative compound heterozygosity for acute intermittent porphyria. J.
Inherit. Metab. Dis. 13: 684-686, 1990.

46. Poblete-Gutierrez, P.; Wiederholt, T.; Martinez-Mir, A.; Merk,
H. F.; Connor, J. M.; Christiano, A. M.; Frank, J.: Demystification
of Chester porphyria: a nonsense mutation in the porphobilinogen deaminase
gene. Physiol. Res. 55 (Suppl. 2): S137-S144, 2006.

47. Puy, H.; Deybach, J.-C.; Bogdan, A.; Callebert, J.; Baumgartner,
M.; Voisin, P.; Nordmann, Y.; Touitou, Y.: Increased delta-aminolevulinic
acid and decreased pineal melatonin production: a common event in
acute porphyria studies in the rat. J. Clin. Invest. 97: 104-110,
1996.

48. Puy, H.; Deybach, J. C.; Lamoril, J.; Robreau, A. M.; Da Silva,
V.; Gouya, L.; Grandchamp, B.; Nordmann, Y.: Molecular epidemiology
and diagnosis of PBG deaminase gene defects in acute intermittent
porphyria. Am. J. Hum. Genet. 60: 1373-1383, 1997.

49. Puy, H.; Gross, U.; Deybach, J. C.; Robreau, A. M.; Frank, M.;
Nordmann, Y.; Doss, M.: Exon 1 donor splice site mutations in the
porphobilinogen deaminase gene in the non-erythroid variant form of
acute intermittent porphyria. Hum. Genet. 103: 570-575, 1998.

50. Sassa, S.; Granick, S.; Bickers, D. R.; Bradlow, H. L.; Kappas,
A.: A microassay for uroporphyrinogen I synthase, one of three abnormal
enzyme activities in acute intermittent porphyria, and its application
to the study of the genetics of this disease. Proc. Nat. Acad. Sci. 71:
732-736, 1974.

51. Sassa, S.; Solish, G.; Levere, R. D.; Kappas, A.: Studies in
porphyria. IV. Expression of the gene defect of acute intermittent
porphyria in cultured human skin fibroblasts and amniotic cells: prenatal
diagnosis of the porphyric trait. J. Exp. Med. 142: 722-731, 1975.

52. Sassa, S.; Zalar, G. L.; Kappas, A.: Studies in porphyria. VII.
Induction of uroporphyrinogen-I synthase and expression of the gene
defect of acute intermittent porphyria in mitogen-stimulated human
lymphocytes. J. Clin. Invest. 61: 499-508, 1978.

53. Scobie, G. A.; Urquhart, A. J.; Elder, G. H.; Kalsheker, N. A.;
Llewellyn, D. H.; Smyth, J.; Harrison, P. R.: Linkage disequilibrium
between DNA polymorphisms within the porphobilinogen deaminase gene. Hum.
Genet. 85: 157-159, 1990.

54. Solis, C.; Martinez-Bermejo, A.; Naidich, T. P.; Kaufmann, W.
E.; Astrin, K. H.; Bishop, D. F.; Desnick, R. J.: Acute intermittent
porphyria: studies of the severe homozygous dominant disease provides
insights into the neurologic attacks in acute porphyrias. Arch. Neurol. 61:
1764-1770, 2004.

55. Soonawalla, Z. F.; Orug, T.; Badminton, M. N.; Elder, G. H.; Rhodes,
J. M.; Bramhall, S. R.; Elias, E.: Liver transplantation as a cure
for acute intermittent porphyria. Lancet 363: 705-706, 2004.

56. Srugo, I.; Said, E.; Korman, S.; Jaffe, M.: Acute intermittent
porphyria--an unusual cause of 'surgical' abdomen: response to propranolol
therapy. Europ. J. Pediat. 146: 305-308, 1987.

57. Stein, J. A.; Tschudy, D. P.: Acute intermittent porphyria: a
clinical and biochemical study of 46 patients. Medicine 49: 1-16,
1970.

58. Strand, L. J.; Felsher, B. F.; Redeker, A. G.; Marver, H. S.:
Heme biosynthesis in intermittent acute porphyria: decreased hepatic
conversion of porphobilinogen to porphyrins and increased delta aminolevulinic
acid synthetase activity. Proc. Nat. Acad. Sci. 67: 1315-1320, 1970.

59. Strand, L. J.; Meyer, U. A.; Felsher, B. F.; Redeker, A. G.; Marver,
H. S.: Decreased red cell uroporphyrinogen I synthetase activity
in intermittent acute porphyria. J. Clin. Invest. 51: 2530-2536,
1972.

60. Tishler, P. V.; Woodward, B.; O'Connor, J.; Holbrook, D. A.; Seidman,
L. J.; Hallett, M.; Knighton, D. J.: High prevalence of intermittent
acute porphyria in a psychiatric patient population. Am. J. Psychiat. 142:
1430-1436, 1985.

61. Tschudy, D. P.; Valsamis, M.; Magnussen, C. R.: Acute intermittent
porphyria: clinical and selected research aspects. Ann. Intern. Med. 83:
851-864, 1975.

