RBCC Red Blood Cell Collection

FAH [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Fumarylacetoacetase; FAA; 3.7.1.2 (Beta-diketonase; Fumarylacetoacetate hydrolase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00031708
IPI00031708 Fumarylacetoacetase Phenylalanine and Tyrosine catabolism, 4-fumarylacetoacetate + H2O = acetoacetate + fumarate 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 n/a found at its expected molecular weight found at molecular weight

UniProt P16930
ID FAAA_HUMAN Reviewed; 419 AA.
AC P16930; B2R9X1; D3DW95;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-AUG-1992, sequence version 2.
DT 22-JAN-2014, entry version 141.
DE RecName: Full=Fumarylacetoacetase;
DE Short=FAA;
DE EC=3.7.1.2;
DE AltName: Full=Beta-diketonase;
DE AltName: Full=Fumarylacetoacetate hydrolase;
GN Name=FAH;
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].
RX PubMed=1998338;
RA Phaneuf D., Labelle Y., Berube D., Arden K., Cavenee W., Gagne R.,
RA Tanguay R.M.;
RT "Cloning and expression of the cDNA encoding human fumarylacetoacetate
RT hydrolase, the enzyme deficient in hereditary tyrosinemia: assignment
RT of the gene to chromosome 15.";
RL Am. J. Hum. Genet. 48:525-535(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PROTEIN SEQUENCE OF 2-25; 32-47; 83-95 AND 195-211, CLEAVAGE OF
RP INITIATOR METHIONINE, ACETYLATION AT SER-2, AND MASS SPECTROMETRY.
RC TISSUE=Ovarian carcinoma;
RA Bienvenut W.V.;
RL Submitted (JAN-2010) to UniProtKB.
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 71-419.
RC TISSUE=Liver;
RX PubMed=2336361; DOI=10.1093/nar/18.7.1887;
RA Agsteribbe E., van Faassen H., Hartog M.V., Reversma T.,
RA Taanman J.-W., Pannekoek H., Evers R.F., Welling G.M., Berger R.;
RT "Nucleotide sequence of cDNA encoding human fumarylacetoacetase.";
RL Nucleic Acids Res. 18:1887-1887(1990).
RN [8]
RP REVIEW ON VARIANTS.
RX PubMed=9101289;
RX DOI=10.1002/(SICI)1098-1004(1997)9:4<291::AID-HUMU1>3.3.CO;2-L;
RA St Louis M., Tanguay R.M.;
RT "Mutations in the fumarylacetoacetate hydrolase gene causing
RT hereditary tyrosinemia type I: overview.";
RL Hum. Mutat. 9:291-299(1997).
RN [9]
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 [10]
RP VARIANT TYRO1 ILE-16.
RX PubMed=1401056; DOI=10.1172/JCI115979;
RA Phaneuf D., Lambert M., Laframboise R., Mitchell G., Lettre F.,
RA Tanguay R.M.;
RT "Type 1 hereditary tyrosinemia. Evidence for molecular heterogeneity
RT and identification of a causal mutation in a French Canadian
RT patient.";
RL J. Clin. Invest. 90:1185-1192(1992).
RN [11]
RP VARIANT TYRO1 ASP-134.
RX PubMed=8364576; DOI=10.1093/hmg/2.7.941;
RA Labelle Y., Phaneuf D., Leclerc B., Tanguay R.M.;
RT "Characterization of the human fumarylacetoacetate hydrolase gene and
RT identification of a missense mutation abolishing enzymatic activity.";
RL Hum. Mol. Genet. 2:941-946(1993).
RN [12]
RP VARIANT TYRO1 GLY-166.
RX PubMed=8318997; DOI=10.1002/humu.1380020205;
RA Grompe M., Al-Dhalimy M.;
RT "Mutations of the fumarylacetoacetate hydrolase gene in four patients
RT with tyrosinemia, type I.";
RL Hum. Mutat. 2:85-93(1993).
RN [13]
RP VARIANT TYRO1 VAL-233.
RX PubMed=7942842;
RA Rootwelt H., Berger R., Gray G., Kelly D.A., Coskun T.,
RA Kvittingen E.A.;
RT "Novel splice, missense, and nonsense mutations in the
RT fumarylacetoacetase gene causing tyrosinemia type 1.";
RL Am. J. Hum. Genet. 55:653-658(1994).
RN [14]
RP VARIANT TYRO1 TRP-341.
RX PubMed=7977370;
RA Rootwelt H., Brodtkorb E., Kvittingen E.A.;
RT "Identification of a frequent pseudodeficiency mutation in the
RT fumarylacetoacetase gene, with implications for diagnosis of
RT tyrosinemia type I.";
RL Am. J. Hum. Genet. 55:1122-1127(1994).
RN [15]
RP VARIANTS TYRO1 ASP-134 AND LEU-342.
RX PubMed=8005583; DOI=10.1007/BF00201558;
RA Rootwelt H., Chou J., Gahl W.A., Berger R., Coskun T., Brodtkorb E.,
RA Kvittingen E.A.;
RT "Two missense mutations causing tyrosinemia type 1 with presence and
RT absence of immunoreactive fumarylacetoacetase.";
RL Hum. Genet. 93:615-619(1994).
RN [16]
RP VARIANTS TYRO1 SER-337 AND GLY-381.
RX PubMed=7757089; DOI=10.1093/hmg/4.2.319;
RA St Louis M., Poudrier J., Phaneuf D., Leclerc B., Laframboise R.,
RA Tanguay R.M.;
RT "Two novel mutations involved in hereditary tyrosinemia type I.";
RL Hum. Mol. Genet. 4:319-320(1995).
RN [17]
RP VARIANT TYRO1 GLY-234.
RX PubMed=7550234; DOI=10.1002/humu.1380060113;
RA Hahn S.H., Krasnewich D., Brantly M., Kvittingen E.A., Gahl W.A.;
RT "Heterozygosity for an exon 12 splicing mutation and a W234G missense
RT mutation in an American child with chronic tyrosinemia type 1.";
RL Hum. Mutat. 6:66-73(1995).
RN [18]
RP VARIANTS TYRO1 ARG-193 AND VAL-369.
RX PubMed=8557261; DOI=10.1007/BF00218833;
RA Ploos van Amstel J.K., Bergman A.J.I.W., van Beurden E.A.C.M.,
RA Roijers J.F.M., Peelen T., van den Berg I.E.T., Poll-The B.T.,
RA Kvittingen E.A., Berger R.;
RT "Hereditary tyrosinemia type 1: novel missense, nonsense and splice
RT consensus mutations in the human fumarylacetoacetate hydrolase gene;
RT variability of the genotype-phenotype relationship.";
RL Hum. Genet. 97:51-59(1996).
RN [19]
RP VARIANTS TYRO1 ASP-158; LEU-261; SER-366 DEL AND HIS-405.
RX PubMed=9633815;
RX DOI=10.1002/(SICI)1098-1004(1998)12:1<19::AID-HUMU3>3.3.CO;2-V;
RA Bergman A.J.I.W., van den Berg I.E.T., Brink W., Poll-The B.T.,
RA Ploos van Amstel J.K., Berger R.;
RT "Spectrum of mutations in the fumarylacetoacetate hydrolase gene of
RT tyrosinemia type 1 patients in northwestern Europe and Mediterranean
RT countries.";
RL Hum. Mutat. 12:19-26(1998).
RN [20]
RP VARIANT TYRO1 ARG-279.
RX PubMed=11196105; DOI=10.1023/A:1026756501669;
RA Kim S.Z., Kupke K.G., Ierardi-Curto L., Holme E., Greter J.,
RA Tanguay R.M., Poudrier J., D'Astous M., Lettre F., Hahn S.H.,
RA Levy H.L.;
RT "Hepatocellular carcinoma despite long-term survival in chronic
RT tyrosinaemia I.";
RL J. Inherit. Metab. Dis. 23:791-804(2000).
RN [21]
RP VARIANT TYRO1 ARG-279.
RX PubMed=11476670; DOI=10.1186/1471-2156-2-9;
RA Dreumont N., Poudrier J.A., Bergeron A., Levy H.L., Baklouti F.,
RA Tanguay R.M.;
RT "A missense mutation (Q279R) in the fumarylacetoacetate hydrolase
RT gene, responsible for hereditary tyrosinemia, acts as a splicing
RT mutation.";
RL BMC Genet. 2:9-9(2001).
RN [22]
RP CHARACTERIZATION OF VARIANTS TYRO1 ILE-16; CYS-62; ASP-134; ARG-193;
RP VAL-233; GLY-234; ARG-279 AND TRP-341.
RX PubMed=11278491; DOI=10.1074/jbc.M009341200;
RA Bergeron A., D'Astous M., Timm D.E., Tanguay R.M.;
RT "Structural and functional analysis of missense mutations in
RT fumarylacetoacetate hydrolase, the gene deficient in hereditary
RT tyrosinemia type 1.";
RL J. Biol. Chem. 276:15225-15231(2001).
RN [23]
RP VARIANT TYRO1 THR-35.
RX PubMed=20003495; DOI=10.1186/1750-1172-4-28;
RA Cassiman D., Zeevaert R., Holme E., Kvittingen E.A., Jaeken J.;
RT "A novel mutation causing mild, atypical fumarylacetoacetase
RT deficiency (Tyrosinemia type I): a case report.";
RL Orphanet J. Rare Dis. 4:28-28(2009).
CC -!- CATALYTIC ACTIVITY: 4-fumarylacetoacetate + H(2)O = acetoacetate +
CC fumarate.
CC -!- COFACTOR: Calcium (By similarity).
CC -!- COFACTOR: Magnesium (By similarity).
CC -!- PATHWAY: Amino-acid degradation; L-phenylalanine degradation;
