RBCC Red Blood Cell Collection

FH [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Fumarate hydratase, mitochondrial; Fumarase; 4.2.1.2; Flags: Precursor
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00296053
IPI00296053 Fumarate hydratase, mitochondrial precursor Tricarboxylic acid cycle soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic and mitochondrial n/a expected molecular weight found in band found in band around 80 kdDa

UniProt P07954
ID FUMH_HUMAN Reviewed; 510 AA.
AC P07954;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 3.
DT 22-JAN-2014, entry version 167.
DE RecName: Full=Fumarate hydratase, mitochondrial;
DE Short=Fumarase;
DE EC=4.2.1.2;
DE Flags: Precursor;
GN Name=FH;
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].
RC TISSUE=Brain;
RA Gellera C., Baratta S., Cavadini P., Invernizzi F., Lamantea E.,
RA Didonato S., Taroni F.;
RL Submitted (MAY-1996) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Bourgeron T., Parfait B., Chretien D., Rotig A., Munnich A.,
RA Rustin P.;
RT "Complete cDNA sequence of the human fumarase.";
RL Submitted (FEB-1996) to the EMBL/GenBank/DDBJ databases.
RN [3]
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 (AUG-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and Uterus;
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 [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 44-510.
RC TISSUE=Liver;
RX PubMed=3828494; DOI=10.1007/BF01116247;
RA Kinsella B.T., Doonan S.;
RT "Nucleotide sequence of a cDNA coding for mitochondrial fumarase from
RT human liver.";
RL Biosci. Rep. 6:921-929(1986).
RN [6]
RP PROTEIN SEQUENCE OF 269-286 AND 422-444, AND MASS SPECTROMETRY.
RC TISSUE=Brain, and Cajal-Retzius cell;
RA Lubec G., Afjehi-Sadat L.;
RL Submitted (MAR-2007) to UniProtKB.
RN [7]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-66; LYS-80; LYS-94; LYS-256
RP AND LYS-292, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [8]
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 [9]
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=22509282; DOI=10.1371/journal.pone.0034237;
RA von Lohneysen K., Scott T.M., Soldau K., Xu X., Friedman J.S.;
RT "Assessment of the red cell proteome of young patients with
RT unexplained hemolytic anemia by two-dimensional differential in-gel
RT electrophoresis (DIGE).";
RL PLoS ONE 7:E34237-E34237(2012).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [11]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 44-510, AND SUBUNIT.
RG Structural genomics consortium (SGC);
RT "Crystal structure of human fumarate hydratase.";
RL Submitted (DEC-2012) to the PDB data bank.
RN [12]
RP VARIANT FHD THR-308.
RA Coughlin E.M., Chalmers R.A., Slaugenhaupt S.A., Gusella J.F.,
RA Shih V.E., Ramesh V.;
RT "Identification of a molecular defect in a fumarase deficient patient
RT and mapping of the fumarase gene.";
RL Am. J. Hum. Genet. 53:A896-A896(1993).
RN [13]
RP VARIANTS FHD ARG-230; THR-308; CYS-312 AND VAL-425.
RX PubMed=9635293; DOI=10.1006/mgme.1998.2684;
RA Coughlin E.M., Christensen E., Kunz P.L., Krishnamoorthy K.S.,
RA Walker V., Dennis N.R., Chalmers R.A., Elpeleg O.N., Whelan D.,
RA Pollitt R.J., Ramesh V., Mandell R., Shih V.E.;
RT "Molecular analysis and prenatal diagnosis of human fumarase
RT deficiency.";
RL Mol. Genet. Metab. 63:254-262(1998).
RN [14]
RP VARIANTS HLRCC THR-107; PRO-117; ARG-180; ARG-185; ARG-230; HIS-233;
RP VAL-282 AND ARG-328.
RX PubMed=11865300; DOI=10.1038/ng849;
RA Tomlinson I.P.M., Alam N.A., Rowan A.J., Barclay E., Jaeger E.E.M.,
RA Kelsell D., Leigh I., Gorman P., Lamlum H., Rahman S., Roylance R.R.,
RA Olpin S., Bevan S., Barker K., Hearle N., Houlston R.S., Kiuru M.,
RA Lehtonen R., Karhu A., Vilkki S., Laiho P., Eklund C., Vierimaa O.,
RA Aittomaeki K., Hietala M., Sistonen P., Paetau A., Salovaara R.,
RA Herva R., Launonen V., Aaltonen L.A.;
RT "Germline mutations in FH predispose to dominantly inherited uterine
RT fibroids, skin leiomyomata and papillary renal cell cancer.";
RL Nat. Genet. 30:406-410(2002).
CC -!- FUNCTION: Also acts as a tumor suppressor.
CC -!- CATALYTIC ACTIVITY: (S)-malate = fumarate + H(2)O.
CC -!- PATHWAY: Carbohydrate metabolism; tricarboxylic acid cycle; (S)-
CC malate from fumarate: step 1/1.
CC -!- SUBUNIT: Homotetramer.
CC -!- SUBCELLULAR LOCATION: Isoform Mitochondrial: Mitochondrion.
CC -!- SUBCELLULAR LOCATION: Isoform Cytoplasmic: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative initiation; Named isoforms=2;
CC Name=Mitochondrial;
CC IsoId=P07954-1; Sequence=Displayed;
CC Name=Cytoplasmic;
CC IsoId=P07954-2; Sequence=VSP_018965;
CC Note=Initiator Met-1 is removed. Contains a N-acetylalanine at
CC position 2 (By similarity);
CC -!- TISSUE SPECIFICITY: Expressed in red blood cells; underexpressed
CC in red blood cells (cytoplasm) of patients with hereditary non-
CC spherocytic hemolytic anemia of unknown etiology.
CC -!- DISEASE: Fumarase deficiency (FHD) [MIM:606812]: Characterized by
CC progressive encephalopathy, developmental delay, hypotonia,
CC cerebral atrophy and lactic and pyruvic acidemia. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- DISEASE: Hereditary leiomyomatosis and renal cell cancer (HLRCC)
CC [MIM:150800]: A disorder characterized by predisposition to
CC cutaneous and uterine leiomyomas, and papillary type 2 renal
CC cancer which occurs in about 20% of patients. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: There are 2 substrate binding sites: the catalytic
CC A site, and the non-catalytic B site that may play a role in the
CC transfer of substrate or product between the active site and the
CC solvent. Alternatively, the B site may bind allosteric effectors
CC (By similarity).
CC -!- SIMILARITY: Belongs to the class-II fumarase/aspartase family.
CC Fumarase subfamily.
CC -!- WEB RESOURCE: Name=TCA Cycle Gene Mutation Database;
CC URL="http://chromium.liacs.nl/LOVD2/SDH/home.php?select_db=FH";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/FHID40573ch1q42.html";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/FH";
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DR EMBL; U59309; AAB66354.1; -; mRNA.
DR EMBL; U48857; AAD00071.1; -; mRNA.
DR EMBL; BT009839; AAP88841.1; -; mRNA.
DR EMBL; BC003108; AAH03108.1; -; mRNA.
DR EMBL; BC017444; AAH17444.1; -; mRNA.
DR EMBL; M15502; AAA52483.1; -; mRNA.
DR PIR; S06213; UFHUM.
DR RefSeq; NP_000134.2; NM_000143.3.
DR UniGene; Hs.592490; -.
DR PDB; 3E04; X-ray; 1.95 A; A/B/C/D=44-510.
DR PDBsum; 3E04; -.
DR ProteinModelPortal; P07954; -.
DR SMR; P07954; 49-510.
DR IntAct; P07954; 6.
DR MINT; MINT-5005927; -.
DR STRING; 9606.ENSP00000355518; -.
DR PhosphoSite; P07954; -.
DR DMDM; 1730117; -.
DR REPRODUCTION-2DPAGE; IPI00296053; -.
DR SWISS-2DPAGE; P07954; -.
DR UCD-2DPAGE; P07954; -.
DR PaxDb; P07954; -.
DR PRIDE; P07954; -.
DR DNASU; 2271; -.
DR Ensembl; ENST00000366560; ENSP00000355518; ENSG00000091483.
DR GeneID; 2271; -.
DR KEGG; hsa:2271; -.
DR UCSC; uc001hyx.3; human.
DR CTD; 2271; -.
DR GeneCards; GC01M241660; -.
DR HGNC; HGNC:3700; FH.
DR HPA; CAB017785; -.
DR HPA; HPA025770; -.
DR HPA; HPA025948; -.
DR HPA; HPA027341; -.
DR MIM; 136850; gene.
DR MIM; 150800; phenotype.
DR MIM; 606812; phenotype.
DR neXtProt; NX_P07954; -.
DR Orphanet; 523; Familial leiomyomatosis.
DR Orphanet; 24; Fumaric aciduria.
DR PharmGKB; PA28139; -.
DR eggNOG; COG0114; -.
DR HOGENOM; HOG000061736; -.
DR HOVERGEN; HBG002183; -.
DR InParanoid; P07954; -.
DR KO; K01679; -.
DR OMA; RIEKDTM; -.
DR OrthoDB; EOG75J0MX; -.
DR PhylomeDB; P07954; -.
DR BioCyc; MetaCyc:ENSG00000091483-MONOMER; -.
DR BRENDA; 4.2.1.2; 2681.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00223; UER01007.
DR EvolutionaryTrace; P07954; -.
DR GenomeRNAi; 2271; -.
DR NextBio; 9235; -.
DR PRO; PR:P07954; -.
DR ArrayExpress; P07954; -.
DR Bgee; P07954; -.
DR CleanEx; HS_FH; -.
DR Genevestigator; P07954; -.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0045239; C:tricarboxylic acid cycle enzyme complex; IEA:InterPro.
DR GO; GO:0004333; F:fumarate hydratase activity; EXP:Reactome.
DR GO; GO:0006106; P:fumarate metabolic process; TAS:ProtInc.
DR GO; GO:0048873; P:homeostasis of number of cells within a tissue; IEA:Ensembl.
DR GO; GO:0006099; P:tricarboxylic acid cycle; TAS:Reactome.
DR Gene3D; 1.10.275.10; -; 1.
DR InterPro; IPR005677; Fum_hydII.
DR InterPro; IPR024083; Fumarase/histidase_N.
DR InterPro; IPR018951; Fumarase_C_C.
DR InterPro; IPR020557; Fumarate_lyase_CS.
DR InterPro; IPR000362; Fumarate_lyase_fam.
DR InterPro; IPR022761; Fumarate_lyase_N.
DR InterPro; IPR008948; L-Aspartase-like.
DR PANTHER; PTHR11444; PTHR11444; 1.
DR Pfam; PF10415; FumaraseC_C; 1.
DR Pfam; PF00206; Lyase_1; 1.
DR PRINTS; PR00149; FUMRATELYASE.
DR SUPFAM; SSF48557; SSF48557; 1.
DR TIGRFAMs; TIGR00979; fumC_II; 1.
DR PROSITE; PS00163; FUMARATE_LYASES; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative initiation; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Disease mutation; Lyase;
KW Mitochondrion; Reference proteome; Transit peptide;
KW Tricarboxylic acid cycle; Tumor suppressor.
FT TRANSIT 1 44 Mitochondrion (By similarity).
FT CHAIN 45 510 Fumarate hydratase, mitochondrial.
FT /FTId=PRO_0000010319.
FT REGION 176 179 B site (By similarity).
FT REGION 186 188 Substrate binding (By similarity).
FT BINDING 147 147 Substrate (By similarity).
FT MOD_RES 61 61 N6-acetyllysine (By similarity).
FT MOD_RES 66 66 N6-acetyllysine.
FT MOD_RES 80 80 N6-acetyllysine.
FT MOD_RES 94 94 N6-acetyllysine.
FT MOD_RES 115 115 N6-acetyllysine (By similarity).
FT MOD_RES 122 122 N6-acetyllysine (By similarity).
FT MOD_RES 213 213 N6-acetyllysine (By similarity).
FT MOD_RES 223 223 N6-acetyllysine (By similarity).
FT MOD_RES 256 256 N6-acetyllysine.
FT MOD_RES 292 292 N6-acetyllysine.
FT MOD_RES 502 502 N6-acetyllysine (By similarity).
FT VAR_SEQ 1 43 Missing (in isoform Cytoplasmic).
FT /FTId=VSP_018965.
FT VARIANT 107 107 N -> T (in HLRCC).
FT /FTId=VAR_013497.
FT VARIANT 117 117 A -> P (in HLRCC).
FT /FTId=VAR_013498.
FT VARIANT 180 180 H -> R (in HLRCC).
FT /FTId=VAR_013499.
FT VARIANT 185 185 Q -> R (in HLRCC).
FT /FTId=VAR_013500.
FT VARIANT 230 230 K -> R (in FHD and HLRCC).
FT /FTId=VAR_002445.
FT VARIANT 233 233 R -> H (in HLRCC; dbSNP:rs28933069).
FT /FTId=VAR_013501.
FT VARIANT 282 282 G -> V (in HLRCC).
FT /FTId=VAR_013502.
FT VARIANT 308 308 A -> T (in FHD).
FT /FTId=VAR_002446.
FT VARIANT 312 312 F -> C (in FHD).
FT /FTId=VAR_002447.
FT VARIANT 328 328 M -> R (in HLRCC).
FT /FTId=VAR_013503.
FT VARIANT 425 425 D -> V (in FHD).
FT /FTId=VAR_002448.
FT STRAND 50 55
FT STRAND 58 63
FT HELIX 70 78
FT HELIX 84 86
FT HELIX 90 106
FT HELIX 107 110
FT HELIX 114 128
FT HELIX 133 135
FT STRAND 139 142
FT HELIX 147 164
FT HELIX 177 181
FT TURN 182 184
FT HELIX 187 205
FT HELIX 207 224
FT TURN 225 227
FT STRAND 229 234
FT STRAND 237 243
FT HELIX 244 264
FT TURN 267 269
FT STRAND 270 272
FT TURN 277 279
FT HELIX 289 301
FT HELIX 311 316
FT HELIX 319 345
FT STRAND 349 352
FT HELIX 375 399
FT HELIX 409 433
FT HELIX 435 437
FT HELIX 442 451
FT HELIX 454 459
FT HELIX 460 463
FT HELIX 465 478
FT HELIX 482 488
FT HELIX 494 500
FT HELIX 503 505
SQ SEQUENCE 510 AA; 54637 MW; 86F91F95DC046F64 CRC64;
MYRALRLLAR SRPLVRAPAA ALASAPGLGG AAVPSFWPPN AARMASQNSF RIEYDTFGEL
KVPNDKYYGA QTVRSTMNFK IGGVTERMPT PVIKAFGILK RAAAEVNQDY GLDPKIANAI
MKAADEVAEG KLNDHFPLVV WQTGSGTQTN MNVNEVISNR AIEMLGGELG SKIPVHPNDH
VNKSQSSNDT FPTAMHIAAA IEVHEVLLPG LQKLHDALDA KSKEFAQIIK IGRTHTQDAV
PLTLGQEFSG YVQQVKYAMT RIKAAMPRIY ELAAGGTAVG TGLNTRIGFA EKVAAKVAAL
TGLPFVTAPN KFEALAAHDA LVELSGAMNT TACSLMKIAN DIRFLGSGPR SGLGELILPE
NEPGSSIMPG KVNPTQCEAM TMVAAQVMGN HVAVTVGGSN GHFELNVFKP MMIKNVLHSA
RLLGDASVSF TENCVVGIQA NTERINKLMN ESLMLVTALN PHIGYDKAAK IAKTAHKNGS
TLKETAIELG YLTAEQFDEW VKPKDMLGPK
//