62. Verma, A.; Nye, J. S.; Snyder, S. H.: Porphyrins are endogenous
ligands for the mitochondrial (peripheral-type) benzodiazepine receptor. Proc.
Nat. Acad. Sci. 84: 2256-2260, 1987.

63. Waldenstrom, J.: Studies on the incidence and heredity of acute
porphyria in Sweden. Acta Genet. Statist. Med. 6: 122-131, 1956.

64. Waldenstrom, J.; Haeger-Aronsen, B.: Different patterns of human
porphyria. Brit. Med. J. 2: 272-276, 1963.

65. Watson, C. J.; Bossenmaier, I.: Present status of the Ehrlich
aldehyde reaction for urinary porphobilinogen. JAMA 190: 501-504,
1964.

66. Whatley, S. D.; Roberts, A. G.; Llewellyn, D. H.; Bennett, C.
P.; Garrett, C.; Elder, G. H.: Non-erythroid form of acute intermittent
porphyria caused by promoter and frameshift mutations distant from
the coding sequence of exon 1 of the HMBS gene. Hum. Genet. 107:
243-248, 2000.

67. Whatley, S. D.; Woolf, J. R.; Elder, G. H.: Comparison of complementary
and genomic DNA sequencing for the detection of mutations in the HMBS
gene in British patients with acute intermittent porphyria: identification
of 25 novel mutations. Hum. Genet. 104: 505-510, 1999.

68. Yeung Laiwah, A. A. C.; Mactier, R.; McColl, K. E. L.; Moore,
M. R.; Goldberg, A.: Early-onset chronic renal failure as a complication
of acute intermittent porphyria. Quart. J. Med. 52: 92-98, 1983.

*FIELD* CS
INHERITANCE:
Autosomal dominant

CARDIOVASCULAR:
[Heart];
Tachycardia;
[Vascular];
Hypertension

RESPIRATORY:
[Lung];
Respiratory paralysis

ABDOMEN:
[Gastrointestinal];
Nausea;
Vomiting;
Diarrhea;
Abdominal pain;
Constipation;
Paralytic ileus

GENITOURINARY:
[Bladder];
Urinary retention;
Dysuria;
Urinary incontinence

NEUROLOGIC:
[Central nervous system];
Acute episodes of neuropathic symptoms;
Paraesthesias;
Seizures;
Psychotic episodes;
Depression;
Anxiety;
[Peripheral nervous system];
Acute episodes of neuropathic symptoms;
Paralysis;
Motor, sensory, or autonomic neuropathy;
Weakness

ENDOCRINE FEATURES:
Syndrome of inappropriate antidiuretic hormone (SIADH)

NEOPLASIA:
Increased incidence of hepatocellular carcinoma

LABORATORY ABNORMALITIES:
Erythrocyte porphobilinogen (PBG) deaminase deficiency (exception:
type II AIP);
Increased urinary delta-aminolevulinic acid (ALA) and porphobilinogen
(PBG) during acute attacks;
Urine occasionally port-wine in color secondary to porphobilinogen

MISCELLANEOUS:
Acute attacks rarely occur before puberty;
Attacks precipitated by drugs (e.g. barbiturates, sulfonamides), alcohol,
infection, starvation, and hormonal changes;
Attacks more common in women;
Ninety percent of patients with PBG deaminase deficiency are clinically
unaffected

MOLECULAR BASIS:
Caused by mutation in the hydroxymethylbilane synthase gene (HMBS,
176000.0001)

*FIELD* CN
Ada Hamosh - reviewed: 1/4/2001
Kelly A. Przylepa - revised: 2/28/2000

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

*FIELD* ED
joanna: 07/23/2013
joanna: 1/5/2001
joanna: 1/4/2001
kayiaros: 2/28/2000

*FIELD* CN
George E. Tiller - updated: 2/8/2011
Cassandra L. Kniffin - updated: 5/22/2009
Ada Hamosh - updated: 7/31/2007
Cassandra L. Kniffin - reorganized: 1/5/2006
Cassandra L. Kniffin - updated: 12/28/2005
Victor A. McKusick - updated: 4/17/2003
Victor A. McKusick - updated: 11/6/2002
Victor A. McKusick - updated: 10/3/2000
Victor A. McKusick - updated: 10/28/1999
Victor A. McKusick - updated: 8/31/1999
Victor A. McKusick - updated: 8/17/1999
Victor A. McKusick - updated: 7/6/1999
Victor A. McKusick - updated: 12/10/1998
Ethylin Wang Jabs - updated: 7/9/1997
Stylianos E. Antonarakis - updated: 7/18/1997
Victor A. McKusick - updated: 6/17/1997
Stylianos E. Antonarakis - updated: 7/4/1996