CC acetoacetate and fumarate from L-phenylalanine: step 6/6.
CC -!- SUBUNIT: Homodimer.
CC -!- TISSUE SPECIFICITY: Mainly expressed in liver and kidney. Lower
CC levels are also detected in many other tissues.
CC -!- DISEASE: Tyrosinemia 1 (TYRO1) [MIM:276700]: An inborn error of
CC metabolism characterized by elevations of tyrosine in the blood
CC and urine, and hepatorenal manifestations. Typical features
CC include hepatic necrosis, renal tubular injury, episodic weakness,
CC self-mutilation, and seizures. Renal tubular dysfunction is
CC associated with phosphate loss and hypophosphataemic rickets.
CC Progressive liver disease can lead to the development of
CC hepatocellular carcinoma. Dietary treatment with restriction of
CC tyrosine and phenylalanine alleviates the rickets, but liver
CC transplantation has so far been the only definite treatment.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the FAH family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/FAH";
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DR EMBL; M55150; AAA52422.1; -; mRNA.
DR EMBL; BT007160; AAP35824.1; -; mRNA.
DR EMBL; AK313951; BAG36668.1; -; mRNA.
DR EMBL; CH471136; EAW99120.1; -; Genomic_DNA.
DR EMBL; CH471136; EAW99121.1; -; Genomic_DNA.
DR EMBL; BC002527; AAH02527.1; -; mRNA.
DR EMBL; X51728; CAA36016.1; -; mRNA.
DR PIR; A37926; A37926.
DR RefSeq; NP_000128.1; NM_000137.2.
DR UniGene; Hs.73875; -.
DR ProteinModelPortal; P16930; -.
DR SMR; P16930; 1-416.
DR IntAct; P16930; 1.
DR STRING; 9606.ENSP00000261755; -.
DR PhosphoSite; P16930; -.
DR DMDM; 119778; -.
DR OGP; P16930; -.
DR REPRODUCTION-2DPAGE; IPI00031708; -.
DR PaxDb; P16930; -.
DR PeptideAtlas; P16930; -.
DR PRIDE; P16930; -.
DR Ensembl; ENST00000261755; ENSP00000261755; ENSG00000103876.
DR Ensembl; ENST00000407106; ENSP00000385080; ENSG00000103876.
DR Ensembl; ENST00000561421; ENSP00000453347; ENSG00000103876.
DR GeneID; 2184; -.
DR KEGG; hsa:2184; -.
DR UCSC; uc002bfm.2; human.
DR CTD; 2184; -.
DR GeneCards; GC15P080445; -.
DR HGNC; HGNC:3579; FAH.
DR HPA; HPA041370; -.
DR HPA; HPA044093; -.
DR MIM; 276700; phenotype.
DR MIM; 613871; gene.
DR neXtProt; NX_P16930; -.
DR Orphanet; 882; Tyrosinemia type 1.
DR PharmGKB; PA27977; -.
DR eggNOG; COG0179; -.
DR HOGENOM; HOG000256845; -.
DR HOVERGEN; HBG001919; -.
DR InParanoid; P16930; -.
DR KO; K01555; -.
DR OMA; LSWKGTK; -.
DR PhylomeDB; P16930; -.
DR BioCyc; MetaCyc:HS02536-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00139; UER00341.
DR ChiTaRS; FAH; human.
DR GeneWiki; Fumarylacetoacetate_hydrolase; -.
DR GenomeRNAi; 2184; -.
DR NextBio; 8817; -.
DR PRO; PR:P16930; -.
DR ArrayExpress; P16930; -.
DR Bgee; P16930; -.
DR CleanEx; HS_FAH; -.
DR Genevestigator; P16930; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0004334; F:fumarylacetoacetase activity; EXP:Reactome.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0006527; P:arginine catabolic process; IEA:Ensembl.
DR GO; GO:0034641; P:cellular nitrogen compound metabolic process; TAS:Reactome.
DR GO; GO:0006559; P:L-phenylalanine catabolic process; TAS:Reactome.
DR GO; GO:0006572; P:tyrosine catabolic process; TAS:ProtInc.
DR Gene3D; 2.30.30.230; -; 1.
DR Gene3D; 3.90.850.10; -; 1.
DR InterPro; IPR005959; Fumarylacetoacetase.
DR InterPro; IPR002529; Fumarylacetoacetase_C.
DR InterPro; IPR011234; Fumarylacetoacetase_C-rel.
DR InterPro; IPR015377; Fumarylacetoacetase_N.
DR PANTHER; PTHR11820:SF1; PTHR11820:SF1; 1.
DR Pfam; PF01557; FAA_hydrolase; 1.
DR Pfam; PF09298; FAA_hydrolase_N; 1.
DR SUPFAM; SSF56529; SSF56529; 1.
DR SUPFAM; SSF63433; SSF63433; 1.
DR TIGRFAMs; TIGR01266; fum_ac_acetase; 1.
PE 1: Evidence at protein level;
KW Acetylation; Calcium; Complete proteome; Direct protein sequencing;
KW Disease mutation; Hydrolase; Magnesium; Metal-binding;
KW Phenylalanine catabolism; Reference proteome; Tyrosine catabolism.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 419 Fumarylacetoacetase.
FT /FTId=PRO_0000156825.
FT ACT_SITE 133 133 Proton acceptor (Probable).
FT METAL 126 126 Calcium (By similarity).
FT METAL 199 199 Calcium (By similarity).
FT METAL 201 201 Calcium (By similarity).
FT METAL 233 233 Calcium (By similarity).
FT METAL 233 233 Magnesium (By similarity).
FT METAL 253 253 Magnesium (By similarity).
FT METAL 257 257 Magnesium (By similarity).
FT BINDING 128 128 Substrate (By similarity).
FT BINDING 142 142 Substrate (By similarity).
FT BINDING 240 240 Substrate (By similarity).
FT BINDING 244 244 Substrate (By similarity).
FT BINDING 350 350 Substrate (By similarity).
FT MOD_RES 2 2 N-acetylserine.
FT VARIANT 16 16 N -> I (in TYRO1; loss of activity).
FT /FTId=VAR_005205.
FT VARIANT 35 35 A -> T (in TYRO1; atypical mild
FT phenotype).
FT /FTId=VAR_065454.
FT VARIANT 62 62 F -> C (in TYRO1; loss of activity).
FT /FTId=VAR_005206.
FT VARIANT 64 64 Q -> H (in TYRO1).
FT /FTId=VAR_005207.
FT VARIANT 134 134 A -> D (in TYRO1; loss of activity).
FT /FTId=VAR_005208.
FT VARIANT 158 158 G -> D (in TYRO1).
FT /FTId=VAR_005209.
FT VARIANT 166 166 V -> G (in TYRO1).
FT /FTId=VAR_005210.
FT VARIANT 193 193 C -> R (in TYRO1; loss of activity).
FT /FTId=VAR_005211.
FT VARIANT 207 207 G -> D (in TYRO1).
FT /FTId=VAR_005212.
FT VARIANT 233 233 D -> V (in TYRO1; loss of activity).
FT /FTId=VAR_005213.
FT VARIANT 234 234 W -> G (in TYRO1; loss of activity).
FT /FTId=VAR_005214.
FT VARIANT 249 249 P -> T (in TYRO1).
FT /FTId=VAR_005215.
FT VARIANT 261 261 P -> L (in TYRO1).
FT /FTId=VAR_005216.
FT VARIANT 279 279 Q -> R (in TYRO1; may affect splicing
FT resulting in skipping of exon 8 alone or
FT together with exon 9; lower activity as
FT compared to wild type).
FT /FTId=VAR_065455.
FT VARIANT 294 294 T -> P (in TYRO1).
FT /FTId=VAR_005217.
FT VARIANT 337 337 G -> S (in TYRO1).
FT /FTId=VAR_005218.
FT VARIANT 341 341 R -> W (in TYRO1; pseudo-deficient
FT phenotype; lower activity;
FT dbSNP:rs11555096).
FT /FTId=VAR_005219.
FT VARIANT 342 342 P -> L (in TYRO1; loss of activity).
FT /FTId=VAR_005220.
FT VARIANT 366 366 Missing (in TYRO1).
FT /FTId=VAR_005221.
FT VARIANT 369 369 G -> V (in TYRO1).
FT /FTId=VAR_005222.
FT VARIANT 381 381 R -> G (in TYRO1; loss of activity).
FT /FTId=VAR_005223.
FT VARIANT 405 405 F -> H (in TYRO1; requires 2 nucleotide
FT substitutions).
FT /FTId=VAR_005224.
SQ SEQUENCE 419 AA; 46374 MW; 12EA8D8074C55BB2 CRC64;
MSFIPVAEDS DFPIHNLPYG VFSTRGDPRP RIGVAIGDQI LDLSIIKHLF TGPVLSKHQD
VFNQPTLNSF MGLGQAAWKE ARVFLQNLLS VSQARLRDDT ELRKCAFISQ ASATMHLPAT
IGDYTDFYSS RQHATNVGIM FRDKENALMP NWLHLPVGYH GRASSVVVSG TPIRRPMGQM
KPDDSKPPVY GACKLLDMEL EMAFFVGPGN RLGEPIPISK AHEHIFGMVL MNDWSARDIQ
KWEYVPLGPF LGKSFGTTVS PWVVPMDALM PFAVPNPKQD PRPLPYLCHD EPYTFDINLS
VNLKGEGMSQ AATICKSNFK YMYWTMLQQL THHSVNGCNL RPGDLLASGT ISGPEPENFG
SMLELSWKGT KPIDLGNGQT RKFLLDGDEV IITGYCQGDG YRIGFGQCAG KVLPALLPS
//

MIM 276700
*RECORD*
*FIELD* NO
276700
*FIELD* TI
#276700 TYROSINEMIA, TYPE I
;;HEPATORENAL TYROSINEMIA;;
FUMARYLACETOACETASE DEFICIENCY;;
read moreFAH DEFICIENCY
*FIELD* TX
A number sign (#) is used because this form of tyrosinemia is caused by
homozygous or compound heterozygous mutation in the FAH gene (613871),
encoding fumarylacetoacetate hydrolase, on chromosome 15q23-q25.