MIM 136850
*RECORD*
*FIELD* NO
136850
*FIELD* TI
*136850 FUMARATE HYDRATASE; FH
;;FUMARASE
FUMARATE HYDRATASE, CYTOSOLIC, INCLUDED; FH1, INCLUDED;;
read moreFUMARATE HYDRATASE, MITOCHONDRIAL, INCLUDED; FH2, INCLUDED
*FIELD* TX

DESCRIPTION

Fumarate hydratase, or fumarase (EC 4.2.1.2), is an enzymatic component
of the tricarboxylic acid, or Krebs, cycle. It catalyzes the conversion
of fumarate to malate.

CLONING

Edwards and Hopkinson (1979) studied a family with an electrophoretic
variant of FH. Two persons had variation in both the soluble and the
mitochondrial forms, suggesting that they are determined by a single
locus. Doonan et al. (1984) cited evidence suggesting that the
isoenzymes of fumarase are translated in precursor form from 2 different
mRNA molecules, these mRNAs in turn arising from alternative splicing of
a single gene transcript.

Using peptide mapping, O'Hare and Doonan (1985) showed that the
cytosolic and mitochondrial fumarases from pig liver are identical over
nearly all of their amino acid sequences, but that they differ at their
N termini.

Kinsella and Doonan (1986) cloned human fumarase from a liver cDNA
library. The deduced 468-amino acid protein, with the exception of an
N-terminal methionine, appeared to be the mitochondrial form. Kinsella
and Doonan (1986) found an unusually high degree of identity of
structure between human fumarase and that from B. subtilis and E. coli.

Suzuki et al. (1989) cloned rat liver fumarase, which encodes a deduced
507-amino acid protein with a 41-amino acid prosequence. Comparison of
mature peptide sequences of mitochondrial and cytosolic fumarases
revealed identity, with the exception that the N-terminal alanine of
cytosolic fumarase was acetylated. Northern blot analysis of rat liver
showed a single mRNA species of about 1.8 kb. Suzuki et al. (1989)
concluded that the mitochondrial and cytosolic forms of fumarase are
encoded by a single transcript and that posttranslational processing
directs its cellular localization.

By immunohistochemical analysis, Bourgeron et al. (1994) found that
fumarase localized to the mitochondrion, but not cytosol, in normal
human brain, consistent with the findings in rat.

MAPPING

Van Someren et al. (1974) and Craig et al. (1976) found that the
fumarase locus is on chromosome 1, possibly in the area 1q42. Despoisses
et al. (1984) narrowed the regional assignment of FH to 1q42.1 by gene
dosage studies in patients with various types of partial trisomy or
partial monosomy of 1q. Coughlin et al. (1993) mapped the FH gene to
chromosome 1 using PCR-amplified cDNA as a probe in Southern blots of
genomic DNA from a series of mouse/human somatic cell hybrids. They
observed related sequences on chromosomes 13 and 5.

GENE FUNCTION

Pollard et al. (2005) stated that the nuclear-encoded Krebs cycle
enzymes fumarate hydratase and succinate dehydrogenases (see, e.g., SDHB
185470) act as tumor suppressors, and germline mutations in these genes
predispose individuals to leiomyomas and renal cancer and to
paragangliomas (see 115310), respectively. Pollard et al. (2005) showed
that FH-deficient cells and tumors accumulated fumarate and, to a lesser
extent, succinate. SDH-deficient tumors principally accumulated
succinate. In situ analysis showed that these tumors also overexpressed
HIF1A (603348), activation of HIF1A targets like VEGF (192240), and high
microvessel density. Pollard et al. (2005) hypothesized that increased
succinate and/or fumarate may stabilize HIF1A, and that the basic
mechanism of tumorigenesis in paragangliomas and leiomyoma and renal
cancer may be pseudohypoxic drive, just as it is in von Hippel-Lindau
syndrome (193300).

Using Fh -/- mouse embryonic fibroblasts and FH-deficient papillary
renal carcinoma tissues, O'Flaherty et al. (2010) showed that deficiency
in cytosolic fumarase directly led to HIF1-alpha activation. As
expected, Fh -/- mouse cells showed elevated fumarate accumulation and
lactate production, and reduced cellular respiration. Fh -/- also showed
upregulated Hif1-alpha transcriptional activity due to reduced
Hif1-alpha prolyl hydroxylation. Profound dysregulation of HIF1-alpha
also occurred in FH-associated neoplasias. Reintroduction of wildtype
human FH lacking the mitochondrial targeting sequence largely ablated
fumarate accumulation and restored HIF1-alpha prolyl hydroxylation and
inactivation without restoration of mitochondrial respiration.
O'Flaherty et al. (2010) proposed that fumarate is a catalytic inhibitor
of HIF1-alpha prolyl hydroxylation, and that fumarase deficiency may
mimic hypoxia, resulting in HIF1-alpha activation.

