FH (fumarate hydratase).

2006-07-01 Allison M Lynch , Cynthia C Morton Affiliation

Brigham, Womens Hospital, Harvard New Research Building, 77 Avenue Louis Pasteur, Room 160, Boston, MA 02115, USA

Identity

HGNC

LOCATION

1q43

LOCUSID

2271

ALIAS

FMRD,HLRCC,HsFH,LRCC,MCL,MCUL1

DNA/RNA

Fig1. Genomic structure of FH. Exons are represented by purple boxes with base pair number above and exon number below. Image is not drawn to scale.

Description

10 exons; 22,152 base pairs.

Transcription

1,1790 bp. Multiple RNA transcripts encode two FH gene products- one with a mitochondrial signal protein and the other lacking the signal sequence.

Proteins

Description

FH encodes the homotetrameric enzyme, fumarase, composed of 510 amino acids (molecular weight 54,637 Da); four identical subunits (50 kDa each); three active DNA binding sites (site A) and one lower affinity substrate (site B). Isoenzyme products have nearly identical amino acid sequences, but vary at the amino terminus.

Expression

Widespread in both fetal and adult tissues; most abundantly expressed in the skin, parathyroid, lymph and colon (four highest NCBI expression profiles). Tumors: expression in benign mesenchymal tissue (e.g., uterine, cutaneous); malignant tumors: leiomyosarcoma and papillary (type II) renal cell carcinoma.

Localisation

Mitochondrial and cytosolic. Subcellular localization is determined by presence or absence of a signal sequence at the amino terminus. Presence of the signal generates the mitochondrial-targeted form while absence of the signal results in the cytosolic form.

Function

Fumarase plays a key enzymatic role in fundamental metabolic pathways. The mitochondrial isoenzyme catalyzes conversion of fumarate to malate in the Krebs, or tricarboxylic acid (TCA) cycle, in which acetyl-CoA produces CO2, reduced electron carriers (FADH2 and NADH) and ATP. The cytosolic isoenzyme is involved with amino acid metabolism.

Mutations

Germinal

Germline mutations in FH are associated with two distinct conditions:

Homozygous and compound heterozygous mutations (e.g., missense and in-frame deletions) of the 3 end result in fumarate hydratase deficiency (FHD).

Heterozygous 5 mutations (e.g., nonsense, missense and deletions ranging from one base pair to whole gene) predispose individuals to somatic mutations in the normal allele leading to Hereditary leiomyomatosis and renal cell carcinoma / multiple cutaneous and uterine leiomyomatosis (HLRCC/MCUL1).

Somatic

Loss-of-heterozygosity of the wild type allele results in functional nullizygosity for fumarate hydratase. Malignant uterine and kidney tumors characteristic of HLRCC can subsequently develop.

Implicated in

Entity name

Uterine Leiomyomata (UL)

Note

Synonyms include uterine fibroids, fibromas, myofibromas and myomas.

Disease

Benign mesenchymal tumors of the uterus.

Prognosis

Excellent, but may require surgical intervention as one- third of hysterectomies performed in the United States have a primary indication of UL.

Cytogenetics

UL rarely associated with cytologically visible 1q42 deletions.

Hybrid gene

Deletions of FH from structural rearrangements of 1q42.1.

Fusion protein

Presumed haploinsufficiency or functional null if mutation in other FH allele occurs.

Entity name

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC)/ multiple cutaneous and uterine leiomyomatosis (MCUL1).

Note

Also known as Reeds syndrome.

Disease

HLRCC is an autosomal dominant disorder, characterized by smooth muscle tumors of the skin and uterus and/or kidney.

Prognosis

Good, if early diagnosis.

Fusion protein

Inherited mutations can predispose to somatic deletions resulting in truncated, non-functional or absent proteins.

Oncogenesis

FH acts as classic tumor suppressor gene in HLRCC/MCUL1. Genetic or epigenetic alterations in FH resulting from substitution, deletion or methylation follow the Knudson two hit mechanism. The resulting functionally null state for fumarase can lead to subsequent oxidative tissue damage and tumorigenesis.

Entity name

Fumarate hydratase deficiency (FHD).

Note

Synonymous with fumarase deficiency and fumaric aciduria.

Disease

Autosomal recessive condition characterized by delayed development, diminished muscle tone, and encephalopathy likely due to limited energy generation during development.

Prognosis

Poor. FHD is a rare condition, but reported cases indicate most affected individuals survive only several months while very few survive into their third decade.

Hybrid gene

The most common allelic abnormality is a 3 base pair- AAA insertion.