DESCRIPTION

Hereditary tyrosinemia type I is an autosomal recessive disorder caused
by deficiency of fumarylacetoacetase (FAH), the last enzyme of tyrosine
degradation. The disorder is characterized by progressive liver disease
and a secondary renal tubular dysfunction leading to hypophosphatemic
rickets. Onset varies from infancy to adolescence. In the most acute
form patients present with severe liver failure within weeks after
birth, whereas rickets may be the major symptom in chronic tyrosinemia.
Untreated, patients die from cirrhosis or hepatocellular carcinoma at a
young age (summary by Bliksrud et al., 2005).

CLINICAL FEATURES

Among the children of first-cousin parents, Lelong et al. (1963)
observed 2 sons with cirrhosis, Fanconi renotubular syndrome, and marked
increase in plasma tyrosine. In the sib most extensively observed,
hepatosplenomegaly was discovered at 3 months of age and rickets at 18
months. Malignant changes developed in the liver, and death from
pulmonary metastases occurred shortly before his 5th birthday. The
author suggested that the basic defect concerns an enzyme involved with
tyrosine metabolism. Earlier, Himsworth (1950) described a similar case.
Zetterstrom (1963) studied 7 cases coming from an isolated area of
southwestern Sweden. Halvorsen et al. (1966) gave details on 6 cases
from Norway.

Perry et al. (1965) described 3 sibs (2 females and a male) in 1 sibship
who died in the third month after an illness characterized by
irritability and progressive somnolence, and terminally by a tendency to
bleed and hypoglycemia. A peculiar odor was noted. Pathologic changes
included hepatic cirrhosis, renal tubular dilatation, and pancreatic
islet hypertrophy. Biochemical studies showed generalized amino
aciduria, marked elevation of methionine in the serum, and a
disproportionately high urinary excretion of methionine.
Alpha-keto-gamma-methiolbutyric acid was present in the urine and may
account for the peculiar odor. The hypertrophy of the islets of
Langerhans was probably due to stimulation by methionine or one of its
metabolites. It seems likely that the disorder in the patients of Perry
et al. (1965) was tyrosinemia since hypermethioninemia occurs secondary
to liver failure in that condition (Scriver et al., 1967; Gaull et al.,
1970).

Gentz et al. (1965) described 7 patients in 4 families with multiple
renal tubular defects like those of the de Toni-Debre-Fanconi syndrome,
nodular cirrhosis of the liver, and impaired tyrosine metabolism. In the
urine, p-hydroxyphenyllactic acid was excreted in unusually large
amounts. A total lack of liver p-hydroxyphenylpyruvate oxidase activity
was demonstrated. Tyrosine-alpha-ketoglutarate transaminase was normal.

Scriver et al. (1967) identified the disease in 35 French-Canadian
infants, of whom 16 were sibs (i.e., 2 or more in each of several
families). Marked tyrosinemia and tyrosyluria were present. The urine
contained parahydroxyphenylpyruvic acid (PHPPA) and lactic and acetic
derivatives. Loading test with tyrosine and with PHPPA suggested
deficient p-hydroxyphenylpyruvate oxidase activity, which was confirmed
by assay of liver biopsy samples. In stage I, infants exhibit hepatic
necrosis and hypermethioninemia. In stage II, nodular cirrhosis and
chronic hepatic insufficiency without hypermethioninemia are found. In
stage III, renal tubular damage (Baber syndrome), often with
hypophosphatemic rickets, appears. Low tyrosine diet arrested
progression of the disease.

Lindblad et al. (1987) suggested that cardiomyopathy, usually
subclinical, is a frequent finding.

Mitchell et al. (1990) pointed out the significance of neurologic crises
in this disorder. They found that of 48 children with tyrosinemia
identified on neonatal screening since 1970, 20 (42%) had neurologic
crises that began at the mean age of 1 year and led to 104 hospital
admissions. These abrupt episodes of peripheral neuropathy were
characterized by severe pain with extensor hypertonia (in 75%), vomiting
or paralytic ileus (69%), muscle weakness (29%), and self-mutilation
(8%). In 8 children, mechanical ventilation was required because of
paralysis and 14 of the 20 children died. Between crises, most survivors
regained normal function. They could identify no reliable biochemical
marker for the crises. Urinary excretion of delta-aminolevulinic acid, a
neurotoxic intermediate of porphyrin biosynthesis, was elevated during
both crises and asymptomatic periods. Electrophysiologic studies and
neuromuscular biopsies showed axonal degeneration and secondary
demyelination. Thus, they demonstrated that episodes of acute, severe,
peripheral neuropathy are common in this disorder and resemble the
crises of the neuropathic porphyrias.

- Fumarylacetoacetase Pseudodeficiency

Kvittingen et al. (1985) described a family that may have had a
pseudodeficiency gene. Presumed homozygotes for this gene had levels of
fumarylacetoacetase activity only slightly higher than those in patients
with tyrosinemia. No clinical abnormalities were observed. Kvittingen et
al. (1992) studied a healthy 41-year-old female homozygous for the
pseudodeficiency gene and 3 tyrosinemia families in which one or both
parents were compound heterozygotes for the tyrosinemia and
pseudodeficiency genes. Only 2 of 7 patients with typical chronic
tyrosinemia had definite immunoreactivity in fibroblasts when bovine
fumarylacetoacetase antibodies were used; none of the patients with the
acute type had detectable immunoreactive protein in fibroblast extracts.
Twenty-eight patients with hereditary tyrosinemia of various clinical
phenotypes were tested. The pseudodeficiency gene product gave almost no
detectable immunoreactivity in fibroblasts.

BIOCHEMICAL FEATURES

La Du and Gjessing (1972) discussed evidence against the hypothesis that
tyrosinemia is a p-hydroxyphenylpyruvic acid oxidase deficiency and
suggested that further investigation is needed to explain the clinical
and pathologic features of tyrosinemia. Lindblad et al. (1977) suggested
that the primary defect is in fumarylacetoacetase (EC 3.7.1.2). This
leads to accumulation of succinylacetone and succinylacetoacetate.
Porphobilinogen synthetase is inhibited by these substances and the
authors suggested that the severe liver and kidney damage of tyrosinemia
is caused by accumulation of tyrosine metabolites. A puzzling feature of
hereditary tyrosinemia has been episodes similar to acute hepatic
porphyria, with excretion of 5-aminolevulinic acid in the urine. The
inhibition of porphobilinogen synthase explains this feature.
Fumarylacetoacetase is the enzyme primarily deficient; deficiency of
parahydroxyphenylpyruvate oxidase is secondary (Scriver, 1982).

Tanguay et al. (1990) concluded that the acute form of hereditary
tyrosinemia has absence of FAH enzyme protein, whereas the chronic form
has presence of immunoreactive enzyme protein. They quoted the work of
others supporting these findings.

In type I tyrosinemia, the defect in FAH, the last enzyme in the
tyrosine catabolism pathway, results in accumulation of succinylacetone
(SA) that reacts with amino acids and proteins to form stable adducts
via Schiff base formation, lysine being the most reactive amino acid.
Patients with this disorder surviving beyond infancy are at considerable
risk for the development of hepatocellular carcinoma, and a high level
of chromosomal breakage is observed in tyrosinemia cells, suggesting a
defect in the processing of DNA. Prieto-Alamo and Laval (1998) showed
that the overall DNA-ligase activity is low in tyrosinemia cells (about
20% of normal) and that Okazaki fragments are rejoined at a reduced rate
compared with normal fibroblasts. No mutation was found by sequencing
the ligase I cDNA (LIG1; 126391) from tyrosinemia cells, and the level
of expression of the ligase I mRNA was similar in normal and tyrosinemia
fibroblasts, suggesting the presence of a ligase inhibitor. SA was shown
to inhibit in vitro the overall DNA-ligase activity present in normal
cell extracts. The activity of purified T4 DNA-ligase, whose active site
is also a lysine residue, was inhibited by SA in a dose-dependent
manner. These results suggested that accumulation of SA reduces the
overall ligase activity in tyrosinemia cells and indicated that
metabolic errors may play a role in regulating enzymatic activities
involved in DNA replication and repair.

PATHOGENESIS

It had been postulated that the severe liver damage in tyrosinemia is
the result of defective degradation of tyrosine. Hostetter et al. (1983)
showed, however, that liver damage is prenatal in onset (as indicated by
greatly elevated alpha-fetoprotein in cord blood) and that
hypertyrosinemia developed only postnatally. Thus, therapy aimed at
reduction of the elevated tyrosine level is unlikely to be of
fundamental value.

POPULATION GENETICS

De Braekeleer and Larochelle (1990) estimated the prevalence of
hereditary tyrosinemia at birth as 1/1,846 liveborn and the carrier rate
as 1/20 inhabitants in the Saguenay-Lac-Saint-Jean region. The mean
coefficient of inbreeding was only slightly elevated in the tyrosinemic
group compared to a control group and was due to remote consanguinity.
The mean kinship coefficient was 2.3 times higher in the tyrosinemic
group than in the control group. This was interpreted as indicating
founder effect.