Using genetically modified mouse kidney cells in which Fh1 had been
deleted, Frezza et al. (2011) applied a newly developed computer model
of the metabolism of these cells to predict and experimentally validate
a linear metabolic pathway beginning with glutamine uptake and ending
with bilirubin excretion from Fh1-deficient cells. This pathway, which
involves the biosynthesis and degradation of heme, enables Fh1-deficient
cells to use accumulated tricarboxylic acid (TCA) cycle metabolites and
permits partial mitochondrial NADH production. Frezza et al. (2011)
predicted and confirmed that targeting this pathway would render
Fh1-deficient cells nonviable, while sparing wildtype Fh1-containing
cells. Frezza et al. (2011) concluded that their work went beyond
identifying a metabolic pathway that is induced in Fh1-deficient cells
to demonstrate that inhibition of heme oxygenation is synthetically
lethal when combined with Fh1 deficiency, providing a potential target
for treating HLRCC (150800) patients.

MOLECULAR GENETICS

- Autosomal Recessive Fumarase Deficiency

In patients with fumarase deficiency (606812), Bourgeron et al. (1993,
1994) and Coughlin et al. (1993) identified mutations in the FH gene
(136850.0001 and 136850.0002).

- Autosomal Dominant Hereditary Leiomyomatosis and Renal Cell
Cancer

In patients with hereditary leiomyomatosis and renal cell cancer (HRLCC;
150800), Tomlinson et al. (2002) identified several heterozygous
mutations in the FH gene (136850.0005 and 136850.0006).

In patients with multiple cutaneous and uterine leiomyomata, Tomlinson
et al. (2002) identified heterozygous mutations in the FH gene
(136850.0003 and 136850.0004).

Using sequence analysis, Toro et al. (2003) identified germline
mutations in the FH gene in 31 of 35 (89%) families with cutaneous
leiomyomas. Eighteen of the 20 different mutations they identified-- 2
insertions, 5 small deletions that caused frameshifts leading to
premature termination of the protein, and 13 missense--were novel. The
same mutation, arg190 to his (R190H; 136850.0007), was identified in 11
unrelated families. Cutaneous leiomyomas were found in 81 individuals
(47 women and 34 men). Uterine leiomyomas were also found in 98% (46 of
47) of women with cutaneous leiomyomas. Total hysterectomy was performed
in 89% (41 of 46) of women with cutaneous and uterine leiomyomas, 44%
before or at age 30 years. In 13 individuals in 5 families, Toro et al.
(2003) identified unilateral and solitary renal tumors. Papillary type
II renal cell carcinoma was present in 7 individuals from 4 families,
and another individual from 1 of these families had collecting duct
carcinoma of the kidney. The study expanded the histologic spectrum of
renal tumors and FH mutations associated with hereditary leiomyomatosis
and renal cell carcinoma.

Barker et al. (2002) analyzed a series of 26 leiomyosarcomas and 129
uterine leiomyomas (from 21 patients) for somatic mutations in fumarate
hydratase and allelic imbalance around 1q43. None of the 26
leiomyosarcomas harbored somatic mutations in fumarate hydratase. Only
5% (7 of 129) of the leiomyomas showed allele imbalance at 1q42-q43, and
no somatic mutations in fumarate hydratase were observed.

Alam et al. (2003) reported 20 FH mutations in 35 of 46 probands with
multiple cutaneous and uterine leiomyomata (MCUL) or FH deficiency.
Disease-associated missense FH changes mapped to highly conserved
residues, mostly in or around the enzyme's active site or activation
site. The mutation spectra in FH deficiency and MCUL were similar,
although in the latter mutations tended to occur more 5-prime in the
gene and were predicted to result in a truncated or absent protein. The
authors reported that not all mutation-carrier parents of FH deficiency
children had a strong predisposition to leiomyomata. Renal carcinoma is
sometimes part of MCUL, as part of the variant hereditary leiomyomatosis
and renal cancer (HLRCC) syndrome; these cancers may have either type II
papillary or collecting duct morphology. There was no association
between the type or site of FH mutation and any aspect of the MCUL
phenotype. Biochemical assay for reduced FH functional activity in the
germline of MCUL patients may indicate carriers of FH mutations with
high sensitivity and specificity, and can detect reduced FH activity in
some patients without detectable FH mutations. The authors concluded
that MCUL is probably a genetically homogeneous tumor predisposition
syndrome, primarily resulting from absent or severely reduced fumarase
activity.

To determine whether FH mutations may predispose women to developing
nonsyndromic uterine leiomyomas (UL; 150669), Gross et al. (2004)
performed a genetic linkage study with DNA from 123 families containing
at least 1 affected sister pair. In addition, to assess the frequency of
FH loss specifically in uterine leiomyomas with 1q rearrangements, they
performed a FISH analysis of UL. Analysis of the genotyping data
revealed evidence suggestive of linkage to the FH region among study
participants who were less than 40 years of age at diagnosis (p = 0.04).
FISH results showed that 1 copy of FH was absent in 9 of 11 ULs. Gross
et al. (2004) concluded that loss of FH may be a significant event in
the pathogenesis of a subset of nonsyndromic ULs.

Because some individuals with HLRCC with a germline FH mutation have
breast cancer (114480), Kiuru et al. (2005) analyzed germline FH
mutations from 85 Finnish breast cancer patients, most of whom were
selected based on positive family or personal history for malignancies
associated with HLRCC. No mutations were found. Kiuru et al. (2005)
concluded that FH is not a major predisposing gene for familial breast
cancer.

Wei et al. (2006) identified 14 mutations in the FH gene, including 9
novel mutations, in affected members of 13 families with HLRCC and 8
families with multiple cutaneous and uterine leiomyomata. Four unrelated
families had the R58X mutation (136850.0003) and 5 unrelated families
had the R190H mutation (136850.0007). Cutaneous leiomyomata were present
in 16 (76%) of 21 families, ranging from mild to severe. All 22 female
mutation carriers from 16 families had uterine fibroids. Renal tumors
occurred in 13 (62%) of 21 families. No genotype/phenotype correlations
were identified.

To examine the cancer risk and tumor spectrum in Finnish families
positive for FH mutations, Lehtonen et al. (2006) collected genealogic
and cancer data from 868 individuals. FH mutation status was analyzed in
all 98 available patients. The standardized incidence ratio (SIR) was
6.5 for renal cell carcinoma (RCC) and 71 for uterine leiomyosarcoma
(ULMS). The overall cancer risk was statistically significantly
increased in the age group of 15 to 29 years, consistent with features
of cancer predisposition families in general. An FH germline mutation
was found in 55% of studied individuals. Most RCC and ULMS displayed
biallelic inactivation of FH, as did breast and bladder cancers. In
addition, Lehtonen et al. (2006) observed several benign tumors
including atypical uterine leiomyomas, kidney cysts, and adrenal gland
adenomas.

As part of the French National Cancer Institute study, Gardie et al.
(2011) identified 32 different heterozygous germline mutations in the FH
gene, including 21 novel mutations, in 40 (71.4%) of 56 families with
proven HLRCC. In addition, FH mutations were found in 4 (17.4%) of 23
probands with isolated type 2 papillary renal cell carcinoma, including
2 patients with no family history. In vitro functional expression
studies showed that all mutations caused about a 50% decrease in FH
enzymatic activity. In addition, there were 5 asymptomatic mutation
carriers in 3 families, indicating incomplete penetrance. The findings
indicated that renal call carcinoma can be the only manifestation of
this disorder. No genotype/phenotype correlations were identified.

*FIELD* AV
.0001
FUMARASE DEFICIENCY
FH, ALA265THR

In a patient of Arab ancestry with fumarase-deficiency (606812),
Coughlin et al. (1993) identified a G-to-A transition at nucleotide 793
changing ala265 to thr (A265T). The father was shown to be heterozygous
for the mutation.

.0002
FUMARASE DEFICIENCY
FH, GLU319GLN

Bourgeron et al. (1993, 1994) described a glu319-to-gln (E319Q) mutation
in the FH gene in 2 daughters of first-cousin Moroccan parents who
presented with progressive encephalopathy, dystonia, leukopenia, and
neutropenia at an early age. Elevation of lactate in the cerebrospinal
fluid (so-called hyperlactatorachia) and high fumarate excretion in the
urine led Bourgeron et al. (1994) to investigate the activities of the
respiratory chain and of the Krebs cycle, and finally to identify
fumarase deficiency (606812). The deficiency was profound, was present
in all tissues investigated, and affected the cytosolic and
mitochondrial isoenzymes to the same degree. The sibs were homozygous
for a missense mutation, a G-to-C transversion at nucleotide 955. The
predicted amino acid substitution occurred in a highly conserved region
of the fumarase cDNA. Both parents exhibited half the expected fumarase
activity in their lymphocytes and were found to be heterozygous for the
mutation.

.0003
HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER
FH, ARG58TER

In 3 families, Tomlinson et al. (2002) found that members affected by
multiple cutaneous and uterine leiomyomata (150800) had a change of
codon 58 from CGA (arg) to TGA (stop) (R58X) in exon 2 of the FH gene.

In 3 unrelated families with hereditary leiomyomatosis and renal cell
cancer, Wei et al. (2006) identified the R58X mutation, resulting from a
172C-T transition. The R58X mutation was also identified in affected
members of a fourth unrelated family with multiple cutaneous and uterine
leiomyomata. Haplotype analysis of the families did not show a founder
effect, suggesting that R58X represents a hotspot mutation.

.0004
HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER
FH, ASN64THR

In 6 separate families, Tomlinson et al. (2002) found that individuals
with multiple cutaneous and uterine leiomyomata (150800) were
heterozygous for a mutation in codon 64 in exon 2 of the FH gene
converting AAC (asn) to ACC (thr) (N64T).

In a 55-year-old man with hereditary leiomyomatosis and renal cell
cancer and the N64T mutation in the FH gene, Carvajal-Carmona et al.
(2006) identified a Leydig cell tumor of the testis.

.0005
HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER
FH, 2-BP DEL

In 2 Finnish families with the hereditary leiomyomatosis and renal cell
cancer syndrome (150800), Tomlinson et al. (2002) found a 2-bp deletion
in codon 181 in exon 4 of the FH gene: conversion of GAGTTT to GTTT.