Fusion protein

Mutations near fumarase active site result in absent or truncated protein.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
12761039	2003	Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.	Alam NA et al
12177782	2002	Low frequency of somatic mutations in the FH/multiple cutaneous leiomyomatosis gene in sporadic leiomyosarcomas and uterine leiomyomas.	Barker KT et al
15334541	2004	Involvement of fumarate hydratase in nonsyndromic uterine leiomyomas: genetic linkage analysis and FISH studies.	Gross KL et al
11549574	2001	Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology.	Kiuru M et al
12183404	2002	Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families.	Kiuru M et al
11248088	2001	Inherited susceptibility to uterine leiomyomas and renal cell cancer.	Launonen V et al
16582132	2006	The genetics of uterine leiomyomata: what clinicians need to know.	Stewart EA et al
11865300	2002	Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.	Tomlinson IP et al
12772087	2003	Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.	Toro JR et al
16319128	2006	Distinct expression profile in fumarate-hydratase-deficient uterine fibroids.	Vanharanta S et al
8909293	1996	Crystallographic studies of the catalytic and a second site in fumarase C from Escherichia coli.	Weaver T et al
3040736	1987	Mitochondrial and cytoplasmic fumarases in Saccharomyces cerevisiae are encoded by a single nuclear gene FUM1.	Wu M et al

Other Information

Locus ID:

NCBI: 2271
MIM: 136850
HGNC: 3700
Ensembl: ENSG00000091483

Variants:

dbSNP: 2271
ClinVar: 2271
TCGA: ENSG00000091483
COSMIC: FH

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000091483	ENST00000366560	P07954
ENSG00000091483	ENST00000366560	A0A0S2Z4C3

Expression (GTEx)

100

150

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Citrate cycle (TCA cycle)	KEGG	ko00020
Pyruvate metabolism	KEGG	ko00620
Renal cell carcinoma	KEGG	ko05211
Citrate cycle (TCA cycle)	KEGG	hsa00020
Pyruvate metabolism	KEGG	hsa00620
Pathways in cancer	KEGG	hsa05200
Renal cell carcinoma	KEGG	hsa05211
Metabolic pathways	KEGG	hsa01100
Citrate cycle, second carbon oxidation, 2-oxoglutarate => oxaloacetate	KEGG	hsa_M00011
Citrate cycle (TCA cycle, Krebs cycle)	KEGG	M00009
Citrate cycle, second carbon oxidation, 2-oxoglutarate => oxaloacetate	KEGG	M00011
Carbon metabolism	KEGG	hsa01200
Carbon metabolism	KEGG	ko01200
Citrate cycle (TCA cycle, Krebs cycle)	KEGG	hsa_M00009
Metabolism	REACTOME	R-HSA-1430728
The citric acid (TCA) cycle and respiratory electron transport	REACTOME	R-HSA-1428517
Pyruvate metabolism and Citric Acid (TCA) cycle	REACTOME	R-HSA-71406
Citric acid cycle (TCA cycle)	REACTOME	R-HSA-71403

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
37312573	2024	Fumarate Hydratase-Deficient Leiomyoma of the Uterine Corpus: Comparative Morphologic Analysis of Protein-Deficient Tumors With and Without Pathogenic Germline Fumarate Hydratase Gene Mutations.	1
38481055	2024	Genomic profile analysis of leiomyomas with bizarre nuclei and fumarate hydratase deficient leiomyomas: Strengths, weaknesses, and limitations of array-CGH interpretation.	0
37312573	2024	Fumarate Hydratase-Deficient Leiomyoma of the Uterine Corpus: Comparative Morphologic Analysis of Protein-Deficient Tumors With and Without Pathogenic Germline Fumarate Hydratase Gene Mutations.	1
38481055	2024	Genomic profile analysis of leiomyomas with bizarre nuclei and fumarate hydratase deficient leiomyomas: Strengths, weaknesses, and limitations of array-CGH interpretation.	0
36495298	2023	Morphologic Characteristics and Mutational Analysis of Fumarate Hydratase Deficient Kidney and Smooth Muscle Tumors.	0
36773955	2023	Fumarate Hydratase Variants and Their Association With Paraganglioma/Pheochromocytoma.	0
36890227	2023	Macrophage fumarate hydratase restrains mtRNA-mediated interferon production.	41
36981015	2023	A Missense Mutation c.1132G > A in Fumarate Hydratase (FH) Leads to Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Syndrome and Insights into Clinical Management in Uterine Leiomyomata.	0
37255402	2023	FH Variant Pathogenicity Promotes Purine Salvage Pathway Dependence in Kidney Cancer.	7
37316640	2023	In deep bioinformatic characterization of a novel fumarate hydratase variant FH c.199T > G; (p.Tyr67Asp) in hereditary leiomyomatosis and renal cell carcinoma.	0
37561409	2023	Cryptic splice mutation in the fumarate hydratase gene in patients with clinical manifestations of Hereditary Leiomyomatosis and Renal Cell Cancer.	0
36495298	2023	Morphologic Characteristics and Mutational Analysis of Fumarate Hydratase Deficient Kidney and Smooth Muscle Tumors.	0
36773955	2023	Fumarate Hydratase Variants and Their Association With Paraganglioma/Pheochromocytoma.	0
36890227	2023	Macrophage fumarate hydratase restrains mtRNA-mediated interferon production.	41
36981015	2023	A Missense Mutation c.1132G > A in Fumarate Hydratase (FH) Leads to Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Syndrome and Insights into Clinical Management in Uterine Leiomyomata.	0

Citation

Allison M Lynch ; Cynthia C Morton

FH (fumarate hydratase).

Atlas Genet Cytogenet Oncol Haematol. 2006-07-01

Online version: http://atlasgeneticsoncology.org/gene/40573/css/lib/deep-insight-explorer/meetings/