DIAGNOSIS

Prenatal diagnosis is possible either by the detection of
succinylacetone in the amniotic fluid (Gagne et al., 1982) or
measurement of fumarylacetoacetase in cultured amniotic cells
(Kvittingen et al., 1983). Holme et al. (1985) demonstrated the
feasibility of enzymatic diagnosis in chorionic villus material. Also,
they showed that normal red cells have fumarylacetoacetase activity.
They proposed that studies of red cells permit rapid diagnosis and
recognition of heterozygotes and that enzyme replacement by blood
transfusion may help patients over acute metabolic crises and until such
time as definitive therapy by orthotopic liver transplantation (Fisch et
al., 1978; Gartner et al., 1984) can be performed.

Laberge et al. (1990) described an enzyme-linked immunosorbent assay
(ELISA) to measure the deficient enzyme in dried blood spots in this
disorder. As mean levels of blood tyrosine in newborn specimens have
declined, probably as a result of dietary changes and early discharge
from nurseries, the traditional approach to screening for tyrosinemia,
which was based on the fluorometric determination of tyrosine on the
first dried blood spot received by neonatal screening programs, has
required replacement.

As an aid to early diagnosis for early institution of drug therapy,
Holme and Lindstedt (1992) suggested a neonatal screening test based on
the measurement of porphobilinogen synthase activity. Porphobilinogen
synthase activity is always low in patients with tyrosinemia type I.
Holme and Lindstedt (1992) were not aware of any drug used neonatally or
of conditions that would interfere with the test or mimic
porphobilinogen synthase activity to result in a false-normal test.
Specificity of the test is not absolute because homozygous
porphobilinogen synthase deficiency (125270) would be detected; in this
disorder also, early diagnosis would presumably benefit the patients.

Tanguay et al. (1990) identified RFLPs for 4 restriction sites within
the FAH gene and proposed the development of a carrier detection test by
linkage analysis.

CLINICAL MANAGEMENT

Dehner et al. (1989) reviewed the pathologic findings in the liver on
the basis of the findings in children undergoing liver transplant. They
concluded that to preclude hepatocellular carcinoma, a liver replacement
is necessary before the age of 2 years. In the view of Van Spronsen et
al. (1989) also, orthotopic liver transplantation is the only definitive
therapy for both the metabolic and the oncologic problem in this
disorder.

Russo and O'Regan (1990) reviewed the pathologic findings in the liver
and kidney. In the Hopital Sainte-Justine in Montreal, 16 patients had
been evaluated for liver transplantation. Renal involvement was found to
be 'more abnormal than expected.' The liver was transplanted in 7
patients of whom 2 also received kidney transplantation. Hepatocarcinoma
was detected in 2 of 8 patients in whom the whole liver was examined. Of
the 9 patients who did not receive transplants, 5 died; of the 7
transplant patients, 1 died in an instance of combined liver-kidney
transplantation. The 6 patients who survived had normal liver function,
normal growth, and no recurrence of neurologic crises on a normal diet.

Sokal et al. (1992) recommended orthotopic liver transplantation at an
early stage. The procedure was performed in 4 children under 1 year of
age, within 5 months of presentation and diagnosis. During the
pretransplant period, intensive medical support and restriction of
dietary tyrosine was initiated to improve the patient's condition and
promote weight gain.

As an alternative to liver transplantation, Lindstedt et al. (1992)
treated patients with type I tyrosinemia with a potent inhibitor of
4-hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27) to prevent the
formation of maleylacetoacetate and fumarylacetoacetate and their
saturated derivatives. The agent used in 1 acute and 4 subacute/chronic
cases was 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione
(NTBC). Signs of improvement included decrease in several metabolites,
correction of the almost complete inhibition of porphobilinogen synthase
in erythrocytes, decrease in alpha-fetoprotein, improved liver and
renotubular function, and regression of hepatic abnormalities by
computed tomography. No side effects were encountered. Inhibition of
4-hydroxyphenylpyruvate dioxygenase may prevent the development of liver
cirrhosis and abolish or diminish the risk of liver cancer. Furthermore,
normalization of porphyrin synthesis should eliminate the risk of
porphyric crises.

Laine et al. (1995) studied renal function after orthotopic liver
transplantation and found that the patients had normal glomerular
filtration rates but showed signs of tubular dysfunction 18 to 36 months
after operation.

Holme and Lindstedt (1998) stated that since the first trial of NTBC
treatment for type I tyrosinemia in 1991, over 220 patients had been
treated by the drug using a protocol that included regular follow-up
with reports of clinical and laboratory investigations. Only 10% of the
patients had not responded clinically to NTBC treatment. In half of
these patients, successful liver transplantation had been performed,
which further reduced the mortality rate during infancy to 5%. The data
indicated a decreased risk for early development of hepatocellular
carcinoma in patients who started treatment at an early age. Of the 101
patients aged 2 to 8 years who had started NTBC treatment before 2 years
of age, no patient developed cancer after 2 years of age.

MOLECULAR GENETICS

Grompe et al. (1994) found that 100% of patients from the
Saguenay-Lac-Saint-Jean region of Quebec and 28% of patients from other
regions of the world carry a splice donor site mutation in intron 12. Of
25 patients from the Saguenay-Lac-Saint-Jean region, 20 were homozygous.
The frequency of carrier status, based on screening of blood spots from
newborns, was about 1 per 25 in that region of Quebec and about 1 per 66
overall in Quebec. Using cDNA probes for the FAH gene, Demers et al.
(1994) identified 10 haplotypes with 5 RFLPs in 118 normal chromosomes
from the French-Canadian population. Among 29 children with hereditary
tyrosinemia, haplotype 6 was found to be strongly associated with
disease, at a frequency of 90% as compared with approximately 18% in 35
control individuals. This frequency increased to 96% in the 24 patients
originating from the Saguenay-Lac-Saint-Jean region. Most patients were
found to be homozygous for a specific haplotype in this population.
Analysis of 24 tyrosinemia patients from 9 countries gave a frequency of
approximately 52% for haplotype 6, suggesting a relatively high
association worldwide.

Kvittingen et al. (1994) demonstrated a mosaic pattern of immunoreactive
FAH protein in liver tissue from 15 of 18 tyrosinemia type I patients of
various ethnic origins. One additional patient had variable levels of
FAH enzyme activity in liver tissue. In 4 patients exhibiting mosaicism
of FAH protein, analysis for the tyrosinemia-causing mutations was
performed in immunonegative and immunopositive areas of liver tissue by
restriction digestion analysis and direct DNA sequencing. In all 4
patients, the immunonegative liver tissue contained the FAH mutations
demonstrated in fibroblasts of the patients. In the immunopositive
nodules of regenerating liver tissue, one of the mutated alleles
apparently had reverted to the normal genotype. This genetic correction
was observed for 3 different tyrosinemia-causing mutations. In each
case, a mutant AT nucleotide pair was reverted to a normal GC pair. One
of the mutations that showed reversion was the splice site mutation
described in 613871.0003. Another was the glu357-to-ter mutation due to
a G-to-T transversion at nucleotide 1069, which is described in
613871.0004. In a compound heterozygous patient, the same mutation was
reverted to wildtype in all 4 nodules investigated. A gene conversion
event or mitotic recombination between homologous chromosomes could
theoretically explain the appearance of a normal allele in a compound
heterozygote. Two of the patients with reverted mutations, however, were
homozygous for their mutations, and no pseudogenes for FAH, for
contribution of wildtype sequences, are known. Early embryonic mutation
with selective growth of the mutated cells could account for the
mosaicism, but a high incidence of such an event would indicate a
precipitating factor. Chemical mutagenesis, reverting the
disease-causing mutation, could result from the metabolites accumulating
in tyrosinemia. Even if the metabolites are not direct mutagens, the
compounds are toxic and induce cell necrosis with a subsequent
accelerated regeneration of hepatocytes. Rapidly replicating cells are
generally prone to mutations. Reversion of the genetic defect resulting
from accelerated cell regeneration should be sought in other genetic
diseases in tissues with an induced, or naturally high, rate of cell
replication.

Hahn et al. (1995) reviewed 7 previously reported mutations in
tyrosinemia type I and added 2 more identified in a compound
heterozygote.

Timmers and Grompe (1996) reported 6 new mutations in the FAH gene in
patients with hereditary tyrosinemia type I: 2 splice mutations, 3
missense mutations, and 1 nonsense mutation.

Rootwelt et al. (1996) classified 62 hereditary tyrosinemia type 1
patients of various ethnic origins clinically into acute, chronic, or
intermediate phenotypes and screened for the 14 published causal
mutations in the FAH gene. Restriction analysis of PCR-amplified genomic
DNA identified 74% of the mutated alleles. The IVS12,G-A,+5 mutation
(613871.0003), which is predominant in the French-Canadian tyrosinemia
type I patients, was the most common mutation being present in 32
alleles in patients from Europe, Pakistan, Turkey, and the United
States. The IVS6,G-T,-1 transversion (613871.0010), encountered in 14
alleles, was common in central and western Europe. There was an apparent
'Scandinavian' 1009G-to-A combined splice and missense mutation (12
alleles), a 'Pakistani' 192G-to-T splice mutation (11 alleles), a
'Turkish' D233V mutation (6 alleles), and a 'Finnish' or northern
European W262X (613871.0009) mutation (7 alleles). Rootwelt et al.
(1996) commented that some of the mutations seemed to predispose for
acute and others for more chronic forms of tyrosinemia type I, although
no clear-cut genotype/phenotype correlation could be established.