.0006
HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER
FH, ARG300TER

In a Finnish family with the hereditary leiomyomatosis and renal cell
cancer syndrome (150800), Tomlinson et al. (2002) found a nonsense
mutation converting codon 300 in exon 6 of the FH gene from CGA (arg) to
TGA (stop) (R300X).

.0007
HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER
FH, ARG190HIS

In 4 individuals from a family with cutaneous and uterine leiomyomatosis
and renal cell cancer (HLRCC; 150800), Toro et al. (2003) identified a
569G-A transition in exon 4 of the FH gene, resulting in an
arg190-to-his (R190H) mutation. The R190H mutation was also present in
10 other unrelated families with cutaneous and uterine leiomyomatosis,
but screening for occult renal tumors in affected individuals from these
10 families did not identify renal tumors. Thus there appeared to be
other genetic and/or environmental factors that influenced the
phenotype.

Wei et al. (2006) identified the R190H mutation in affected members of 3
unrelated families with HLRCC. The R190H mutation was also identified in
affected members of 2 additional families with multiple cutaneous and
uterine leiomyomata. A founder effect could not be determined.

.0008
HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER
FH, ARG190LEU

Toro et al. (2003) described a family with leiomyomatosis and renal cell
cancer (150800) associated with a 569G-T transition in exon 4 of the FH
gene, resulting in an arg190-to-leu (R190L) mutation. The nucleotide
substitution occurred at the same position as that changed in the common
R190H mutation (136850.0007).

.0009
HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER
FH, ARG58PRO

In affected members of a family with multiple cutaneous and uterine
leiomyomata (150800), Chan et al. (2005) identified a heterozygous
173G-C transversion in exon 3 of the FH gene, resulting in an
arg58-to-pro (R58P) substitution. The proband was a 77-year-old Polish
woman with multiple cutaneous leiomyomas and uterine fibroids. Her
eldest daughter had a similar phenotype, and 2 unaffected daughters did
not have the mutation. Her son had multiple skin leiomyomas and was
diagnosed with metastatic papillary renal cell cancer at age 50 years,
and his asymptomatic 20-year-old son was also found to carry the
mutation and was thus likely to develop skin leiomyomas, but the risk of
renal cancer was difficult to predict. Chan et al. (2005) noted that a
nonsense mutation in the same residue had been reported (R58X;
136850.0003).

Heinritz et al. (2008) identified the R58P mutation in affected members
of a large German family with multiple cutaneous and uterine leiomyomata
without renal cancer. Family history revealed that this German family
originally came from Poland but was dispersed after World War II.
Haplotype analysis of this family and that reported by Chan et al.
(2005) demonstrated a founder effect for the mutation.

.0010
FUMARASE DEFICIENCY
FH, PRO174ARG

In 2 brothers with infantile-lethal fumarase deficiency (606812), Mroch
et al. (2012) identified compound heterozygosity for a 521C-G
transversion in the FH gene, resulting in a pro174-to-arg (P174R)
substitution, and a whole gene deletion (136850.0011). The older sib was
born prematurely and showed hypotonia and respiratory insufficiency
after birth. Both sibs had structural brain malformations, including
ventriculomegaly and agenesis of the corpus callosum, detected by
prenatal ultrasound. Both also had hepatic involvement, with
cholestasis, variable iron deposition, fibrosis, and liver failure.
Electron microscopy of the liver revealed multiple swollen mitochondria
with flat, plate-like, haphazardly arranged cristae. Biochemical studies
showed increased urinary tyrosine metabolites, citric cycle
intermediates, citrulline, fumaric, malic, and succinic acids, and skin
biopsy showed fumarase deficiency. Postmortem examination showed a
distended abdomen, and the liver showed intrahepatic bile stasis. Both
patients died at about 3 weeks of age. The second sib was diagnosed
prenatally by molecular testing of amniocytes.

.0011
FUMARASE DEFICIENCY
FH, DEL

See 136850.0010 and Mroch et al. (2012).

*FIELD* SA
Busby et al. (1976); Edwards and Hopkinson (1979); Petrova-Benedict
et al. (1987); Tolley and Craig (1975); van Someren et al. (1974)
*FIELD* RF
1. Alam, N. A.; Rowan, A. J.; Wortham, N. C.; Pollard, P. J.; Mitchell,
M.; Tyrer, J. P.; Barclay, E.; Calonje, E.; Manek, S.; Adams, S. J.;
Bowers, P. W.; Burrows, N. P.; and 18 others: Genetic and functional
analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis,
hereditary leiomyomatosis and renal cancer, and fumarate hydratase
deficiency. Hum. Molec. Genet. 12: 1241-1252, 2003.

2. Barker, K. T.; Bevan, S.; Wang, R.; Lu, Y.-J.; Flanagan, A. M.;
Bridge, J. A.; Fisher, C.; Finlayson, C. J.; Shipley, J.; Houlston,
R. S.: Low frequency of somatic mutations in the FH/multiple cutaneous
leiomyomatosis gene in sporadic leiomyosarcomas and uterine leiomyomas. Brit.
J. Cancer 87: 446-448, 2002.

3. Bourgeron, T.; Chretien, D.; Poggi-Bach, J.; Doonan, S.; Rabier,
D.; Letouze, P.; Munnich, A.; Rotig, A.; Landrieu, P.; Rustin, P.
: Mutation of the fumarase gene in two siblings with progressive encephalopathy
and fumarase deficiency. J. Clin. Invest. 93: 2514-2518, 1994.

4. Bourgeron, T.; Chretien, D.; Rotig, A.; Munnich, A.; Landrieu,
P.; Rustin, P.: Molecular characterization of fumarase deficiency
in two children with progressive encephalopathy. (Abstract) Am. J.
Hum. Genet. 53 (suppl.): A891 only, 1993.

5. Busby, N.; Courval, J.; Francke, U.: Regional assignments of the
genes for fumarate hydratase and guanylate kinase on chromosome 1
and for lysosomal acid phosphatase and esterase A4 on chromosome 11. Cytogenet.
Cell Genet. 16: 105-107, 1976.

6. Carvajal-Carmona, L. G.; Alam, N. A.; Pollard, P. J.; Jones, A.
M.; Barclay, E.; Wortham, N.; Pignatelli, M.; Freeman, A.; Pomplun,
S.; Ellis, I.; Poulsom, R.; El-Bahrawy, M. A.; Berney, D. M.; Tomlinson,
I. P. M.: Adult Leydig cell tumors of the testis caused by germline
fumarate hydratase mutations. J. Clin. Endocr. Metab. 91: 3071-3075,
2006.

7. Chan, I.; Wong, T.; Martinez-Mir, A.; Christiano, A. M.; McGrath,
J. A.: Familial multiple cutaneous and uterine leiomyomas associated
with papillary renal cell cancer. Clin. Exp. Derm. 30: 75-78, 2005.

8. Coughlin, E. M.; Chalmers, R. A.; Slaugenhaupt, S. A.; Gusella,
J. F.; Shih, V. E.; Ramesh, V.: Identification of a molecular defect
in a fumarase deficient patient and mapping of the fumarase gene.
(Abstract) Am. J. Hum. Genet. 53 (suppl.): A896 only, 1993.

9. Craig, I.; Tolley, E.; Bobrow, M.: Mitochondrial and cytoplasmic
forms of fumarate hydratase assigned to chromosome 1. Cytogenet.
Cell Genet. 16: 118-121, 1976.

10. Despoisses, S.; Noel, L.; Choiset, A.; Portnoi, M.-F.; Turleau,
C.; Quack, B.; Taillemite, J.-L.; de Grouchy, J.; Junien, C.: Regional
mapping of FH to band 1q42.1 by gene dosage studies. (Abstract) Cytogenet.
Cell Genet. 37: 450-451, 1984.

11. Doonan, S.; Barra, D.; Bossa, F.: Structural and genetic relationships
between cytosolic and mitochondrial isoenzymes. Int. J. Biochem. 16:
1193-1199, 1984.

12. Edwards, Y. H.; Hopkinson, D. A.: Further characterization of
the human fumarase variant, FH2-1. Ann. Hum. Genet. 43: 103-108,
1979.

13. Edwards, Y. H.; Hopkinson, D. A.: The genetic determination of
fumarase isozymes in human tissues. Ann. Hum. Genet. 42: 303-313,
1979.

14. Frezza, C.; Zheng, L.; Folger, O.; Rajagopalan, K. N.; MacKenzie,
E. D.; Jerby, L.; Micaroni, M.; Chaneton, B.; Adam, J.; Hedley, A.;
Kalna, G.; Tomlinson, I. P. M.; Pollard, P. J.; Watson, D. G.; Deberardinis,
R. J.; Shlomi, T.; Ruppin, E.; Gottlieb, E.: Haem oxygenase is synthetically
lethal with the tumour suppressor fumarate hydratase. Nature 477:
225-228, 2011.

15. Gardie, B.; Remenieras, A.; Kattygnarath, D.; Bombled, J.; Lefevre,
S.; Perrier-Trudova, V.; Rustin, P.; Barrois, M.; Slama, A.; Avril,
M.-F.; Bessis, D.; Caron, O.; and 41 others: Novel FH mutations
in families with hereditary leiomyomatosis and renal cell cancer (HLRCC)
and patients with isolated type 2 papillary renal cell carcinoma. J.
Med. Genet. 48: 226-234, 2011. Note: Erratum: J. Med. Genet. 48:
576 only, 2011.

16. Gross, K. L.; Panhuysen, C. I. M.; Kleinman, M. S.; Goldhammer,
H.; Jones, E. S.; Nassery, N.; Stewart, E. A.; Morton, C. C.: Involvement
of fumarate hydratase in nonsyndromic uterine leiomyomas: genetic
linkage analysis and FISH studies. Genes Chromosomes Cancer 41:
183-190, 2004.

17. Heinritz, W.; Paasch, U.; Sticherling, M.; Wittekind, C.; Simon,
J. C.; Froster, U. G.; Renner, R.: Evidence for a founder effect
of the germline fumarate hydratase gene mutation R58P causing hereditary
leiomyomatosis and renal cell cancer (HLRCC). Ann. Hum. Genet. 72:
35-40, 2008.

18. Kinsella, B. T.; Doonan, S.: Nucleotide sequence of a cDNA coding
for mitochondrial fumarase from human liver. Biosci. Rep. 6: 921-929,
1986.

