FH (fumarate hydratase).
2006-07-01 Allison M Lynch , Cynthia C Morton AffiliationBrigham, Womens Hospital, Harvard New Research Building, 77 Avenue Louis Pasteur, Room 160, Boston, MA 02115, USA
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
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
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 |
|---|
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)
Pathways
Protein levels (Protein atlas)
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/fh