According to the review of St-Louis and Tanguay (1997), 26 mutations in
the FAH gene had been reported in type I tyrosinemia. All consisted of
single-base substitutions resulting in 16 amino acid replacements, 1
silent mutation causing a splicing defect, 5 nonsense codons, and 4
putative splicing defects. The mutations were spread over the entire FAH
gene, with a particular clustering between amino acid residues 230 and
250.

Arranz et al. (2002) determined the FAH genotype in a group of 29
patients, most of them from the Mediterranean area, with hereditary
tyrosinemia type I. They identified 7 novel mutations and 2 previously
described mutations. At least one splice site mutation was found in
92.8% of patients, with IVS6-1G-T (613871.0010) accounting for 58.9% of
the total number of alleles. The group of patients with splice mutations
showed heterogeneous phenotypic patterns ranging from the acute form,
with severe liver malfunction, to chronic forms, with renal
manifestations and slow progressive hepatic alterations. Despite the
high prevalence of the IVS12+5G-A mutation (613871.0003) in the
northwestern European population, Arranz et al. (2002) found only 2
patients with this mutation from the group of 29 patients. One patient,
who was a double heterozygote for a nonsense and a frameshift mutation,
showed an atypical clinical picture of hypotonia and repeated
infections.

Bliksrud et al. (2005) described revertant mosaicism in a patient with
type I tyrosinemia.

- Fumarylacetoacetase Pseudodeficiency

Rootwelt et al. (1994) presented evidence for the existence of a
'pseudodeficiency' FAH allele. In an individual homozygous for
pseudodeficiency of FAH and in 3 hereditary tyrosinemia type I families
also carrying the pseudodeficiency allele, Western blotting of
fibroblast extracts showed that the pseudodeficiency allele gave very
little immunoreactive FAH protein, whereas Northern analysis revealed a
normal amount of FAH mRNA. All the pseudodeficiency alleles were found
to carry a C-to-T transition in nucleotide 1021, predicting an
arg341-to-trp substitution (613871.0006). Site-directed mutagenesis and
expression in a rabbit reticulocyte lysate system demonstrated that the
arg341-to-trp mutation gave reduced FAH activity and reduced amounts of
the full-length protein. The normal and the mutated sequences could be
distinguished by BsiEI restriction digestion of PCR products. Among 516
healthy volunteers of Norwegian origin, the arg341-to-trp mutation was
found in 2.2% of alleles. Testing for this specific mutation may solve
the problem of prenatal diagnosis and carrier detection in families with
compound heterozygote genotypes for type I tyrosinemia and
pseudodeficiency.

ANIMAL MODEL

Mice homozygous for an FAH gene disruption have a neonatal lethal
phenotype caused by liver dysfunction. Grompe et al. (1995) demonstrated
that treatment of affected animals with NTBC abolished neonatal
lethality, corrected liver function, and partially normalized the
altered expression pattern of hepatic mRNAs. The prolonged life span of
affected animals resulted in a phenotype analogous to human tyrosinemia
type I, including hepatocellular carcinoma. These animals will serve as
a useful model for studies of the pathophysiology and treatment of
hereditary tyrosinemia type I as well as hepatic cancer.

In mice deficient in FAH through targeted disruption of the Fah gene,
Overturf et al. (1996) found that as few as 1,000 transplanted wildtype
hepatocytes were able to repopulate mutant liver, demonstrating their
strong competitive growth advantage. Mutant hepatocytes corrected in
situ by retroviral gene transfer were also positively selected. In
mutant animals treated by multiple retrovirus injections, more than 90%
of hepatocytes became FAH positive and liver function was restored to
normal. These studies were prompted by a number of observations
including the finding that the livers of patients with hereditary
tyrosinemia frequently contained discrete nodules with FAH enzyme
activity, due to a somatic reversion event (Kvittingen et al., 1993).
Wilson (1996) commented on the significance of these results for the
liver gene therapy for genetic diseases in general. He stated that,
based on the encouraging data in the mouse model, it would seem
reasonable to evaluate this approach in patients with hereditary
tyrosinemia. A similar approach might be considered for other liver
metabolic diseases in which genetically corrected hepatocytes would have
a selective advantage over degenerating mutant cells. Wilson (1996)
suggested that a useful extension of this approach might be to introduce
into the vector a gene that confers upon the hepatocyte a selective
advantage such as resistance to a hepatotoxic drug. This concept was
being developed in bone marrow using the multidrug resistance (MDR) gene
(171050).

Overturf et al. (1997) injected Fah-deficient mice with a
first-generation adenoviral vector expressing the human FAH gene and
followed them for up to 9 months. Nontreated FAH mutant control mice
died within 6 weeks from fulminant liver failure, whereas FAH
adenovirus-infected animals survived until sacrifice at 2 to 9 months.
Hepatocellular cancer developed in 9 of 13 virus-treated animals.
Immunohistochemical analysis revealed a mosaic of FAH-deficient and
FAH-positive cells in all animals and liver function tests were improved
compared to controls. Even mice harvested 9 months after viral infection
had more than 50% FAH-positive cells. These results demonstrated a
strong selective advantage of FAH-expressing cells in an FAH-deficient
liver but also illustrated the danger of carcinomas arising from
FAH-deficient hepatocytes in this disorder.

The 'albino lethal' mouse, first described by Gluecksohn-Waelsch (1979),
has a large deletion on chromosome 7, including the albino locus and the
Fah gene. Another Fah-deficient mouse was generated by targeted
disruption of the Fah gene (Grompe et al., 1995). Endo et al. (1997)
generated mice with disruption of both the Fah gene and the Hpd gene,
which encodes 4-hydroxyphenylpyruvate dioxygenase at a step earlier in
the metabolic pathway. This doubly mutant tyrosinemic mouse model showed
apoptosis of hepatocytyes and acute onset of liver failure after
administration of homogentisic acid (HGA), the intermediate metabolite
between the enzymes HPD and FAH (Kubo et al., 1998). Cytochrome c was
released from mitochondria prior to liver failure in the double-mutant
mice after administration of HGA. In a cell-free system, the addition of
fumarylacetoacetate induced release of cytochrome c from the
mitochondria. Kubo et al. (1998) also found that caspase inhibitors were
highly effective in preventing the liver failure induced by HGA in the
double-mutant mice. Therefore, fumarylacetoacetate apparently induces
the release of cytochrome c, which in turn triggers activation of the
caspase cascade in hepatocytes of subjects with hereditary tyrosinemia
type I.

Mice homozygous for certain chromosome 7 deletions that include Fah die
perinatally as a result of liver dysfunction and exhibit a complex
syndrome characterized by structural abnormalities and alterations in
gene expression in the liver and kidney. Aponte et al. (2001) showed
that 2 independent, postnatally lethal mutations induced by
N-ethyl-N-nitrosourea were alleles of Fah. One was a missense mutation
in exon 6, and the other a splice mutation causing loss of exon 7, with
subsequent frameshift in the resulting mRNA, and a severe reduction of
Fah mRNA levels. Increased levels of the diagnostic metabolite
succinylacetone in the urine of both mutants indicated that these
mutations cause a decrease in Fah enzymatic activity. The mutants were
proposed as mouse models for acute and chronic forms of human
hepatorenal tyrosinemia.

HISTORY

Malpuech et al. (1981) described tyrosinemia in a child with partial
monosomy 4p-. The parents were not consanguineous and were chromosomally
normal.

*FIELD* SA
Berube et al. (1989); Fritzell et al. (1964); Gaull et al. (1968);
Halvorsen and Gjessing (1964); Kang and Gerald (1970); Kvittingen
et al. (1986); Kvittingen et al. (1981); Kvittingen et al. (1986);
Laberge (1969); La Du (1967); Paradis et al. (1990); Pettit et al.
(1985); Scriver et al. (1967); Tuchman et al. (1985); Weinberg et
al. (1976); Whelan and Zannoni (1974)
*FIELD* RF
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C. M.; Carpenter, D. A.; Rinchik, E. M.; Culiat, C. T.; Johnson, D.
K.: Point mutations in the murine fumarylacetoacetate hydrolase gene:
animal models for the human genetic disorder hereditary tyrosinemia
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2. Arranz, J. A.; Pinol, F.; Kozak, L.; Perez-Cerda, C.; Cormand,
B.; Ugarte, M.; Riudor, E.: Splicing mutations, mainly IVS6-1(G-T),
account for 70% of fumarylacetoacetate hydrolase (FAH) gene alterations,
including 7 novel mutations, in a survey of 29 tyrosinemia type I
patients. Hum. Mutat. 20: 180-188, 2002.

