Genetics of Uterine Leiomyomata
John C. Petrozza in Uterine Fibroids, 2020
Loss-of-function heterozygous mutations in FH (fumarate hydratase) at 1q43 are etiologic in a rare autosomal dominant tumor predisposition syndrome known as hereditary leiomyomatosis and renal cell carcinoma (HLRCC) [58–62]. Individuals with FH mutations may develop cutaneous leiomyomas of the erector piliform muscles, earlier-onset UL, uterine leiomyosarcoma and renal cell carcinoma [58,60,63,64]. As shown in Figure 5.2b, somatic inactivation of the wild-type copy of FH either through loss of heterozygosity or mutation is frequently observed in HLRCC-associated neoplasms and is consistent with Knudson's two-hit hypothesis, suggesting FH is a bona fide tumor suppressor gene [59,65–67]. In cells deficient in FH, both fumarate and succinate accumulate and inhibit the hypoxia-inducible factor prolyl hydroxylase, which in turn results in overexpression of the transcription factor HIF-1α (hypoxia-inducible factor 1α) and a “pseudo-hypoxic” state [68–71]. Of note, a single functional copy of FH is sufficient for maintaining normal metabolic activity [72]. In HLRCC, patients heterozygous for a missense or nonsense FH mutation, MED12 mutations and somatic biallelic inactivation of FH appear to be mutually exclusive, suggesting a distinct molecular mechanism involving oxidative phosphorylation through mitochondrial complex 2, leading to UL in HLRCC [52,61,66–68,72,73]. Albeit an infrequent event, biallelic inactivation of FH has also been reported in sporadic cases of UL [74–76].
Mitochondrial and peroxisomal disorders
Steve Hannigan in Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
Fumarase deficiency is a rare disorder of the Kreb’s cycle (also known as the citric acid cycle), a metabolic pathway that is central to the breakdown of carbohydrates, fats and proteins to carbon dioxide and water in order to generate energy. Individuals afected by this disorder develop postnatal neurological problems. Patients who have a more severe form of fumarase deiciency usually develop respiratory diiculties, and this results in their life expectancy not extending beyond early childhood, whereas patients who are less severely afected develop non-progressive brain problems and survive into adolescence or adulthood.
Hereditary Leiomyomatosis and Renal Cell Cancer
Dongyou Liu in Handbook of Tumor Syndromes, 2020
Heterogeneous germline mutations in the fumarate hydratase (FH) gene located on chromosome 1q42.1, which converts fumarate to malate in the Kreb cycle, form the molecular basis of HLRCC. In contrast, homozygous mutations in FH resulting in fumarate hydratase deficiency (FMRD) are associated with an autosomal recessive hereditary phenotype characterized by severe neonatal encephalopathy, poor feeding, failure to thrive, hypotonia, lethargy, seizures, and early death [1].
Fumarate hydratase as a therapeutic target in renal cancer
Published in Expert Opinion on Therapeutic Targets, 2020
Priyanka Kancherla, Michael Daneshvar, Rebecca A. Sager, Mehdi Mollapour, Gennady Bratslavsky
Developing new therapeutics is predicated on understanding the molecular basis of disease. FH is an enzyme in the citric acid cycle, a series of metabolic reactions downstream of glycolysis ultimately responsible for generating cellular energy via oxidative phosphorylation (Figure 2). Specifically, fumarate hydratase catalyzes the hydration reaction that converts fumarate to malate [33]. FH is not the only citric acid cycle enzyme implicated in familial cancer syndromes. In the preceding citric acid cycle reaction, succinate dehydrogenase (SDH) catalyzes the oxidation of succinate to fumarate (Figure 2). SDH functions as a heterotetramer with each subunit individually encoded by the genes SDHA-D. Mutations in SDHB, SDHC, and SDHD have been implicated in hereditary paraganglioma-pheochromocytoma syndromes [33]. This association between disrupted cellular metabolism and tumor growth is paradoxical. Nonetheless, these two syndromes establish the role of mitochondrial and metabolic dysfunction in tumorigenesis. Understanding the mechanisms by which this occurs is important for identifying targets for treating associated malignancy.
The evolution and competitive strategies of Akkermansia muciniphila in gut
Published in Gut Microbes, 2022
Ji-Sun Kim, Se Won Kang, Ju Huck Lee, Seung-Hwan Park, Jung-Sook Lee
Multiple genome alignments were performed to identify the structural differences in the genome. Genome synteny also showed no significant differences between the KGMB strains. However, it was found that there are length variations in the homopolymeric polyguanine (poly G) region in the promoter of fumarate hydratase between type strain KCTC 15667 T and KGMB strains (Figure S1). KGMB strains had a greater number of homopolymeric guanosine repeats, 22–29 mer Gs, compared to the type strain with 18-mer Gs. Fumarate hydratase, also known as fumarase, converts fumaric acid to L-malic acid in the tricarboxylic acid (TCA) cycle, and is a conserved protein in all organisms, from bacteria to humans, with respect to its sequence, structure, and enzymatic activity.37,38 Although the intergenic region (297 bp) of fumarase was identical between the type strain KCTC 15667 T and KGMB strains, differences in the number of poly G repeats in the promoter may cause physiological differences between them.
Identification of hub genes with prognostic values in multiple myeloma by bioinformatics analysis
Published in Hematology, 2021
Jie Yang, Fei Wang, Shanliang Zhong, Baoan Chen
Fumarate hydratase (FH) is an integral enzyme component of the Krebs cycle and tricarboxylic acid cycle, and it can also act in different kinds of cancer [21]. Ha YS et al. [22] evaluated FH mRNA levels in 140 tumor specimens from the patients with primary renal cell cancer and in 62 specimens of corresponding normal-appearing kidney tissue. The results showed that FH was down-regulated in tumor specimens. Sudarshan S [23], with his team, demonstrated that reduced expression of FH was associated with HIF-2α accumulation and tumor progression. However, another study found that FH inhibition, together with elevated intracellular fumarate, coincides with HIF upregulation. Besides, fumarate could increase the expression level of HIF-regulated genes [24]. TSTA3, also known as GFUS (GDP-L-fucose synthase), is the substrate of several fucosyltransferases involved in the expression of many glycoconjugates [25]. Changes in glycoprotein structure were common in cancer cells that can affect the adhesion, invasion, and metastasis of cells. Yang J et al. [25] found high expression of TSTA3 was a potential biomarker for poor prognosis of esophageal squamous cell carcinoma patients. The same result was found in breast cancer, and the study further revealed that miR-125a-5p and miR-125b could regulate the expression of TSTA3 [26]. POLR3G (RNA polymerase III subunit G), a version of RNA polymerase III, which is enriched in stem and cancer cells [27]. Recently, Petrie JL et al. [28] demonstrated the inhibition effect of POLR3G on cell differentiation and down-regulated POLR3G significantly reduced in the proliferation, invasiveness, tumor-initiating activity, and viability of prostate cancer cells.
Related Knowledge Centers
- Catalysis
- Enzyme
- Fumaric Acid
- Isozyme
- Malic Acid
- Metabolism
- Amino Acid
- Citric Acid Cycle
- Mitochondrion
- Cytosol