19. Kiuru, M.; Lehtonen, R.; Eerola, H.; Aittomaki, K.; Blomqvist,
C.; Nevanlinna, H.; Aaltonen, L. A.; Launonen, V.: No germline FH
mutations in familial breast cancer patients. Europ. J. Hum. Genet. 13:
506-509, 2005.

20. Lehtonen, H. J.; Kiuru, M.; Ylisaukko-oja, S. K.; Salovaara, R.;
Herva, R.; Koivisto, P. A.; Vierimaa, O.; Aittomaki, K.; Pukkala,
E.; Launonen, V.; Aaltonen, L. A.: Increased risk of cancer in patients
with fumarate hydratase germline mutation. J. Med. Genet. 43: 523-526,
2006.

21. Mroch, A. R.; Laudenschlager, M.; Flanagan, J. D.: Detection
of a novel FH whole gene deletion in the propositus leading to subsequent
prenatal diagnosis in a sibship with fumarase deficiency. Am. J.
Med. Genet. 158A: 155-158, 2012.

22. O'Flaherty, L.; Adam, J.; Heather, L. C.; Zhdanov, A. V.; Chung,
Y.-L.; Miranda, M. X.; Croft, J.; Olpin, S.; Clarke, K.; Pugh, C.
W.; Griffiths, J.; Papkovsky, D.; Ashrafian, H.; Ratcliffe, P. J.;
Pollard, P. J.: Dysregulation of hypoxia pathways in fumarate hydratase-deficient
cells is independent of defective mitochondrial metabolism. Hum.
Molec. Genet. 19: 3844-3851, 2010.

23. O'Hare, M. C.; Doonan, S.: Purification and structural comparisons
of the cytosolic and mitochondrial isoenzymes of fumarase from pig
liver. Biochim. Biophys. Acta 827: 127-134, 1985.

24. Petrova-Benedict, R.; Robinson, B. H.; Stacey, T. E.; Mistry,
J.; Chalmers, R. A.: Deficient fumarase activity in an infant with
fumaricacidemia and its distribution between the different forms of
the enzyme seen on isoelectric focusing. Am. J. Hum. Genet. 40:
257-266, 1987.

25. Pollard, P. J.; Briere, J. J.; Alam, N. A.; Barwell, J.; Barclay,
E.; Wortham, N. C.; Hunt, T.; Mitchell, M.; Olpin, S.; Moat, S. J.;
Hargreaves, I. P.; Heales, S. J.; and 9 others: Accumulation of
Krebs cycle intermediates and over-expression of HIF1-alpha in tumours
which result from germline FH and SDH mutations. Hum. Molec. Genet. 14:
2231-2239, 2005.

26. Suzuki, T.; Sato, M.; Yoshida, T.; Tuboi, S.: Rat liver mitochondrial
and cytosolic fumarases with identical amino acid sequences are encoded
from a single gene. J. Biol. Chem. 264: 2581-2588, 1989.

27. Tolley, E.; Craig, I.: Presence of two forms of fumarase (fumarate
hydratase EC 4.2.1.2) in mammalian cells: immunological characterisation
and genetic analysis in somatic cell hybrids; confirmation of the
assignment of a gene necessary for the enzyme expression to human
chromosome 1. Biochem. Genet. 13: 867-883, 1975.

28. Tomlinson, I. P. M.; Alam, N. A.; Rowan, A. J.; Barclay, E.; Jaeger,
E. E. M.; Kelsell, D.; Leigh, I.; Gorman, P.; Lamlum, H.; Rahman,
S.; Roylance, R. R.; Olpin, S.; and 19 others: Germline mutations
in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata
and papillary renal cell cancer. Nature Genet. 30: 406-410, 2002.

29. Toro, J. R.; Nickerson, M. L.; Wei, M.-H.; Warren, M. B.; Glenn,
G. M.; Turner, M. L.; Stewart, L.; Duray, P.; Tourre, O.; Sharma,
N.; Choyke, P.; Stratton, P.; Merino, M.; Walther, M. M.; Linehan,
W. M.; Schmidt, L. S.; Zbar, B.: Mutations in the fumarate hydratase
gene cause hereditary leiomyomatosis and renal cell cancer in families
in North America. Am. J. Hum. Genet. 73: 95-106, 2003.

30. van Someren, H.; Van Henegouwen, H. B.; de Wit, J.: Evidence
for synteny between the human loci for fumarate hydratase, UDG glucose
pyrophosphorylase, 6-phosphogluconate dehydrogenase, phosphoglucomutase-1,
and peptidase-C in man-Chinese hamster somatic cell hybrids. Cytogenet.
Cell Genet. 13: 150-152, 1974.

31. van Someren, H.; Van Henegouwen, H. B.; Westerveld, A.; Bootsma,
D.: Synteny of the human loci for fumarate hydratase and UDPG pyrophosphorylase
with chromosome 1 markers in somatic cell hybrids. Cytogenet. Cell
Genet. 13: 551-557, 1974.

32. Wei, M.-H.; Toure, O.; Glenn, G. M.; Pithukpakorn, M.; Neckers,
L.; Stolle, C.; Choyke, P.; Grubb, R.; Middelton, L.; Turner, M. L.;
Walther, M. M.; Merino, M. J.; Zbar, B.; Linehan, W. M.; Toro, J.
R.: Novel mutations in FH and expansion of the spectrum of phenotypes
expressed in families with hereditary leiomyomatosis and renal cell
cancer. J. Med. Genet. 43: 18-27, 2006.

*FIELD* CN
Patricia A. Hartz - updated: 8/3/2012
Cassandra L. Kniffin - updated: 2/16/2012
Ada Hamosh - updated: 9/21/2011
George E. Tiller - updated: 11/21/2008
Cassandra L. Kniffin - updated: 10/6/2008
John A. Phillips, III - updated: 6/21/2007
Victor A. McKusick - updated: 7/5/2006
Cassandra L. Kniffin - updated: 2/13/2006
Victor A. McKusick - updated: 4/26/2005
George E. Tiller - updated: 3/9/2005
Victor A. McKusick - updated: 12/20/2004
Victor A. McKusick - updated: 6/25/2003
Victor A. McKusick - updated: 10/23/2002
Cassandra L. Kniffin - reorganized: 4/4/2002
Victor A. McKusick - updated: 2/28/2002

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

*FIELD* ED
carol: 09/18/2013
carol: 3/25/2013
carol: 8/15/2012
terry: 8/3/2012
carol: 2/21/2012
ckniffin: 2/16/2012
alopez: 9/22/2011
terry: 9/21/2011
ckniffin: 9/13/2011
wwang: 8/16/2011
ckniffin: 8/11/2011
wwang: 11/21/2008
wwang: 10/16/2008
ckniffin: 10/6/2008
carol: 6/21/2007
alopez: 7/7/2006
terry: 7/5/2006
wwang: 2/28/2006
ckniffin: 2/13/2006
tkritzer: 4/29/2005
terry: 4/26/2005
alopez: 3/9/2005
tkritzer: 1/10/2005
terry: 12/20/2004
tkritzer: 7/17/2003
tkritzer: 7/11/2003
terry: 6/25/2003
alopez: 10/24/2002
terry: 10/23/2002
alopez: 4/12/2002
ckniffin: 4/4/2002
carol: 4/4/2002
ckniffin: 4/4/2002
terry: 3/27/2002
alopez: 3/1/2002
terry: 2/28/2002
terry: 7/24/1998
jason: 6/15/1994
terry: 4/27/1994
carol: 10/28/1993
carol: 10/18/1993
supermim: 3/16/1992
carol: 11/20/1990

MIM 150800
*RECORD*
*FIELD* NO
150800
*FIELD* TI
#150800 HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER; HLRCC
;;MULTIPLE CUTANEOUS AND UTERINE LEIOMYOMATA 1, WITH OR WITHOUT RENAL
read moreCELL CARCINOMA; MCUL1;;
LEIOMYOMATOSIS AND RENAL CELL CANCER, HEREDITARY; LRCC;;
LEIOMYOMA, MULTIPLE CUTANEOUS; MCL
*FIELD* TX
A number sign (#) is used with this entry because multiple cutaneous and
uterine leiomyomatosis, with or without renal cell carcinoma, also
referred to as hereditary leiomyatosis and renal cell cancer (HLRCC), is
caused by heterozygous mutation in the gene encoding fumarate hydratase
(FH; 136850) on chromosome 1q42.

Homozygous mutation in the FH gene causes fumarase deficiency (606812).

DESCRIPTION

Hereditary leiomyomatosis and renal cell cancer is an autosomal dominant
tumor predisposition syndrome characterized by the variable development
of 3 tumors: cutaneous piloleiomyomata that develop in essentially all
patients by age 40 years; leiomyomata (fibroids) of the uterus, and
rarely leiomyosarcomas, at a mean age of 30 years (range, 18 to 52
years); and type 2 papillary renal cell carcinoma at a mean age of 46
years (range, 17 to 75 years), which occurs in about 20% of patients.
Type 2 papillary renal cell carcinoma is a pathologic subtype
characterized by large tumor cells with eosinophilic cytoplasm and
pseudostratified nuclei; it shows an aggressive clinical course. Some
patients with FH mutations may develop collecting duct renal cell
carcinoma. The main focus of management in HLRCC is prevention of
disease and death due to renal cancer (summary by Gardie et al., 2011;
Smit et al., 2011; and Lehtonen, 2011).

For a general discussion of papillary renal cell carcinoma, see RCCP1
(605074).

CLINICAL FEATURES

Kloepfer et al. (1958) described 3 Italian half first cousins with
multiple leiomyomata of the skin. The parents and common grandparent
were not known to be affected, but all critical individuals were not
examined. The skin tumors were composed of smooth muscle fibers and were
thought to arise from the erector pilorum muscles. Mezzadra (1965)
described 3 generations of an Italian family with cutaneous leiomyomata
associated with uterine myomata.

Guillet et al. (1987) described a nonfamilial case of associated
multiple cutaneous leiomyomas and uterine fibromas. Rudner et al. (1972)
described identical twins with multiple cutaneous leiomyomata and a
history of hysterectomy for uterine leiomyomata. Reed et al. (1973) also
emphasized the association of uterine myomata. Engelke and Christophers
(1979) commented on the unusually early age of onset of uterine
myofibromas.