3. Berube, D.; Phaneuf, D.; Tanguay, R. M.; Gagne, R.: Assignment
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4. Bliksrud, Y. T.; Brodtkorb, E.; Andresen, P. A.; van den Berg,
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in liver tissue suppressing an inborn splicing defect. J. Molec.
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6. Dehner, L. P.; Snover, D. C.; Sharp, H. L.; Ascher, N.; Nakhleh,
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8. Endo, F.; Kubo, S.; Awata, H.; Kiwaki, K.; Katoh, H.; Kanegae,
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Matsuda, I.: Complete rescue of lethal albino c14o5 mice by null
mutation of 4-hydroxyphenylpyruvate-dioxygenase and induction of apoptosis
of hepatocytes in these mice in vivo retrieval of the tyrosine catabolic
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9. Fisch, R. O.; McCabe, E. R. B.; Doeden, D.; Koep, L. J.; Kohlhoff,
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10. Fritzell, S.; Jagenburg, O. R.; Schnurer, L. B.: Familial cirrhosis
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11. Gagne, R.; Lescault, A.; Grenier, A.; Laberge, C.; Melancon, S.
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13. Gaull, G. E.; Rassin, D. K.; Solomon, G. E.; Harris, R. C.; Sturman,
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16. Gluecksohn-Waelsch, S.: Genetic control of morphogenetic and
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18. Grompe, M.; St-Louis, M.; Demers, S. I.; Al-Dhalimy, M.; Leclerc,
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19. Hahn, S. H.; Krasnewich, D.; Brantly, M.; Kvittingen, E. A.; Gahl,
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29. Kvittingen, E. A.; Borresen, A. L.; Stokke, O.; van der Hagen,
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tyrosinemia. Clin. Genet. 27: 550-554, 1985.

30. Kvittingen, E. A.; Guibaud, P. P.; Divry, P.; Mandon, G.; Rolland,
M. O.; Domenichini, Y.; Jakobs, C.; Christensen, E.: Prenatal diagnosis
of hereditary tyrosinaemia type I by determination of fumarylacetoacetase
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1986.

31. Kvittingen, E. A.; Halvorsen, S.; Jellum, E.: Deficient fumarylacetoacetate
fumarylhydrolase activity in lymphocytes and fibroblasts from patients
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32. Kvittingen, E. A.; Jellum, E.; Stokke, O.: Assay of fumarylacetoacetate
fumarylhydrolase in human liver: deficient activity in a case of hereditary
tyrosinemia. Clin. Chim. Acta 115: 311-319, 1981.

33. Kvittingen, E. A.; Jellum, E.; Stokke, O.; Flatmark, A.; Bergan,
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in a 23-year-old tyrosinaemia patient: effects on the renal tubular
dysfunction. J. Inherit. Metab. Dis. 9: 216-224, 1986.

34. Kvittingen, E. A.; Rootwelt, H.; Berger, R.; Brandtzaeg, P.:
Self-induced correction of the genetic defect in tyrosinemia type
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35. Kvittingen, E. A.; Rootwelt, H.; Brandtzaeg, P.; Bergan, A.; Berger,
R.: Hereditary tyrosinemia type I: self-induced correction of the
fumarylacetoacetase defect. J. Clin. Invest. 91: 1816-1821, 1993.

36. Kvittingen, E. A.; Rootwelt, H.; van Dam, T.; van Faassen, H.;
Berger, R.: Hereditary tyrosinemia type I: lack of correlation between
clinical findings and amount of immunoreactive fumarylacetoacetase
protein. Pediat. Res. 31: 43-46, 1992.

37. Laberge, C.: Hereditary tyrosinemia in a French-Canadian isolate. Am.
J. Hum. Genet. 21: 36-45, 1969.

38. Laberge, C.; Grenier, A.; Valet, J. P.; Morissette, J.: Fumarylacetoacetase
measurement as a mass-screening procedure for hereditary tyrosinemia
type I. Am. J. Hum. Genet. 47: 325-328, 1990.

39. La Du, B. N.: The enzymatic deficiency in tyrosinemia. Am. J.
Dis. Child. 113: 54-57, 1967.

40. La Du, B. N.; Gjessing, L. R.: Tyrosinosis and tyrosinemia.In:
Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S.: The Metabolic
Basis of Inherited Disease. New York: McGraw-Hill (pub.) (3rd
ed.): 1972. Pp. 256-267.

41. Laine, J.; Salo, M. K.; Krogerus, L.; Karkkainen, J.; Wahlroos,
O.; Holmberg, C.: The nephropathy of type I tyrosinemia after liver
transplantation. Pediat. Res. 37: 640-645, 1995.

42. Lelong, M.; Alagille, D.; Gentil, C. I.; Colin, J.; Le Tan, V.;
Gabilan, J. C.: Cirrhose congenitale et familiale avec diabete phospho-gluco-amine,
rachitisme vitamin D-resistant et tyrosinurie massive. Rev. Franc.
Etud. Clin. Biol. 8: 37-50, 1963.

43. Lindblad, B.; Fallstrom, S. P.; Hoyer, S.; Nordborg, C.; Solymar,
L.; Velander, H.: Cardiomyopathy in fumarylacetoacetase deficiency
(hereditary tyrosinaemia): a new feature of the disease. J. Inherit.
Metab. Dis. 10 (suppl. 2): 319-322, 1987.

44. Lindblad, B.; Lindstedt, S.; Steen, G.: On the enzymic defects
in hereditary tyrosinemia. Proc. Nat. Acad. Sci. 74: 4641-4645,
1977.

45. Lindstedt, S.; Holme, E.; Lock, E. A.; Hjalmarson, O.; Strandvik,
B.: Treatment of hereditary tyrosinaemia type I by inhibition of
4-hydroxyphenylpyruvate dioxygenase. Lancet 340: 813-817, 1992.

46. Malpuech, G.; Mattei, J. F.; Gaulme, J.; Palcoux, J. B.; Lesec,
G.; Vanlieferinghen, P.: Association, chez le meme sujet, d'une deletion
du bras court du chromosome 4 (4p-) et d'un deficit complet en parahydroxyphenylpyruvate
oxydase hepatique (tyrosinose). J. Genet. Hum. 29: 455-461, 1981.

47. Mitchell, G.; Larochelle, J.; Lambert, M.; Michaud, J.; Grenier,
A.; Ogier, H.; Gautheir, M.; Lacroix, J.; Vanasse, M.; Larbrisseau,
A.; Paradis, K.; Weber, A.; Lefevre, Y.; Melancon, S.; Dallaire, L.
: Neurologic crises in hereditary tyrosinemia. New Eng. J. Med. 322:
432-437, 1990.

48. Overturf, K.; Al-Dhalimy, M.; Ou, C. N.; Finegold, M.; Tanguay,
R.; Lieber, A.; Kay, M.; Grompe, M.: Adenovirus-mediated gene therapy
in a mouse model of hereditary tyrosinemia type I. Hum. Gene Therapy 8:
513-521, 1997.

49. Overturf, K.; Al-Dhalimy, M.; Tanguay, R.; Brantly, M.; Ou, C.-N.;
Finegold, M.; Grompe, M.: Hepatocytes corrected by gene therapy are
selected in vivo in a murine model of hereditary tyrosinaemia type
I. Nature Genet. 12: 266-273, 1996. Note: Erratum: Nature Genet.
12: 458 only, 1996.

50. Paradis, K.; Weber, A.; Seidman, E. G.; Larochelle, J.; Garel,
L.; Lenaerts, C.; Roy, C. C.: Liver transplantation for hereditary
tyrosinemia: the Quebec experience. Am. J. Hum. Genet. 47: 338-342,
1990.

51. Perry, T. L.; Hardwick, D. F.; Dixon, G. H.; Dolman, C. L.; Hansen,
S.: Hypermethioninemia: a metabolic disorder associated with cirrhosis,
islet cell hyperplasia, and renal tubular degeneration. Pediatrics 36:
236-250, 1965.

52. Pettit, B. R.; Kvittingen, E. A.; Leonard, J. V.: Early prenatal
diagnosis of hereditary tyrosinaemia. (Letter) Lancet 325: 1038
only, 1985. Note: Originally Volume I.

53. Prieto-Alamo, M. J.; Laval, F.: Deficient DNA-ligase activity
in the metabolic disease tyrosinemia type I. Proc. Nat. Acad. Sci. 95:
12614-12618, 1998.

54. Rootwelt, H.; Brodtkorb, E.; Kvittingen, E. A.: Identification
of a frequent pseudodeficiency mutation in the fumarylacetoacetase
gene, with implications for diagnosis of tyrosinemia type I. Am.
J. Hum. Genet. 55: 1122-1127, 1994.

55. Rootwelt, H.; Hoie, K.; Berger, R.; Kvittingen, E. A.: Fumarylacetoacetase
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56. Russo, P.; O'Regan, S.: Visceral pathology of hereditary tyrosinemia
type I. Am. J. Hum. Genet. 47: 317-324, 1990.

57. Scriver, C. R.: Personal Communication. Montreal, Quebec, Canada
2/15/1982.

58. Scriver, C. R.; Larochelle, J.; Silverberg, M.: Hereditary tyrosinemia
and tyrosyluria in a French-Canadian geographic isolate. Am. J. Dis.
Child. 113: 41-46, 1967.

59. Scriver, C. R.; Partington, M. W.; Sass-Kortsak, A.: Conference
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60. Sokal, E. M.; Bustos, R.; Van Hoof, F.; Otte, J. B.: Liver transplantation
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Mutat. 9: 291-299, 1997.

62. Tanguay, R. M.; Phaneuf, D.; Labelle, Y.; Demers, S.: Molecular
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63. Tanguay, R. M.; Valet, J. P.; Lescault, A.; Duband, J. L.; Laberge,
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hydrolase deficiency in the two clinical forms of hereditary tyrosinemia
(type I). Am. J. Hum. Genet. 47: 308-316, 1990.