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
terry: 04/21/2011
terry: 3/14/2011
wwang: 3/11/2011
terry: 2/8/2011
carol: 8/6/2010
terry: 6/3/2009
wwang: 6/3/2009
ckniffin: 5/22/2009
terry: 4/8/2009
alopez: 8/3/2007
terry: 7/31/2007
carol: 1/5/2006
ckniffin: 12/28/2005
carol: 3/17/2004
tkritzer: 2/6/2004
tkritzer: 5/1/2003
terry: 4/17/2003
carol: 11/13/2002
tkritzer: 11/11/2002
terry: 11/6/2002
mcapotos: 10/12/2000
mcapotos: 10/9/2000
terry: 10/3/2000
carol: 11/4/1999
terry: 10/28/1999
jlewis: 8/31/1999
terry: 8/17/1999
carol: 7/19/1999
terry: 7/6/1999
mgross: 3/17/1999
carol: 12/15/1998
terry: 12/10/1998
carol: 7/9/1998
alopez: 7/8/1998
mark: 9/11/1997
alopez: 9/9/1997
alopez: 9/8/1997
alopez: 8/4/1997
terry: 7/18/1997
alopez: 7/10/1997
terry: 6/23/1997
terry: 6/17/1997
alopez: 6/2/1997
terry: 8/16/1996
marlene: 8/6/1996
terry: 7/26/1996
carol: 7/4/1996
mark: 2/5/1996
terry: 2/1/1996
mark: 1/29/1996
terry: 1/29/1996
mark: 7/12/1995
terry: 12/22/1994
pfoster: 11/3/1994
davew: 8/19/1994
mimadm: 4/29/1994
warfield: 4/12/1994

MIM 609806
*RECORD*
*FIELD* NO
609806
*FIELD* TI
*609806 HYDROXYMETHYLBILANE SYNTHASE; HMBS
;;PORPHOBILINOGEN DEAMINASE; PBGD;;
PRE-UROPORPHYRINOGEN SYNTHASE;;
read moreUROPORPHYRINOGEN I SYNTHASE;;
UROPORPHYRINOGEN I SYNTHETASE
*FIELD* TX
Porphobilinogen deaminase (PBGD; EC 4.3.1.8) is the third enzyme of the
biosynthetic pathway leading to the production of heme. It catalyzes the
synthesis of hydroxymethylbilane by stepwise condensation of 4
porphobilinogen units. Hydroxymethylbilane is then converted to
uroporphyrinogen III by uroporphyrinogen III synthetase (UROS; 606938)
(Raich et al., 1986).

CLONING

Raich et al. (1986) isolated a cDNA clone corresponding to the human
erythrocyte porphobilinogen deaminase gene from a human erythrocyte
library prepared from human spleen. The deduced 334-amino acid protein
has a calculated molecular mass of approximately 37.6 kD. Northern blot
analysis identified a single 1.6-kb mRNA transcript.

Grandchamp et al. (1987) determined that there are 2 PBGD isoforms that
differ by approximately 2 kD (40 and 42 kD). One is active in all
tissues and can be isolated from liver, and the other is restricted to
erythrocytes. The nonerythrocyte isoform contains an additional 17 amino
acid residues at the N terminus.

Chretien et al. (1988) demonstrated that the PBGD gene undergoes
alternative splicing with 2 different promoters to yield 2 mRNAs. The
first 'upstream' promoter is active in all tissues and has structural
features of a housekeeping promoter, whereas the second promoter,
located 3 kb downstream, is active only in erythrocytes and shows
structural homology to the beta-globin gene (141900) promoters. The 2
mRNAs differ only in their first exon.

Gubin and Miller (2001) identified 2 alternatively spliced isoforms of
erythroid PBGD in CD34+/- (142230) erythroid precursor cells. Complete
sequencing showed that the alternatively spliced form, designated
PBGD-EA, contained the intron between exons 2 and 3, thus extending the
5-prime untranslated region of the erythroid transcript by 176 bp.
Northern blot analysis identified a distinct 1.5-kb mRNA corresponding
to the alternatively spliced erythrocyte isoform only in bone marrow and
fetal spleen.

GENE STRUCTURE

Chretien et al. (1988) determined that the HMBS gene contains 15 exons
and spans approximately 10 kb of DNA.

The housekeeping HMBS transcript contains exons 1 and 3-15; the
erythroid HMBS transcript is encoded by exons 2-15 (Chen et al., 1994).

MAPPING

By study of mouse-human hybrid clones, Meisler et al. (1980, 1981)
showed that PBG-deaminase is determined by a gene on chromosome 11; Wang
et al. (1981) assigned the locus to the long arm in the segment
11q23-qter. In 3 children with trisomy of 11qter, de Verneuil et al.
(1982) studied expression of uroporphyrinogen I synthase. Dosage effect
supported assignment to the region 11q23.2-qter.

By in situ hybridization and by gene dosage studies in patients with
monosomy or trisomy of the terminal portion of 11q, Namba et al. (1991)
refined the assignment of the PBGD gene to 11q24.1-q24.2.

Tunnacliffe and McGuire (1990) constructed a long-range restriction map
extending over 1.8 Mb of 11q23.3 using pulsed field gel electrophoresis
and concluded that PBGD is situated in the following relation to 5 other
genes: cen--CD3E--CD3D--CD3G--PBGD--CBL2--THY1--qter. They determined
that the CD3G (186740) gene and PBGD are separated by 750 kb.