Launonen et al. (2001) reported the clinical, histopathologic, and
molecular features of a cancer syndrome with predisposition to uterine
leiomyomas and papillary renal cell carcinoma. In the Finnish family
they studied, 11 members had uterine leiomyomas and 2 had uterine
leiomyosarcoma. Seven individuals had a history of cutaneous nodules, 2
of which were confirmed to be cutaneous leiomyomatosis. The 4 kidney
cancer cases occurred in young (33- to 48-year-old) females and
displayed a unique natural history. All these kidney cancers displayed a
distinct papillary histology and presented as unilateral solitary
lesions that had metastasized at the time of diagnosis. A second,
smaller family was also studied.

In a 55-year-old man with HLRCC and an N64T mutation in the FH gene
(136850.0004), Carvajal-Carmona et al. (2006) identified a Leydig cell
tumor of the testis. They suggested that this was part of the phenotypic
spectrum of HLRCC.

As part of the French National Cancer Institute study, Gardie et al.
(2011) identified 44 families with genetically-confirmed HLRCC.
Cutaneous leiomyomas occurred in 37 (84.1%) of 44 families and in 102
(67.5%) of 151 affected members. Uterine leiomyomas occurred in 32
families and in 76 (81.7%) of 93 female affected members; renal tumors
occurred in 15 (34%) families and in 27 (17.9%) of 151 affected members.
The average age at diagnosis of renal cell carcinoma was 43 years
(range, 28 to 70 years). Twenty (74.1%) of 27 patient died of metastatic
renal cell carcinoma. Four patients had isolated type 2 papillary renal
cell carcinoma, indicating that this can be a sole manifestation of the
disorder. There was significant intrafamilial variability.

In a retrospective study, Smit et al. (2011) analyzed 14 families from
the Netherlands with genetically-confirmed HLRCC. There was
intrafamilial variability, but all families had at least 1 member with
multiple cutaneous piloleiomyomas, which manifested between the second
and fourth decade of life. These skin lesions tended to grow in size and
number over time, and about 75% of patients reported pain or itching.
Uterine leiomyomas occurred in 17 of 21 mutation carriers, with most
(86%) occurring before 40 years of age. Renal cell cancer occurred in 1
member of 2 unrelated families: 1 patient had type 2 papillary renal
cell carcinoma at age 30 years, and the other had a Wilms tumor at age
2, although it was unclear if this was related. A patient in a third
family had reportedly died of metastatic renal cancer at age 21. Three
mutation carriers had other malignancies: 2 with basal cell carcinoma
and 1 with leukemia. One patient had an incidental adrenal adenoma.

INHERITANCE

Based on an affected Italian family, Kloepfer et al. (1958) suggested
autosomal dominant inheritance with reduced penetrance. Dominant
inheritance with incomplete penetrance was supported by the pedigree of
Mezzadra (1965), who described cutaneous leiomyomata associated with
uterine myomata in 3 generations of an Italian family.

Weilbaecher (1967) observed a Swedish family with 5 affected in 3
generations and male-to-male transmission.

Autosomal dominant skin disorders sometimes become manifest in a mosaic
form, involving the body in a linear, patchy, or otherwise circumscribed
arrangement. Such cases can be explained by an early postzygotic
mutation. The segmental lesions usually show the same degree of severity
as that found in the corresponding nonmosaic trait, which Happle (1997)
referred to as type 1 segmental involvement. Occasionally, however, the
intensity of involvement observed in the circumscribed area is far more
pronounced. Happle (1997) suggested that this phenomenon can be
explained by the loss of heterozygosity (LOH) at the same locus that
caused the less severe, diffuse involvement. Happle (1997) pointed to
cutaneous leiomyomatosis as an autosomal dominant disorder in which
sporadic cases of segmental leiomyomatosis had been reported by many
authors. He referred to this involvement as type 1. He pointed to
several families affected with cutaneous leiomyomatosis in which there
was superimposed severe segmental leiomyomatosis, providing evidence of
type 2 involvement. Sporadic cases showing both severe segmental and
ordinary disseminated lesions can be best explained as examples of type
2 involvement.

The transmission pattern in the families studied by Launonen et al.
(2001) was consistent with autosomal dominant inheritance.

DIAGNOSIS

Smit et al. (2011) proposed criteria for the clinical diagnosis of
HLRCC. The major criterion is multiple cutaneous piloleiomyomas; minor
criteria include severely symptomatic early-onset uterine leiomyomas,
type 2 papillary renal carcinoma before age 40, and a first-degree
relative who meets 1 of the these criteria.

PATHOGENESIS

Kiuru et al. (2001) concluded that familial cutaneous leiomyomatosis is
a 2-hit condition associated with renal cell carcinoma with
characteristic histopathology.

BIOCHEMICAL FEATURES

Pithukpakorn et al. (2006) studied FH enzyme activity in the whole cell
and in cytosolic, and mitochondrial fractions in 50 lymphoblastoid and
16 fibroblast cell lines including cell lines from individuals with
HLRCC with 16 different mutations. Lower FH enzyme activity was observed
in cells from individuals with HLRCC than in cells from normal controls.
The enzyme activity in lymphoblastoid cell lines from 3 individuals with
mutations in R190 was not significantly different from individuals with
other missense mutations. Cell lines from other hereditary renal cancer
syndromes showed FH enzyme levels not significantly different from those
of control cell lines.

MAPPING

Alam et al. (2001) performed a genomewide screen of 11 families with
this disorder and found linkage to 1q42.3-q43 (maximum multipoint lod
score of 5.40). By haplotype construction and analysis of
recombinations, they refined the minimal interval containing the locus,
which they designated MCUL1 (multiple cutaneous and uterine
leiomyomata), to a region of approximately 14 cM, flanked by markers
D1S517 and D1S2842. Allelic loss studies of tumors indicated that MCUL1
may act as a tumor suppressor. Alam et al. (2001) suggested that the
MCUL1 gene may harbor low-penetrance variants predisposing to the common
form of uterine fibroids and/or may undergo somatic mutation in sporadic
leiomyomata.

By genetic marker analysis, Launonen et al. (2001) mapped the gene for
hereditary susceptibility to uterine leiomyomas and renal cell cancer,
which they called HLRCC, to 1q42-q44. They suggested that the HLRCC gene
is likely to be a tumor suppressor.

MOLECULAR GENETICS

Following up on the demonstration that both multiple leiomyoma and the
leiomyomatosis/renal cell cancer syndrome maps to chromosome 1q42.3-q43,
Tomlinson et al. (2002) identified 15 different heterozygous germline
mutations in the FH gene (see, e.g., 136850.0003-136850.0006) in 25
families with the disorder. Six families from the U.K. had the same
mutation (N64T; 136850.0004). Activity of this enzyme of the
tricarboxylic acid cycle was reduced in lymphoblastoid cells from
individuals with leiomyomatosis. The enzyme acts as a tumor suppressor
in familial leiomyomata, and its measured activity was very low or
absent in tumors from individuals with leiomyomatosis, consistent with a
Knudson 2-hit hypothesis. The results provided clues to the pathogenesis
of fibroids and emphasized the importance of mutations of housekeeping
and mitochondrial proteins in the pathogenesis of common types of
tumors.

Wei et al. (2006) identified 14 heterozygous mutations in the FH gene,
including 9 novel mutations, in affected members of 13 families with
HLRCC and 8 families with multiple cutaneous and uterine leiomyomata.
Four unrelated families had the R58X mutation (136850.0003), and 5
unrelated families had the R190H mutation (136850.0007). Cutaneous
leiomyomata were present in 16 (76%) of 21 families, ranging from mild
to severe. All 22 female mutation carriers from 16 families had uterine
fibroids. Renal tumors occurred in 13 (62%) of 21 families. No
genotype/phenotype correlations were identified.

As part of the French National Cancer Institute study, Gardie et al.
(2011) identified 32 different heterozygous germline mutations in the FH
gene, including 21 novel mutations, in 40 (71.4%) of 56 families with
proven HLRCC. In addition, FH mutations were found in 4 (17.4%) of 23
probands with isolated type 2 papillary renal cell carcinoma, including
2 patients with no family history. In vitro functional expression
studies showed that all mutations caused about a 50% decrease in FH
enzymatic activity. In addition, there were 5 asymptomatic mutation
carriers in 3 families, indicating incomplete penetrance. The findings
indicated that renal call carcinoma can be the only manifestation of
this disorder. No genotype/phenotype correlations were identified.

HISTORY

Fryns et al. (1985) described a severely mentally retarded woman with 9p
trisomy/18pter monosomy. The patient was judged to have phenotypic
features typical of 9p trisomy (Rethore et al., 1970) but she also had
multiple cutaneous leiomyomata, of which some were nodular, some linear,
and all looked rather like keloids. The authors raised the question of
whether this was another example of a specific chromosomal deletion
(18pter) in a dominantly inherited multiple tumor, like retinoblastoma
and nephroblastoma.

*FIELD* SA
Berendes et al. (1971)
*FIELD* RF
1. Alam, N. A.; Bevan, S.; Churchman, M.; Barclay, E.; Barker, K.;
Jaeger, E. E. M.; Nelson, H. M.; Healy, E.; Pembroke, A. C.; Friedmann,
P. S.; Dalziel, K.; Calonje, E.; and 12 others: Localization of
a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids
to chromosome 1q42.3-q43. Am. J. Hum. Genet. 68: 1264-1269, 2001.

2. Berendes, U.; Kuhner, A.; Schnyder, U. W.: Segmentary and disseminated
lesions in multiple hereditary cutaneous leiomyoma. Humangenetik 13:
81-82, 1971.

3. Carvajal-Carmona, L. G.; Alam, N. A.; Pollard, P. J.; Jones, A.
M.; Barclay, E.; Wortham, N.; Pignatelli, M.; Freeman, A.; Pomplun,
S.; Ellis, I.; Poulsom, R.; El-Bahrawy, M. A.; Berney, D. M.; Tomlinson,
I. P. M.: Adult Leydig cell tumors of the testis caused by germline
fumarate hydratase mutations. J. Clin. Endocr. Metab. 91: 3071-3075,
2006.