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65. Tuchman, M.; Freese, D. K.; Sharp, H. L.; Whitley, C. B.; Ramnaraine,
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1963.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Failure to thrive

CARDIOVASCULAR:
[Heart];
Hypertrophic cardiomyopathy

ABDOMEN:
[External features];
Ascites;
[Liver];
Hepatomegaly;
Acute liver failure;
Cirrhosis;
[Pancreas];
Pancreatic islet-cell hypertrophy;
[Spleen];
Splenomegaly;
[Gastrointestinal];
GI bleeding;
Paralytic ileus

GENITOURINARY:
[Kidneys];
Renal Fanconi syndrome;
Renal failure;
Glomerulosclerosis;
Nephromegaly;
Nephrocalcinosis

SKELETAL:
Rickets

MUSCLE, SOFT TISSUE:
Chronic weakness

NEUROLOGIC:
[Central nervous system];
Episodic paralysis;
[Peripheral nervous system];
Episodic peripheral neuropathy

METABOLIC FEATURES:
Renal Fanconi syndrome;
Hypophosphatemic rickets

HEMATOLOGY:
Abnormal blood coagulation studies (prolonged PT and PTT)

NEOPLASIA:
Hepatocellular carcinoma

LABORATORY ABNORMALITIES:
Fumarylacetoacetate hydrolase (FAH) deficiency;
Deficient hepatic 4-hydroxyphenylpyruvate dioxygenase;
Tyrosinemia;
Methioninemia;
Elevated plasma and urine succinylacetone;
Elevated hepatic transaminases;
Elevated alpha-fetoprotein;
Hypophosphatemia;
Hypoglycemia;
Elevated urinary delta-aminolevulinic acid

MISCELLANEOUS:
High incidence in Saguenay-Lac St. Jean region of the province of
Quebec, Canada and northern Europe;
Unusual cabbage-like odor;
Symptoms highly variable - rapidly progressive course leading to hepatic
failure versus acute hepatic crisis

MOLECULAR BASIS:
Caused by mutation in the fumarylacetoacetase gene (FAH, 613871.0001)

*FIELD* CN
Kelly A. Przylepa - revised: 2/19/2002

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

*FIELD* ED
joanna: 07/02/2013
joanna: 4/7/2011
alopez: 4/7/2011
joanna: 2/20/2002
joanna: 2/19/2002

*FIELD* CN
Victor A. McKusick - updated: 10/12/2005
Victor A. McKusick - updated: 9/24/2002
George E. Tiller - updated: 1/22/2002
Victor A. McKusick - updated: 2/26/2001
Ada Hamosh - updated: 2/6/2001
Victor A. McKusick - updated: 6/7/1999
Victor A. McKusick - updated: 11/2/1998
Victor A. McKusick - updated: 10/14/1998
Victor A. McKusick - updated: 9/29/1998
Victor A. McKusick - updated: 6/23/1997

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

*FIELD* ED
carol: 09/17/2013
terry: 6/8/2012
terry: 10/26/2011
alopez: 4/7/2011
terry: 3/25/2009
terry: 10/12/2005
terry: 4/21/2005
carol: 3/17/2004
cwells: 9/24/2002
cwells: 2/13/2002
cwells: 1/22/2002
mcapotos: 3/2/2001
terry: 2/26/2001
mcapotos: 2/12/2001
mcapotos: 2/8/2001
terry: 2/6/2001
mgross: 6/17/1999
terry: 6/7/1999
carol: 11/9/1998
terry: 11/2/1998
carol: 10/20/1998
terry: 10/14/1998
dkim: 10/12/1998
carol: 9/30/1998
terry: 9/29/1998
terry: 6/3/1998
terry: 7/10/1997
terry: 6/23/1997
terry: 6/20/1997
terry: 7/2/1996
terry: 6/27/1996
terry: 6/11/1996
terry: 6/7/1996
mark: 6/7/1996
terry: 5/30/1996
mark: 2/29/1996
terry: 2/26/1996
mark: 8/2/1995
carol: 1/4/1995
terry: 11/9/1994
davew: 7/28/1994
warfield: 4/20/1994
mimadm: 4/14/1994

MIM 613871
*RECORD*
*FIELD* NO
613871
*FIELD* TI
*613871 FUMARYLACETOACETATE HYDROLASE; FAH
;;FUMARYLACETOACETASE
*FIELD* TX

DESCRIPTION
read more
The enzyme fumarylacetoacetate hydrolase (FAH; EC 3.7.1.2) is the last
enzyme in the catabolic pathway of tyrosine (summary by Tanguay et al.,
1990).

CLONING

Phaneuf et al. (1991) isolated human FAH cDNA clones by screening a
liver cDNA expression library using specific antibodies and plaque
hybridization with a rat FAH cDNA probe. From transient expression in
transfected mammalian cells, a single polypeptide chain encoded by the
FAH gene appeared to contain all the genetic information required for
functional activity, indicating that the dimer found in vivo is a
homodimer.

Grompe et al. (1993) stated that Fah is predominantly expressed in liver
and kidney in mice.

MAPPING

By in situ hybridization, Berube et al. (1989) assigned the FAH gene to
chromosome 15q23-q25. Using in situ hybridization, Tanguay et al. (1990)
confirmed the assignment to chromosome 15 by analysis of rodent-human
hybrid cells.

By study of somatic cell hybrids and by in situ hybridization using the
FAH cDNA, Phaneuf et al. (1991) demonstrated that the gene maps to
chromosome 15q23-q25.

GENE FUNCTION

Jorquera and Tanguay (2001) reported that a subapoptogenic dose of
fumarylacetoacetate, the mutagenic metabolite accumulating in hereditary
type I tyrosinemia, induced spindle disturbances and segregational
defects in both rodent and human cells. A sustained activation of the
extracellular signal-regulated protein kinase (ERK; see MAPK1, 176948)
was also observed. Primary skin fibroblasts derived from type I
tyrosinemia patients not exogenously treated with fumarylacetoacetate
showed similar mitotic-derived alterations and ERK activation.
Replenishment of intracellular glutathione (GSH) with GSH monoethylester
abolished ERK activation and reduced the chromosomal instability induced
by fumarylacetoacetate by 80%. The authors speculated that this
tumorigenic-related phenomenon may rely on the biochemical/cellular
effects of fumarylacetoacetate as a thiol-reacting and organelle/mitotic
spindle-disturbing agent.

MOLECULAR GENETICS

Tanguay et al. (1990) analyzed the FAH in livers of unrelated patients
using mRNA levels, immunoreactive protein, and enzyme activity. The
results suggest molecular heterogeneity of mutations causing
tyrosinemia. They demonstrated a missense mutation in the FAH gene in
cDNA from 1 patient with normal FAH mRNA but without immunoreactive
protein or enzymatic activity.

For a complete discussion of the molecular genetics of tyrosinemia type
I, see 276700.

ANIMAL MODEL

Grompe et al. (1993) found that Fah -/- mice exhibited a phenotype
significantly different from that of humans with null mutations in FAH.
Fah -/- mice appeared normal at birth, but they rapidly developed
hypoglycemia and liver dysfunction and died within 12 hours of birth.
Fah -/- mice were not tyrosinemic. Electron microscopy revealed
disruption of the endoplasmic reticulum in liver of Fah -/- mice.

Wuestefeld et al. (2013) noted that lethality in Fah -/- mice can be
prevented by continuous treatment with the drug nitisinone (NTBC). Using
short hairpin RNA screening, they found that stable knockdown of Mkk4
(601335) countered lethality in Fah -/- mice following NTBC withdrawal.
Knockdown of Mkk4 robustly increased the regenerative capacity of
hepatocytes and reduced the number of apoptotic hepatocytes in FAH -/-
mice following NTBC withdrawal, as well as in mouse models of acute and
chronic liver failure.

*FIELD* AV
.0001
TYROSINEMIA, TYPE I
FAH, ASN16ILE

In a French-Canadian patient with type I hereditary tyrosinemia
(276700), Phaneuf et al. (1992) demonstrated compound heterozygosity for
an FAH allele that appeared not to be expressed in the liver of the
proband and a second allele which carried an A-to-T transversion which
substituted isoleucine for asparagine-16 (N16I). These findings
demonstrated that there are at least 2 different tyrosinemia mutations
in the French-Canadian population.

.0002
TYROSINEMIA, TYPE I
FAH, ALA134ASP

In a patient with type I hereditary tyrosinemia (276700) and very low
FAH enzymatic activity in the liver, Labelle et al. (1993) found
heterozygosity for an ala134-to-asp (A134D) mutation in the FAH gene.
The nature of the other allele was not identified.

.0003
TYROSINEMIA, TYPE I
FAH, IVS12, G-A, +5

In a patient from eastern Quebec with tyrosinemia type I (276700),
Grompe and Al-Dhalimy (1993) demonstrated homozygosity for a splice
mutation consisting of a guanine-to-adenine alteration in the donor
consensus sequence of intron 12 (IVS12,G-A,+5) of the FAH gene. Two
other mutations, glu357-to-ter (E357X) and glu364-to-ter (E364X), were
identified. Grompe et al. (1994) designed allele-specific
oligonucleotide tests to detect the 3 mutations and used them to
demonstrate that all patients with tyrosinemia type I in eastern Quebec
carried the splice-donor site mutation, most of them in homozygous
state. St-Louis et al. (1995) found the same mutation in a compound
heterozygote Norwegian patient. The fact that this is the predominant
mutation in French-Canadian cases (having a frequency of 77.6% among
Quebec patients with tyrosinemia type I) may indicate its ancient
origin. The other mutation in the Norwegian patient was G337S
(613871.0007).