BIOCHEMICAL FEATURES

By the method of isoelectric focusing, Meisler and Carter (1980)
identified structural variants of PBG-deaminase.

Louie et al. (1992) defined the 3-domain structure of PBGD by x-ray
analysis. Two of the domains structurally resembled the transferrins
(see, e.g., TF; 190000). The x-ray structure and results from
site-directed mutagenesis provided evidence for a single catalytic site.

MOLECULAR GENETICS

In a large Dutch family with the nonerythroid variant of AIP, Grandchamp
et al. (1989) identified a heterozygous splice site mutation in intron 1
of the PBGD gene (609806.0001). The mutation interrupted the sequence
coding for the nonerythroid isoform of PBGD; thus, expression of the
erythroid isoform was unaffected. In a patient with CRM-positive AIP,
Grandchamp et al. (1989) identified a mutation in the HMBS gene,
resulting in the skipping of exon 12 (609806.0002).

In affected members of 11 different families with either CRM-negative or
CRM-positive AIP, Grandchamp et al. (1990) identified 7 different point
mutations in the PBGD gene.

In a patient with the nonerythroid variant of AIP, Chen et al. (1994)
identified a mutation in the initiation codon of the housekeeping HMBS
isoform (M1V; 609806.0044). Puy et al. (1998) identified 3 different
mutations in the donor splice site of the HMBS gene in 4 unrelated
patients with the nonerythroid variant of AIP. They found that the
splice site mutations resulted in activation of a cryptic splice site
located 67 nucleotides downstream from the normal splice site, leading
to a frameshift and premature stop codon in exon 4.

In 28 Finnish families representing 72% of all AIP families in the
Finnish population of 5 million, Kauppinen et al. (1995) found 19
separate mutations in HMBS: 13 novel mutations, including 1 de novo
event, and 6 previously characterized mutations.

Whatley et al. (1999) found 39 different mutations in the HMBS gene in
54 of 57 consecutive patients with AIP.

In patients with the nonerythroid variant of AIP, Whatley et al. (2000)
identified mutations in the housekeeping promoter (-154delG;
609806.0041) and in exon 3 (41delA; 609806.0042) of the HMBS gene.

Floderus et al. (2002) studied most of the AIP kindreds in Sweden. They
identified 27 novel mutations in the HMBS gene, bringing the total
number of known mutations in the HMBS gene in Sweden to 39. Most of the
mutations were located in exons 10 and 12, with fewer in exon 7.
Floderus et al. (2002) used the 3-dimensional structure of the
porphobilinogen deaminase enzyme to predict the possible molecular and
functional consequences of the novel Swedish missense and nonsense
mutations.

In a patient with AIP, Hessels et al. (2004) detected a novel homozygous
leu81-to-pro (L81P) mutation in exon 6 of the HMBS gene (609806.0045).
Porphobilinogen deaminase activity in red cells was decreased to 2 to
4%.

ANIMAL MODEL

Clavero et al. (2010) described a naturally occurring feline model of
AIP in 4 unrelated cat lines that presented phenotypically as congenital
erythropoietic porphyria (CEP; 263700). Affected cats had erythrodontia,
brownish urine, fluorescent bones, and markedly elevated urinary
uroporphyrin and coproporphyrin, consistent with CEP. However, their
UROS activities (deficient in CEP) were normal. Notably, affected cats
had half-normal HMBS activities and elevated urinary 5-aminolevulinic
acid and porphobilinogen. Sequencing the feline Hmbs gene revealed
different mutations in each line, including a duplication, an in-frame
3-bp deletion (842delGAG), and 2 missense (A84T and R149W) mutations.
The 842delGAG and R149W mutations were identical to mutations reported
in human. Prokaryotic expression of the 842delGAG and R149W mutations
resulted in mutant enzymes with less than 1% wildtype activity, whereas
the A84T mutation expressed a stable enzyme with approximately 35% of
wildtype activity. The discolored teeth from the affected cats contained
markedly elevated URO I and III, accounting for the CEP-like phenocopy.
In 3 lines, the phenotype was an autosomal dominant trait, while
affected cats with the A84T mutation were homozygous, a unique recessive
form of AIP.

*FIELD* AV
.0001
PORPHYRIA, ACUTE INTERMITTENT, NONERYTHROID VARIANT
HMBS, IVS1DS, G-A, +1

In affected members of a large Dutch family with the nonerythroid
variant of acute intermittent porphyria (176000), Grandchamp et al.
(1989) identified a G-to-A transition in the 5-prime splice donor site
of intron 1 of the HMBS gene. The mutation interrupted the sequence
coding for the nonerythroid isoform of PBGD; thus, expression of the
erythroid isoform was unaffected. Hybridization analysis using
oligonucleotide probes after in vitro amplification of genomic DNA
offered another possibility of detecting asymptomatic carriers of the
mutation in affected families.

Puy et al. (1997, 1998) identified this splice site mutation in patients
with nonerythroid variant AIP.

Petrides (1998) identified the G-to-A transition in intron 1 of the HMBS
gene in 9 members of a German kindred in which the proband had a
life-threatening coma due to the nonerythroid variant of AIP. The newly
identified family members were taught how to prevent porphyric attacks.