4. Engelke, H.; Christophers, E.: Leiomyomatosis cutis et uteri. Acta
Derm. Venerol. 59 (suppl. 85): 51-54, 1979.

5. Fryns, J. P.; Haspeslagh, M.; de Muelenaere, A.; van den Berghe,
H.: 9p trisomy/18p distal monosomy and multiple cutaneous leiomyomata:
another specific chromosomal site (18pter) in dominantly inherited
multiple tumors? Hum. Genet. 70: 284-286, 1985.

6. Gardie, B.; Remenieras, A.; Kattygnarath, D.; Bombled, J.; Lefevre,
S.; Perrier-Trudova, V.; Rustin, P.; Barrois, M.; Slama, A.; Avril,
M.-F.; Bessis, D.; Caron, O.; and 41 others: Novel FH mutations
in families with hereditary leiomyomatosis and renal cell cancer (HLRCC)
and patients with isolated type 2 papillary renal cell carcinoma. J.
Med. Genet. 48: 226-234, 2011. Note: Erratum: J. Med. Genet. 48:
576 only, 2011.

7. Guillet, G.; Grau, P.; Sassolas, B.; Zagnoli, A.; Leroy, J. P.;
Labouche, F.: Leiomyomes cutanes multiples et fibromes uterins: a
propos d'une observation d'un cas non familial. Semin. Hop. Paris 63:
65-67, 1987.

8. Happle, R.: A rule concerning the segmental manifestation of autosomal
dominant skin disorders: review of clinical examples providing evidence
for dichotomous types of severity. Arch. Derm. 133: 1505-1509, 1997.

9. Kiuru, M.; Launonen, V.; Hietala, M.; Aittomaki, K.; Vierimaa,
O.; Salovaara, R.; Arola, J.; Pukkala, E.; Sistonen, P.; Herva, R.;
Aaltonen, L. A.: Familial cutaneous leiomyomatosis is a two-hit condition
associated with renal cell cancer of characteristic histopathology. Am.
J. Path. 159: 825-829, 2001.

10. Kloepfer, H. W.; Krafchuk, J.; Derbes, V.; Burks, J.: Hereditary
multiple leiomyoma of the skin. Am. J. Hum. Genet. 10: 48-52, 1958.

11. Launonen, V.; Vierimaa, O.; Kiuru, M.; Isola, J.; Roth, S.; Pukkala,
E.; Sistonen, P.; Herva, R.; Aaltonen, L. A.: Inherited susceptibility
to uterine leiomyomas and renal cell cancer. Proc. Nat. Acad. Sci. 98:
3387-3392, 2001.

12. Lehtonen, H. J.: Hereditary leiomyomatosis and renal cell cancer:
update on clinical and molecular characteristics. Familial Cancer 10:
397-411, 2011.

13. Mezzadra, G.: Leiomioma cutaneo multiplo ereditario. Studio di
un caso sistematizzato in soggetto maschile appartenente a famiglia
portatrice di leiomiomatosi cutanea e fibromiomatosi uterina. Minerva
Derm. 40: 388-393, 1965.

14. Pithukpakorn, M.; Wei, M.-H.; Toure, O.; Steinbach, P. J.; Glenn,
G. M.; Zbar, B.; Linehan, W. M.; Toro, J. R.: Fumarate hydratase
enzyme activity in lymphoblastoid cells and fibroblasts of individuals
in families with hereditary leiomyomatosis and renal cell cancer.
(Letter) J. Med. Genet. 43: 755-762, 2006.

15. Reed, W. B.; Walker, R.; Horowitz, R.: Cutaneous leiomyomata
with uterine leiomyomata. Acta Derm. Venerol. 53: 409-416, 1973.

16. Rethore, M. O.; Larget-Piet, L.; Abonyi, D.; Boeswillwald, M.;
Berger, P.; Carpentier, S.; Cruveiller, J.; Dutrillaux, B.; Lafourcade,
J.; Penneau, M.; Lejeune, J.: Sur quatre cas de trisomie pour le
bras court du chromosome 9: individualisation d'une nouvelle entite
morbide. Ann. Genet. 13: 217-232, 1970.

17. Rudner, E. J.; Schwartz, O. D.; Greekin, J. N.: Multiple cutaneous
leiomyoma in identical twins. Arch. Derm. 104: 81-82, 1972.

18. Smit, D. L.; Mensenkamp, A. R.; Badeloe, S.; Breuning, M. H.;
Simon, M. E. H.; van Spaendonck, K. Y.; Aalfs, C. M.; Post, J. G.;
Shanley, S.; Krapels, I. P. C.; Hoefsloot, L. H.; van Moorselaar,
R. J. A.; Starink, T. M.; Bayley, J.-P.; Frank, J.; van Steensel,
M. A. M.; Menko, F. H.: Hereditary leiomyomatosis and renal cell
cancer in families referred for fumarate hydratase germline mutation
analysis. Clin. Genet. 79: 49-59, 2011.

19. Tomlinson, I. P. M.; Alam, N. A.; Rowan, A. J.; Barclay, E.; Jaeger,
E. E. M.; Kelsell, D.; Leigh, I.; Gorman, P.; Lamlum, H.; Rahman,
S.; Roylance, R. R.; Olpin, S.; and 19 others: Germline mutations
in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata
and papillary renal cell cancer. Nature Genet. 30: 406-410, 2002.

20. Wei, M.-H.; Toure, O.; Glenn, G. M.; Pithukpakorn, M.; Neckers,
L.; Stolle, C.; Choyke, P.; Grubb, R.; Middelton, L.; Turner, M. L.;
Walther, M. M.; Merino, M. J.; Zbar, B.; Linehan, W. M.; Toro, J.
R.: Novel mutations in FH and expansion of the spectrum of phenotypes
expressed in families with hereditary leiomyomatosis and renal cell
cancer. J. Med. Genet. 43: 18-27, 2006.

21. Weilbaecher, R. G.: Personal Communication. New Orleans, La.
1967.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GENITOURINARY:
[Internal genitalia, female];
Uterine leiomyomata;
Uterine leiomyosarcoma;
Uterine fibroids;
[Kidney];
Renal cell carcinoma, papillary type 2 (about 20% of patients);
Collecting duct carcinoma

SKIN, NAILS, HAIR:
[Skin];
Cutaneous piloleiomyomas (may be single or multiple);
Leiomyomas are sensitive to light touch;
Cutaneous leiomyosarcoma (rare)

NEOPLASIA:
Uterine leiomyosarcoma (less common);
Cutaneous leiomyosarcoma (less common);
Renal cell carcinoma, solitary papillary type 2 (about 20% of patients)

LABORATORY ABNORMALITIES:
Decreased fumarate hydratase activity

MISCELLANEOUS:
Highly variable phenotype;
Cutaneous leiomyomas increase in number over time;
Mean age of diagnosis of uterine leiomyomas is 30 years;
Mean age of diagnosis of renal cell carcinoma is 46 years;
Incomplete penetrance

MOLECULAR BASIS:
Caused by mutation in the fumarate hydratase gene (FH, 136850.0003)

*FIELD* CN
Cassandra L. Kniffin - updated: 8/11/2011
Kelly A. Przylepa - revised: 10/6/2004

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

*FIELD* ED
joanna: 05/02/2012
ckniffin: 8/11/2011

*FIELD* CN
Cassandra L. Kniffin - updated: 8/11/2011
Cassandra L. Kniffin - updated: 2/13/2006
Victor A. McKusick - updated: 2/28/2002
Victor A. McKusick - updated: 6/5/2001
Victor A. McKusick - updated: 8/5/1999

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

*FIELD* ED
carol: 09/15/2011
ckniffin: 9/13/2011
wwang: 8/16/2011
ckniffin: 8/11/2011
wwang: 3/1/2006
ckniffin: 2/13/2006
alopez: 6/7/2002
carol: 4/4/2002
ckniffin: 4/4/2002
alopez: 3/18/2002
alopez: 3/1/2002
terry: 2/28/2002
cwells: 6/13/2001
carol: 6/13/2001
cwells: 6/8/2001
terry: 6/5/2001
jlewis: 8/25/1999
terry: 8/5/1999
carol: 5/18/1999
terry: 5/3/1999
mimadm: 11/5/1994
supermim: 3/16/1992
supermim: 3/24/1990
supermim: 3/20/1990
ddp: 10/27/1989
root: 12/15/1988

MIM 606812
*RECORD*
*FIELD* NO
606812
*FIELD* TI
#606812 FUMARASE DEFICIENCY
;;FUMARIC ACIDURIA
*FIELD* TX
A number sign (#) is used with this entry because fumarate deficiency is
read morecaused by homozygous or compound heterozygous mutation in the fumarate
hydratase gene (FH; 136850) on chromosome 1.

Heterozygous mutation in the FH gene can cause hereditary leiomyomatosis
and renal cell cancer (HLRCC; 150800).

DESCRIPTION

Fumarase deficiency is a severe autosomal recessive metabolic disorder
characterized by early-onset hypotonia, profound psychomotor
retardation, and brain abnormalities, such as agenesis of the corpus
callosum, gyral defects, and ventriculomegaly. Many patients show
neonatal distress, metabolic acidosis, and/or encephalopathy (summary by
Kerrigan et al., 2000 and Mroch et al., 2012).

CLINICAL FEATURES

Zinn et al. (1986) reported the case of a male infant with mitochondrial
encephalopathy who presented at 1 month of age with failure to thrive,
developmental delay, hypotonia, cerebral atrophy, lactic and pyruvic
acidemia, and fumaric aciduria. The patient died at 8 months of age.
Mitochondria isolated from skeletal muscle showed selective defects in
the oxidation of glutamate and succinate, whereas isolated liver
mitochondria oxidized these normally. Fumarase activity was virtually
absent in mitochondria of both sources. Homogenates of liver and muscle
also showed very much reduced fumarase activity, indicating that the
cytosolic form of the enzyme was also deficient. Organ differences in
intramitochondrial accumulation of fumarase were thought to account for
the selective oxidative defects observed in skeletal muscle and not in
liver mitochondria.