The 2 extremes of the clinical phenotype of tyrosinemia type I are the
'acute' (a severe disorder with early onset and death), and 'chronic'
(showing delayed onset and slow course) forms. Allelic heterogeneity
and/or mutation reversion in hepatic cells had been proposed to explain
the clinical heterogeneity. Poudrier et al. (1998) studied 2 probands
from the French-Canadian isolate where type I tyrosinemia is prevalent,
one with the acute and the other with the chronic form. Both were found
to be germline homozygotes for the IVS12,G-A,+5 splice site mutation.
Both showed liver mosaicism for FAH immunoreactivity with evidence for
mutation reversion to heterozygosity in FAH-stained nodules as shown by
amplification of DNA extracted from microdissected nodules. Western blot
analysis of proteins from a reverted FAH-expressing nodule showed 29 +/-
3% FAH immunoreactive material as compared to an average normal liver.
This was consistent with the measured FAH hydrolytic activity (25%) in
this large regenerating nodule. These findings showed that genotypic
heterogeneity is not a sufficient explanation for clinical heterogeneity
and implicated epigenetic and other factors modifying the phenotype in
this disorder.

.0004
TYROSINEMIA, TYPE I
FAH, GLU357TER

Grompe and Al-Dhalimy (1993) found that a patient with tyrosinemia type
I (276700) was a compound heterozygote for 2 different nonsense
mutations in the FAH gene that changed the codon for glutamic acid at
positions 357 and 364 of the enzyme to a stop codon (E357X, E364X). One
parent was from Quebec and the other from England.

.0005
TYROSINEMIA, TYPE I
FAH, GLU364TER

See 613871.0004 and Grompe and Al-Dhalimy (1993).

.0006
FUMARYLACETOACETASE PSEUDODEFICIENCY
FAH, ARG341TRP

Rootwelt et al. (1994) found fumarylacetoacetase pseudodeficiency (see
276700) due to a C-to-T transition in nucleotide 1021 leading to an
arg341-to-trp (R341W) amino acid substitution in 2.2% of FAH alleles
among 516 healthy Norwegian volunteers.

.0007
TYROSINEMIA, TYPE I
FAH, GLU337SER

St-Louis et al. (1995) found that a Norwegian patient with hepatorenal
tyrosinemia (276700) was a compound heterozygote for the IVS12+5G-A
mutation (613871.0003), the most frequent mutation in French-Canadian
cases, and a new mutation resulting in substitution of serine for
glycine-337 (E337S).

.0008
TYROSINEMIA, TYPE I
FAH, ARG381GLY

In a French-Canadian case of hereditary tyrosinemia type I (276700),
St-Louis et al. (1995) found an arg381-to-gly (R381G) mutation in the
FAH gene inherited from the father. The other mutation in this compound
heterozygote was E357X (613871.0004), inherited from the mother.

.0009
TYROSINEMIA, TYPE I
FAH, TRP262TER

St-Louis et al. (1994) reported a stop mutation in the FAH gene (W262X)
in 5 Finnish hereditary tyrosinemia type I (276700) patients. This
mutation seemed to predominate in the Finnish population, where it
accounted for 95% of the alleles (19/20) in 10 affected patients tested
(St-Louis et al. (1996)), and had not been found in any other
population. The remaining allele carried the IVS12+5G-A splice mutation
(613871.0003) that is predominant in the French-Canadian population but
is also seen in patients of other origins. St-Louis et al. (1996)
described a simple test for the 'Finnish' mutation.

.0010
TYROSINEMIA, TYPE I
FAH, IVS6, G-T, -1

In a study of 62 tyrosinemia type I (276700) patients of various ethnic
origins, Rootwelt et al. (1996) found that the second most frequent FAH
mutation was a G-to-T transversion in the last nucleotide of exon 6.
Encountered in 14 alleles, the mutation was common in Central and
Western Europe.

.0011
TYROSINEMIA, TYPE I
FAH, GLN279ARG

In a 37-year-old woman with type I tyrosinemia (276700) whose liver
disease in infancy and rickets during childhood resolved with dietary
therapy, Kim et al. (2000) reported an A-to-G transition in exon 9 of
the FAH gene, resulting in a glu279-to-arg (Q279R) substitution, in
compound heterozygosity with the IVS6-1G-T mutation (613871.0010). From
14 years of age the patient resumed an unrestricted diet with the
continued presence of the biochemical features of tyrosinemia, yet
maintained normal liver function. In adulthood she accumulated only
small amounts of succinylacetone. Despite this evolution to a mild
biochemical and clinical phenotype, she eventually developed
hepatocellular carcinoma.

*FIELD* RF
1. Berube, D.; Phaneuf, D.; Tanguay, R. M.; Gagne, R.: Assignment
of the fumarylacetoacetate hydrolase gene to chromosome 15q23-15q25.
(Abstract) Cytogenet. Cell Genet. 51: 962 only, 1989.

2. Grompe, M.; Al-Dhalimy, M.: Mutations of the fumarylacetoacetate
hydrolase gene in four patients with tyrosinemia, type I. Hum. Mutat. 2:
85-93, 1993.

3. Grompe, M.; Al-Dhalimy, M.; Finegold, M.; Ou, C.-N.; Burlingame,
T.; Kennaway, N. G.; Soriano, P.: Loss of fumarylacetoacetate hydrolase
is responsible for the neonatal hepatic dysfunction phenotype of lethal
albino mice. Genes Dev. 7: 2298-2307, 1993.

4. Grompe, M.; St-Louis, M.; Demers, S. I.; Al-Dhalimy, M.; Leclerc,
B.; Tanguay, R. M.: A single mutation of the fumarylacetoacetate
hydrolase gene in French Canadians with hereditary tyrosinemia type
I. New. Eng. J. Med. 331: 353-357, 1994.

5. Jorquera, R.; Tanguay, R. M.: Fumarylacetoacetate, the metabolite
accumulating in hereditary tyrosinemia, activates the ERK pathway
and induces mitotic abnormalities and genomic instability. Hum. Molec.
Genet. 10: 1741-1752, 2001.

6. Kim, S. Z.; Kupke, K. G.; Ierardi-Curto, L.; Holme, E.; Greter,
J.; Tanguay, R. M.; Poudrier, J.; D'Astous, M.; Lettre, F.; Hahn,
S. H.; Levy, H. L.: Hepatocellular carcinoma despite long-term survival
in chronic tyrosinaemia I. J. Inherit. Metab. Dis. 23: 791-804,
2000.

7. Labelle, Y.; Phaneuf, D.; Leclerc, B.; Tanguay, R. M.: Characterization
of the human fumarylacetoacetate hydrolase gene and identification
of a missense mutation abolishing enzymatic activity. Hum. Molec.
Genet. 2: 941-946, 1993.

8. Phaneuf, D.; Labelle, Y.; Berube, D.; Arden, K.; Cavenee, W.; Gagne,
R.; Tanguay, R. M.: Cloning and expression of the cDNA encoding human
fumarylacetoacetate hydrolase, the enzyme deficient in hereditary
tyrosinemia: assignment of the gene to chromosome 15. Am. J. Hum.
Genet. 48: 525-535, 1991.

9. Phaneuf, D.; Lambert, M.; Laframboise, R.; Mitchell, G.; Lettre,
F.; Tanguay, R. M.: Type 1 hereditary tyrosinemia: evidence for molecular
heterogeneity and identification of a causal mutation in a French
Canadian patient. J. Clin. Invest. 90: 1185-1192, 1992.

10. Poudrier, J.; Lettre, F.; Scriver, C. R.; Larochelle, J.; Tanguay,
R. M.: Different clinical forms of hereditary tyrosinemia (type I)
in patients with identical genotypes. Molec. Genet. Metab. 64: 119-125,
1998.

11. Rootwelt, H.; Brodtkorb, E.; Kvittingen, E. A.: Identification
of a frequent pseudodeficiency mutation in the fumarylacetoacetase
gene, with implications for diagnosis of tyrosinemia type I. Am.
J. Hum. Genet. 55: 1122-1127, 1994.

12. Rootwelt, H.; Hoie, K.; Berger, R.; Kvittingen, E. A.: Fumarylacetoacetase
mutations in tyrosinaemia type I. Hum. Mutat. 7: 239-243, 1996.

13. St-Louis, M.; Leclerc, B.; Laine, J.; Salo, M. K.; Holmberg, C.;
Tanguay, R. M.: Identification of a stop mutation in five Finnish
patients suffering from hereditary tyrosinemia type I. Hum. Molec.
Genet. 3: 69-72, 1994.

14. St-Louis, M.; Poudrier, J.; Phaneuf, D.; Leclerc, B.; Laframboise,
R.; Tanguay, R. M.: Two novel mutations involved in hereditary tyrosinemia
type I. Hum. Molec. Genet. 4: 319-320, 1995.

15. St-Louis, M.; Poudrier, J.; Tanguay, R. M.: Simple Detection
of a (Finnish) hereditary tyrosinemia type 1 mutation. (Letter) Hum.
Mutat. 7: 379-380, 1996.

16. Tanguay, R. M.; Phaneuf, D.; Labelle, Y.; Demers, S.: Molecular
cloning and expression of the c-DNA encoding the enzyme deficient
in hereditary tyrosinemia: evidence for molecular heterogeneity. (Abstract) Am.
J. Hum. Genet. 47 (suppl.): A168 only, 1990.

17. Wuestefeld, T.; Pesic, M.; Rudalska, R.; Dauch, D.; Longerich,
T.; Kang, T.-W.; Yevsa, T.; Heinzmann, F.; Hoenicke, L.; Hohmeyer,
A.; Potapova, A.; Rittelmeier, I.; and 11 others: A direct in vivo
RNAi screen identifies MKK4 as a key regulator of liver regeneration. Cell 153:
389-401, 2013.

*FIELD* CN
Patricia A. Hartz - updated: 06/06/2013

*FIELD* CD
Anne M. Stumpf: 4/6/2011

*FIELD* ED
mgross: 06/06/2013
terry: 5/11/2011
alopez: 4/7/2011