.0002
PORPHYRIA, ACUTE INTERMITTENT
HMBS, EX12DEL

In a patient with acute intermittent porphyria (176000), Grandchamp et
al. (1989) identified a G-to-A transition in exon 12 of the HMBS gene,
resulting in the skipping of exon 12. The resulting aberrant mRNA
encoded a truncated protein that was inactive, but stable, and could be
detected using antibodies directed against the normal enzyme
(CRM-positive).

.0003
PORPHYRIA, ACUTE INTERMITTENT, NONERYTHROID VARIANT
HMBS, IVS1DS, G-T, +1

In a Finnish family with the nonerythroid variant of acute intermittent
porphyria (176000) Grandchamp et al. (1989) identified a G-to-T
transversion in the 5-prime splice donor sequence of intron 1 of the
HMBS gene. This is only 1 nucleotide removed from the mutation listed as
609806.0001, in which the change occurred in the first nucleotide of
intron 1. Grandchamp et al. (1989) proposed that both of these mutations
resulted in an abnormal splicing of primary transcripts initiated at the
upstream promoter of the gene without affecting the expression of the
PBGD gene in erythroid cells where the downstream promoter is utilized.
A similar mutation located at the last position of exon 1 of the
beta-globin gene was found by Vidaud et al. (1989) to be responsible for
a splicing defect leading to beta-thalassemia.

.0004
PORPHYRIA, ACUTE INTERMITTENT
HMBS, ARG116TRP

In affected members of a Swedish family with AIP (176000), Lee et al.
(1990) identified a C-to-T transition in exon 8 of the HMBS gene,
resulting in an arg116-to-trp (R116W) substitution.

The R116W mutation was found by Gu et al. (1993) in 15 Dutch AIP
families and in 1 French AIP family.

.0005
PORPHYRIA, ACUTE INTERMITTENT
HMBS, ARG167GLN

In patients with AIP (176000), Delfau et al. (1990) identified a G-to-A
transition in exon 10 of the HMBS gene, resulting in an arg167-to-gln
(R167Q) substitution.

In a brother and sister with severe AIP (176000), Llewellyn et al.
(1992) identified compound heterozygosity for 2 mutations in the PBGD
gene: a 500G-A transition, resulting in an R167Q substitution, and a
499C-T transition, resulting in an R167W substitution (609806.0013). The
mutations occurred in adjacent nucleotides.

.0006
PORPHYRIA, ACUTE INTERMITTENT
HMBS, ARG173GLN

In patients with AIP (176000), Delfau et al. (1990) identified a G-to-A
transition in exon 10 of the HMBS gene, resulting in an arg173-to-gln
(R173Q) substitution.

Kauppinen et al. (1992) identified the R173Q substitution in 3 out of 7
Finnish families with CRM-positive AIP.

.0007
PORPHYRIA, ACUTE INTERMITTENT
HMBS, GLN155TER

In 1 of 43 unrelated patients with AIP (176000), Scobie et al. (1990)
identified a C-to-T transition in the HMBS gene, resulting in a
gln155-to-ter (Q155X) substitution.

.0008
PORPHYRIA, ACUTE INTERMITTENT
HMBS, ARG149GLN

In a patient with AIP (176000), Delfau et al. (1991) identified a 446G-A
transition in exon 9 of the HMBS gene, resulting in an arg149-to-gln
(R159Q) substitution.

.0009
PORPHYRIA, ACUTE INTERMITTENT
HMBS, LEU245ARG

In a patient with AIP (176000), Delfau et al. (1991) identified a 734T-G
transversion in exon 12 of the HMBS gene, resulting in a leu245-to-arg
(L245R) substitution.

.0010
PORPHYRIA, ACUTE INTERMITTENT
HMBS, 1-BP DEL, 900T

In a patient with CRM-positive AIP (176000), Delfau et al. (1991)
identified a 1-bp deletion (900delT) in exon 1 of the HMBS gene,
resulting in a stop codon located 15 codons downstream from the
deletion.

.0011
PORPHYRIA, ACUTE INTERMITTENT
HMBS, 9-BP DEL, EX10

In a patient with CRM-positive AIP (176000), Delfau et al. (1991)
identified a deletion of the last 9 bp of exon 10. This resulted from
abnormal splicing of intron 10 which was a consequence of a G-to-T
substitution of the last base of exon 10.

.0012
PORPHYRIA, ACUTE INTERMITTENT
HMBS, TRP198TER

In affected members of a northern Swedish (Lappland) family with AIP
(176000), Lee and Anvret (1991) identified a G-to-A transition in exon
10 of the HMBS gene, resulting in a trp198-to-ter (W198X) substitution.
The same mutation was found in 15 of 33 Swedish AIP families. Genealogic
data showed that 12 of the 15 were related, indicating a founder effect.

.0013
PORPHYRIA, ACUTE INTERMITTENT
HMBS, ARG167TRP

In a brother and sister with severe AIP (176000), Llewellyn et al.
(1992) identified compound heterozygosity for 2 mutations in the PBGD
gene: a 499C-T transition, resulting in an arg167-to-trp (R167W)
substitution, and an adjacent 500G-A transition, resulting in an R167Q
(609806.0005) substitution.

