Mutated genes in cancer (70) – FH

FH

In databases:

● Entrez (http://www.ncbi.nlm.nih.gov/sites/gquery): 2271 or FH

● Ensembl (http://www.ensembl.org/index.html): ENSG00000091483

● UniProt (http://www.uniprot.org/): P07954

● OMIM (http://www.ncbi.nlm.nih.gov/omim): 136850

● GeneCards (http://www.genecards.org/): FH

● HGNC (http://www.genenames.org/): 3700 or FH

● EC enzyme number : EC 4.2.1.2

Gene locus:

1q42.1

Protein name:

Fumarate hydratase (fumarase)

Protein Size:

510 amino acids; about 55 kDa

Function:

Fumarase is a homotetramer that 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.

Cancer-related alterations:

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). FHD is characterized by progressive encephalopathy, developmental delay, hypotonia, cerebral atrophy and lactic and pyruvic acidemia. The most common allelic abnormality is a 3 base pair- AAA insertion.

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 mutations:    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. Uterine leiomyomatosis has also been observed in patients with deletion of FH from structural rearrangements of 1q42.1. The probable mechanism is presumably haploinsufficiency

Références (open access):

Genetic and epigenetic alterations during renal carcinogenesis. Arai E, Kanai Y. Int J Clin Exp Pathol. 2010 Dec 13;4(1):58-73.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3016104/pdf/ijcep0004-0058.pdf

HIF and fumarate hydratase in renal cancer. Sudarshan S, Linehan WM, Neckers L. Br J Cancer. 2007 Feb 12;96(3):403-7.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360036/pdf/6603547a.pdf

Genetic heterogeneity among uterine leiomyomata: insights into malignant progression. Hodge JC, Morton CC. Hum Mol Genet. 2007 Apr 15;16 Spec No 1:R7-13.

http://hmg.oxfordjournals.org/content/16/R1/R7.full.pdf+html

Structural basis of fumarate hydratase deficiency. Picaud S, Kavanagh KL, Yue WW, Lee WH, Muller-Knapp S, Gileadi O, Sacchettini J, Oppermann U. J Inherit Metab Dis. 2011 Jun;34(3):671-6.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109261/pdf/10545_2011_Article_9294.pdf