Whelan et al. (1983) reported isolated fumaric aciduria in 2 adult sibs
with mental retardation and speech impairment. The authors attributed
the increased urinary excretion to a defect in renal clearance; fumarase
activity was not assessed. Petrova-Benedict et al. (1987) reported a
case of fumarase deficiency in a mentally retarded child who presented
at 6 months of age with hypotonia, microcephaly, and delayed
development. Fumarase was deficient in both the mitochondrial and the
cytosolic compartments, but the cytosolic enzyme appeared to be more
severely affected. Snodgrass (1987) commented on the occurrence of mild
hyperammonemia in fumarase deficiency. Gellera et al. (1990) described
the clinical features of fumarase deficiency. A 7-month old boy died in
a demented state after a clinical course characterized by generalized
seizures, psychomotor deterioration, and fumaric aciduria. Marked
deficiency of both mitochondrial and cytosolic fumarases was found in
skeletal muscle, brain, cerebellum, heart, kidney, liver, and cultured
fibroblasts. Anti-fumarase crossreacting material was present in
negligible amounts in these tissues.

Kerrigan et al. (2000) reported the clinical features of 8 affected
members of a large consanguineous family with fumarase deficiency living
in an isolated community in the southwestern United States. The ages of
the patients ranged from 20 months to 12 years. All patients were
profoundly developmentally retarded and had no language development.
Only 1 child had achieved independent walking; all the others were
unable to sit. All patients had relative macrocephaly and ventricular
enlargement. Other common features included hypotonia, seizures, and
status epilepticus. Dysmorphic features included frontal bossing,
hypertelorism, depressed nasal bridge, anteverted nares, and high-arched
palate. Five of 8 had polycythemia at birth. Neuroimaging showed
striking abnormalities of the brain, including polymicrogyria,
angulation of the frontal horns, decreased periventricular white matter,
and small brainstem. Four patients had optic nerve hypoplasia or pallor.

Mroch et al. (2012) reported 2 brothers, born of unrelated parents, with
genetically confirmed FH deficiency resulting in death in infancy. The
first boy was born prematurely from a pregnancy complicated by
polyhydramnios, and showed hypotonia and respiratory insufficiency after
birth. An ultrasound at 20 weeks' gestation had shown agenesis of the
corpus callosum, ventriculomegaly, bilateral renal pyelectasis, and a
ventriculoseptal defect. Postmortem imaging showed lissencephaly. He
developed severe metabolic acidosis, necrotizing enterocolitis, liver
failure associated with coagulopathy and hyperbilirubinemia, and
encephalopathy, resulting in death at age 22 days. Biochemical studies
showed increased urinary tyrosine metabolites, citric cycle
intermediates, citrulline, fumaric, malic, and succinic acids, and skin
biopsy showed fumarase deficiency. Postmortem examination showed a
distended abdomen, and the liver showed intrahepatic bile stasis.
Electron microscopy of the liver revealed multiple swollen mitochondria
with flat, plate-like, haphazardly arranged cristae. Genetic analysis
identified compound heterozygosity for a point mutation in the FH gene
and a deletion of the FH gene (136850.0010 and 136850.0011). Prenatal
diagnosis confirming the deficiency was performed on the subsequent
pregnancy by genetic testing of amniocytes. Ultrasound at 20 weeks
showed ventriculomegaly, dangling choroid plexus, and possible agenesis
of the corpus callosum. The parents elected to continue with the
pregnancy, but the infant died on day 26. Postmortem examination again
showed hepatic involvement, with fibrosis, iron deposition, and bile
stasis. Electron microscopy showed abnormal mitochondria similar to that
observed in his affected brother. Each unaffected parent was
heterozygous for 1 of the mutations, and neither showed cancer or
abnormal cutaneous findings suggesting HLRCC.

INHERITANCE

In the case reported by Petrova-Benedict et al. (1987), the parents of
the affected child were first cousins. In the case reported by Gellera
et al. (1990), autosomal recessive inheritance was supported by the
finding of fumarase activities 30 to 50% of normal in both mitochondria
and cytosol from cultured fibroblasts of the parents.

MOLECULAR GENETICS

Coughlin et al. (1993) identified a homozygous mutation in the FH gene
(136850.0001) in a patient with fumarase deficiency. Bourgeron et al.
(1993, 1994) identified a homozygous mutation in the fumarase gene
(136850.0002) in 2 patients with progressive encephalopathy associated
with fumarase deficiency.

POPULATION GENETICS

There is an unusually high incidence of fumarase deficiency in the
southwestern United States among members of the Fundamentalist Church of
Jesus Christ of Latter Day Saints (FLDS), a religious community that
practices inbreeding and polygamy. The genetic defect was traced to one
of the community's founding patriarchs, the late Joseph Smith Jessop,
and the first of his plural wives, who had 14 children together
(Dougherty, 2005).

*FIELD* RF
1. Bourgeron, T.; Chretien, D.; Poggi-Bach, J.; Doonan, S.; Rabier,
D.; Letouze, P.; Munnich, A.; Rotig, A.; Landrieu, P.; Rustin, P.
: Mutation of the fumarase gene in two siblings with progressive encephalopathy
and fumarase deficiency. J. Clin. Invest. 93: 2514-2518, 1994.

2. Bourgeron, T.; Chretien, D.; Rotig, A.; Munnich, A.; Landrieu,
P.; Rustin, P.: Molecular characterization of fumarase deficiency
in two children with progressive encephalopathy. (Abstract) Am. J.
Hum. Genet. 53 (suppl.): A891 only, 1993.

3. Coughlin, E. M.; Chalmers, R. A.; Slaugenhaupt, S. A.; Gusella,
J. F.; Shih, V. E.; Ramesh, V.: Identification of a molecular defect
in a fumarase deficient patient and mapping of the fumarase gene.
(Abstract) Am. J. Hum. Genet. 53 (suppl.): A896 only, 1993.

4. Dougherty, J.: Forbidden fruit: inbreeding among polygamists along
the Arizona-Utah border is producing a caste of severely retarded
and deformed children. Phoenix New Times , 12/29/2005.

5. Gellera, C.; Uziel, G.; Rimoldi, M.; Zeviani, M.; Laverda, A.;
Carrara, F.; DiDonato, S.: Fumarase deficiency is an autosomal recessive
encephalopathy affecting both the mitochondrial and the cytosolic
enzymes. Neurology 40: 495-499, 1990.

6. Kerrigan, J. F.; Aleck, K. A.; Tarby, T. J.; Bird, C. R.; Heidenreich,
R. A.: Fumaric aciduria: clinical and imaging features. Ann. Neurol. 47:
583-588, 2000.

7. Mroch, A. R.; Laudenschlager, M.; Flanagan, J. D.: Detection of
a novel FH whole gene deletion in the propositus leading to subsequent
prenatal diagnosis in a sibship with fumarase deficiency. Am. J.
Med. Genet. 158A: 155-158, 2012.

8. Petrova-Benedict, R.; Robinson, B. H.; Stacey, T. E.; Mistry, J.;
Chalmers, R. A.: Deficient fumarase activity in an infant with fumaricacidemia
and its distribution between the different forms of the enzyme seen
on isoelectric focusing. Am. J. Hum. Genet. 40: 257-266, 1987.

9. Snodgrass, P. J.: Fumarase deficiency. (Letter) New Eng. J. Med. 316:
345 only, 1987.

10. Whelan, D. T.; Hill, R. E.; McClorry, S.: Fumaric aciduria: a
new organic aciduria, associated with mental retardation and speech
improvement. Clin. Chim. Acta 132: 301-308, 1983.

11. Zinn, A. B.; Kerr, D. S.; Hoppel, C. L.: Fumarase deficiency:
a new cause of mitochondrial encephalomyopathy. New Eng. J. Med. 315:
469-475, 1986.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Failure to thrive

HEAD AND NECK:
[Head];
Macrocephaly, relative;
[Face];
Frontal bossing;
[Eyes];
Hypertelorism;
Optic pallor;
Optic atrophy;
Visual impairment;
[Nose];
Depressed nasal bridge;
Anteverted nares;
[Mouth];
High-arched palate

ABDOMEN:
[Liver];
Liver failure;
Cholestasis;
Fibrosis;
Iron deposition;
Abnormal swollen mitochondria with flat, haphazardly arranged cristae

SKIN, NAILS, HAIR:
[Skin];
Cutaneous leiomyomata (heterozygote carriers)

MUSCLE, SOFT TISSUE:
Hypotonia;
Decreased muscle bulk;
Decreased subcutaneous fat

NEUROLOGIC:
[Central nervous system];
Mental retardation, profound;
Developmental delay;
No language development;
Cerebral atrophy;
Seizures;
Status epilepticus;
Hypotonia;
Most patients do not achieve independent sitting or walking;
Ventricular enlargement;
Polymicrogyria;
Open operculum;
Choroid plexus cysts;
Decreased white matter volume;
Angulation of the frontal horns;
Small brainstem;
Agenesis of the corpus callosum

HEMATOLOGY:
Polycythemia, neonatal;
Coagulopathy in those with liver failure

METABOLIC FEATURES:
Metabolic acidosis

LABORATORY ABNORMALITIES:
Lactic acidemia;
Pyruvic acidemia;
Fumaric aciduria;
Fumarase activity (mitochondrial and cytosolic) is decreased;
Increased urinary citric acid cycle intermediates;
Increased urinary fumaric acid;
Increased urinary malic acid;
Increased urinary succinic acid;
Hyperbilirubinemia in those with liver failure

MISCELLANEOUS:
Allelic to hereditary multiple leiomyoma of skin (see 150800) and
hereditary leiomyomatosis and renal cell cancer (150800)

MOLECULAR BASIS:
Caused by mutation in the fumarate hydratase gene (FH, 136850.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 5/20/2008
Kelly A. Przylepa - updated: 10/6/2004

*FIELD* CD
Cassandra L. Kniffin: 5/8/2002

*FIELD* ED
joanna: 02/28/2012
ckniffin: 2/16/2012
wwang: 8/16/2011
terry: 2/19/2009
joanna: 1/28/2009
ckniffin: 5/20/2008
joanna: 4/30/2008
joanna: 10/6/2004
ckniffin: 5/8/2002

*FIELD* CN
Cassandra L. Kniffin - updated: 2/16/2012
Cassandra L. Kniffin - updated: 5/20/2008

*FIELD* CD
Cassandra L. Kniffin: 4/1/2002

*FIELD* ED
terry: 03/21/2012
carol: 2/21/2012
ckniffin: 2/16/2012
ckniffin: 8/11/2011
wwang: 5/23/2008
ckniffin: 5/20/2008
terry: 4/21/2005
carol: 4/4/2002
ckniffin: 4/4/2002