The seemingly high frequency of mutations in exon 10 (Delfau et al.,
1990) prompted Gu et al. (1992) to screen this exon in 41 unrelated AIP
patients by use of denaturing gradient gel electrophoresis (DGGE) after
PCR amplification. In about one-fourth of the patients, they
distinguished 3 abnormal migration patterns, indicating the presence of
mutation in heterozygous state. Sequencing demonstrated the presence of
3 different single-base substitutions: R167Q, R173Q (609806.0006), and
R167W.

In Finland, Kauppinen et al. (1992) found an R167W mutation in 3 out of
7 families with CRM-positive AIP. DNA analyses of family members
demonstrated that conventional assays of erythrocyte PBGD activity
identified correctly only 72% of the carriers of the mutation.

Solis et al. (2004) reported a Spanish AIP patient who was homozygous
for the R167W substitution. Both parents were heterozygous for the
mutation. The patient had a severe course, with psychomotor delay,
dystonic movements, axial hypotonia, delayed myelination, and death at
age 40 months.

Solis et al. (2004) noted that the R167W, R173Q, and R167Q mutations all
occur at CpG dinucleotides within exon 10, and can thus be considered
mutation hotspots. All 3 substitutions alter highly conserved arginines
in the enzyme's active site, which interact with the precursor
porphobilinogen and the acidic side chains of the enzyme's
dipyrromethane cofactor. Functional expression studies showed that all 3
substitutions resulted in less than 2% normal HMBS activity.

.0014
PORPHYRIA, ACUTE INTERMITTENT
HMBS, ARG167LEU

Using site-directed mutagenesis, Lander et al. (1991) demonstrated that
an arg167-to-leu (R167L) substitution in the HMBS protein resulted in a
profound decrease of PBGD activity, consistent with AIP (176000). It is
noteworthy that substitution of arg167 by glutamine (R167Q; 609806.0005)
and by tryptophan (R167W; 609806.0013) resulted in loss of enzyme
activity.

.0015
PORPHYRIA, ACUTE INTERMITTENT
HMBS, ARG26HIS

In a patient with CRM-positive AIP (176000), Llewellyn et al. (1993)
identified a 77G-A transversion in exon 3 of the HMBS gene, resulting in
an arg26-to-his (R26H) substitution.

.0016
PORPHYRIA, ACUTE INTERMITTENT
HMBS, ALA31THR

In a patient with CRM-positive AIP (176000), Gu et al. (1994) identified
a 91G-A transversion in exon 4 of the HMBS gene, leading to an
ala31-to-thr (A31T) substitution.

.0017
PORPHYRIA, ACUTE INTERMITTENT
HMBS, GLN34LYS

In a patient with CRM-negative AIP (176000), Mgone et al. (1992)
identified a 100C-A transversion in exon 4 of the HMBS gene, resulting
in a gln34-to-lys (Q34K) substitution.

.0018
PORPHYRIA, ACUTE INTERMITTENT
HMBS, ALA55SER

In a patient with CRM-positive AIP (176000), Gu et al. (1994) identified
a 163G-T transversion in exon 5 of the HMBS gene, resulting in an
ala55-to-ser (A55S) substitution.

.0019
PORPHYRIA, ACUTE INTERMITTENT
HMBS, 1-BP DEL, 174C

In a patient with CRM-negative AIP (176000), Gu et al. (1994) identified
a 1-bp deletion (174delC) in exon 5 of the HMBS gene. This frameshift
mutation leads to a premature termination 40 codons downstream and a
truncated protein.

.0020
PORPHYRIA, ACUTE INTERMITTENT
HMBS, 1-BP INS, 182G

In a patient with CRM-negative AIP (176000), Gu et al. (1994) identified
a 1-bp insertion (182insG) in exon 5 of the HMBS gene. This frameshift
mutation leads to a premature termination 5 codons downstream and a
truncated protein.

.0021
PORPHYRIA, ACUTE INTERMITTENT
HMBS, IVS5DS, G-A, +1

In a patient with CRM-negative AIP (176000), Gu et al. (1994) identified
a 210G-A substitution in the first nucleotide of the donor splice site
of intron 5 of the HMBS gene, resulting in abnormal splicing.

.0022
PORPHYRIA, ACUTE INTERMITTENT
HMBS, 2-BP DEL, 218AG

In a patient with CRM-negative AIP (176000), Gu et al. (1994) identified
a 2-bp deletion (218delAG) in exon 6 of the HMBS gene. This frameshift
mutation leads to a premature termination 9 codons downstream and a
truncated protein.

.0023
PORPHYRIA, ACUTE INTERMITTENT
HMBS, GLY111ARG

In a patient with CRM-negative AIP (176000), Gu et al. (1994) identified
a 331G-A transversion in exon 7 of the HMBS gene, resulting in a
gly111-to-arg (G111R) substitution.

In Argentina, De Siervi et al. (1999) found that the G111R mutation was
present in 12 of 26 (46%) presumably unrelated propositi with AIP;
haplotype analysis with intragenic and flanking markers indicated an
ancestral founder.

.0024
PORPHYRIA, ACUTE INTERMITTENT
HMBS, IVS9AS, G-A, -1

In a patient with AIP (176000), Lundin et al. (1994) identified a 499G-A
transition in the first nucleotide of the acceptor splice site of intron
9 of the HMBS gene, resulting in abnormal splicing.

.0025
PORPHYRIA, ACUTE INTERMITTENT
HMBS, LEU177ARG

In affected members of several unrelated Finnish and Dutch families with
AIP (176000), Mgone et al. (1992) identified a 530T-G transversion in
exon 10 of the HMBS gene, resulting in a leu177-to-arg (L177R)
substitution.

.0026
PORPHYRIA, ACUTE INTERMITTENT
HMBS, ARG201TRP

In a patient with AIP (176000), Lundin et al. (1994) identified a 601C-T
transition in exon 10 of the HMBS gene, resulting in an arg201-to-trp
(R201W) substitution.

.0027
PORPHYRIA, ACUTE INTERMITTENT
HMBS, GLU223LYS

In a patient with CRM-negative AIP (176000), Gu et al. (1994) identified
a 667G-A transversion in exon 12 of the HMBS gene, resulting in a
glu223-to-lys (E223K) substitution.

.0028
PORPHYRIA, ACUTE INTERMITTENT
HMBS, 2-BP DEL, 730CT

In a patient with CRM-negative AIP (176000), Mgone et al. (1993) and Gu
et al. (1994) identified a 2-bp deletion (730delCT) exon 12 of the HMBS
gene. This frameshift mutation leads to a premature termination 6 codons
downstream and a truncated protein.

.0029
PORPHYRIA, ACUTE INTERMITTENT
HMBS, CYS247ARG

In a patient with AIP (176000), Mgone et al. (1993) identified a 739T-C
transversion in exon 12 of the HMBS gene, resulting in a cys247-to-arg
(C247R) substitution.

.0030
PORPHYRIA, ACUTE INTERMITTENT
HMBS, 8-BP INS

In a patient with CRM-negative AIP (176000), Gu et al. (1994) identified
an 8-bp insertion at position 742 of the coding sequence in exon 12 of
the HMBS gene. This frameshift mutation leads to a premature termination
10 codons downstream and a truncated protein.

.0031
PORPHYRIA, ACUTE INTERMITTENT
HMBS, GLU250LYS

In a patient with CRM-negative AIP (176000), Gu et al. (1994) identified
a 748G-A transversion in exon 12 of the HMBS gene, resulting in a
glu250-to-lys (E250K) substitution.

.0032
PORPHYRIA, ACUTE INTERMITTENT
HMBS, ALA252THR

In a patient with AIP (176000), Mgone et al. (1993) identified a 754G-A
transversion in exon 12 of the HMBS gene, resulting in an ala252-to-thr
(A252T) substitution.

.0033
PORPHYRIA, ACUTE INTERMITTENT
HMBS, ALA252VAL

In a patient with AIP (176000), Mgone et al. (1993) identified a 755C-T
transition in exon 12 of the HMBS gene, resulting in an ala252-to-val
(A252V) substitution.

.0034
PORPHYRIA, ACUTE INTERMITTENT
HMBS, HIS256ASN

In a patient with AIP (176000), Mgone et al. (1993) identified a 766C-A
transversion in exon 12 of the HMBS gene, resulting in a his256-to-asn
(H256N) substitution.

.0035
PORPHYRIA, ACUTE INTERMITTENT
HMBS, IVS12DS, G-C, +1

In a Japanese patient with AIP (176000), Daimon et al. (1993) identified
a 771G-C transversion in the first nucleotide of the donor site of
intron 12 of the HMBS gene, resulting in aberrant splicing and the
skipping of exon 12.

.0036
PORPHYRIA, ACUTE INTERMITTENT
HMBS, IVS14DS, G-A, +1

In a patient with CRM-negative AIP (176000), Gu et al. (1993) identified
a 912G-A transition in the first nucleotide of the donor splice site of
intron 14 of the HMBS gene, resulting in abnormal splicing and the
skipping of exon 14.

.0037
PORPHYRIA, ACUTE INTERMITTENT
HMBS, IVS6DS, G-C, +1

In affected members of 28 Swedish families with CRM-negative AIP
(176000), Lundin et al. (1997) identified a G-to-C transversion at the
splice donor site of intron 6 of the HMBS gene.

.0038
PORPHYRIA, ACUTE INTERMITTENT
HMBS, GLY216ASP

In affected members of a Swedish family with CRM-negative AIP (176000),
Lundin et al. (1997) identified a 646G-A transition in exon 11 of the
HMBS gene, resulting in a gly216-to-asp (G216D) substitution.

.0039
PORPHYRIA, ACUTE INTERMITTENT
HMBS, 2-BP DEL, 847TG

In affected members of a Swedish family with AIP (176000), Lundin et al.
(1997) identified a 2-bp deletion (847delTG) in exon 14 of the HMBS
gene, resulting in an mRNA translational frameshift.

.0040
PORPHYRIA, ACUTE INTERMITTENT
HMBS, ALU INS

Mustajoki et al. (1999) reported a large Finnish family in which an Alu
element interfered with the coding region of the PBGD gene, resulting in
acute intermittent porphyria (176000). A 333-bp Alu sequence was
directly inserted into exon 5 in antisense orientation. Mustajoki et al.
(1999) noted that this Alu cassette belongs to a Ya5 subfamily, one of
the evolutionarily youngest and at that time most active Alu
subfamilies.

.0041
PORPHYRIA, ACUTE INTERMITTENT, NONERYTHROID VARIANT
HMBS, 1-BP DEL, -154G

Whatley et al. (2000) identified a 1-bp deletion (-154delG) in the
promoter region of the HMBS gene as the cause of the nonerythroid
variant of AIP (176000). Reporter gene and electromobility shift assays
showed that the G nucleotide at position -154, the most 5-prime of
several transcription initiation sites in the ubiquitous HMBS promoter,
which lies immediately 3-prime to a transcription factor IIB binding
motif, is essential for normal transcription.

.0042
PORPHYRIA, ACUTE INTERMITTENT, NONERYTHROID VARIANT
HMBS, 1-BP DEL, 41A

Whatley et al. (2000) identified a 1-bp deletion (41delA) in exon 3 of
the HMBS gene as the cause of the nonerythroid variant of AIP (176000).
The frameshift mutation introduced a stop codon into mRNA for the
ubiquitous isoform only.

.0043
PORPHYRIA, ACUTE INTERMITTENT
HMBS, TRP283TER

In a patient with AIP (176000), Chen et al. (1994) identified a
heterozygous 848G-A transition in exon 14 of the HMBS gene, resulting in
a trp283-to-ter (W283X) substitution.

Nearly 60% of all Swiss AIP patients carry the W283X mutation. In
France, the prevalence of W283X is less than 5% (Schneider-Yin et al.,
2002). In 12 of 25 AIP families of Swiss and French origin,
Schneider-Yin et al. (2002) identified a common haplotype containing the
W283X HMBS mutation. The authors suggested that a single mutational
event took place approximately 40 generations ago (i.e., 1,000 years
ago).

.0044
PORPHYRIA, ACUTE INTERMITTENT, NONERYTHROID VARIANT
HMBS, MET1VAL

In a patient with the nonerythroid variant of AIP (176000), Chen et al.
(1994) identified a heterozygous 3G-A transition in exon 1 of the HMBS
gene, resulting in a met1-to-val (M1V) substitution in the initiation of
translation codon for the housekeeping transcript. Thus, translation of
the erythrocyte transcript was unaffected.

.0045
PORPHYRIA, ACUTE INTERMITTENT
HMBS, LEU81PRO

In a 7-year-old boy with acute intermittent porphyria (176000), Hessels
et al. (2004) detected a homozygous leu-to-pro substitution at codon 81
(L81P) in exon 6 of the HMBS gene. Porphobilinogen activity in red cells
was decreased to 2 to 4%. Both parents were heterozygous and
asymptomatic. Leu81 in PBG deaminase is an evolutionarily conserved
residue in the second alpha helix, suggesting its structural importance
for preservation of enzyme activity.

.0046
PORPHYRIA, ACUTE INTERMITTENT
HMBS, ARG149TER

In affected members of 2 Finnish families with acute intermittent
porphyria (176000), Kauppinen et al. (1995) identified a heterozygous
445C-T transition in exon 9 of the HMBS gene, resulting in an
arg149-to-ter (R149X) substitution.

Poblete-Gutierrez et al. (2006) identified a heterozygous R149X
substitution in affected members of the original family with so-called
'Chester type porphyria' (McColl et al., 1985) (see 176000). The
mutation was not found in 200 control chromosomes. The family had
originally been reported as having features of both AIP and variegated
porphyria (VP; 176200), but no mutations in the PPOX gene (600923) were
identified. The mutation occurred at a hypermutable CpG dinucleotide.
The findings confirmed that Chester type porphyria is a variant of AIP.
Poblete-Gutierrez et al. (2006) suggested that the original biochemical
studies indicating PPOX deficiency may have been erroneous or
misinterpreted. A different mutation in this codon has also been
associated with AIP (R149Q; 609806.0008).

*FIELD* SA
Llewellyn et al. (1987); Picat et al. (1990)
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*FIELD* CN
George E. Tiller - updated: 2/8/2011
Cassandra L. Kniffin - updated: 5/22/2009
Ada Hamosh - updated: 7/31/2007

*FIELD* CD
Cassandra L. Kniffin: 12/22/2005

*FIELD* ED
wwang: 03/11/2011
terry: 2/8/2011
wwang: 6/3/2009
ckniffin: 5/22/2009
terry: 4/13/2009
alopez: 8/3/2007
terry: 7/31/2007
carol: 1/5/2006
ckniffin: 1/4/2006
ckniffin: 12/28/2005

RBCC Red Blood Cell Collection

Full text data of HMBS