Germline Mutations in Steroid Metabolizing Enzymes: A Focus on Steroid Transforming Aldo-Keto Reductases

Abstract

Steroid hormones synchronize a variety of functions throughout all stages of life. Importantly, steroid hormone-transforming enzymes are ultimately responsible for the regulation of these potent signaling molecules. Germline mutations that cause dysfunction in these enzymes cause a variety of endocrine disorders. Mutations in SRD5A2, HSD17B3, and HSD3B2 genes that lead to disordered sexual development, salt wasting, and other severe disorders provide a glimpse of the impacts of mutations in steroid hormone transforming enzymes. In a departure from these established examples, this review examines disease-associated germline coding mutations in steroid-transforming members of the human aldo-keto reductase (AKR) superfamily. We consider two main categories of missense mutations: those resulting from nonsynonymous single nucleotide polymorphisms (nsSNPs) and cases resulting from familial inherited base pair substitutions. We found mutations in human AKR1C genes that disrupt androgen metabolism, which can affect male sexual development and exacerbate prostate cancer and polycystic ovary syndrome (PCOS). Others may be disease causal in the AKR1D1 gene that is responsible for bile acid deficiency. However, given the extensive roles of AKRs in steroid metabolism, we predict that with expanding publicly available data and analysis tools, there is still much to be uncovered regarding germline AKR mutations in disease.

Description of Chemical Synthesis, Nuclear Magnetic Resonance Characterization and Biological Activity of Estrane-Based Inhibitors/Activators of Steroidogenesis

“…Inhibitor 5: 17β-Hydroxysteroid dehydrogenase type 5 (17β-HSD5), or aldo-keto reductase (AKR) 1C3, catalyzes the conversion of 4-dione into T, DHEA into 5-diol, and E1 into E2; consequently, its inhibition could be a strategy to lower the level of androgen T and estrogens E2 and 5-diol [19,20,[65][66][67]. Inhibitor 5 was obtained by modifying 17β-HSD2 inhibitor 4.…”

Role of sphingolipid metabolites in the homeostasis of steroid hormones and the maintenance of testicular functions

“…Steroid hormone is an important regulator of many physiological processes in mammalians (19)(20)(21). It is specifically synthesized in steroid-producing tissues through a series of multistep reactions under the catalysis of monooxygenase and hydroxysteroid dehydrogenase superfamily members (20)(21)(22)(23). It plays a very important regulatory role in maintaining testicular functions (19)(20)(21)(22)(23)(24)(25)(26)(27).…”

“…It is specifically synthesized in steroid-producing tissues through a series of multistep reactions under the catalysis of monooxygenase and hydroxysteroid dehydrogenase superfamily members (20)(21)(22)(23). It plays a very important regulatory role in maintaining testicular functions (19)(20)(21)(22)(23)(24)(25)(26)(27). Many sphingolipid metabolites can regulate the signaling pathways of steroid production, through acting as a second messenger in the signaling cascade to participate in the regulation of reproductive functions (5,15,17,(27)(28)(29).…”

Long read sequencing characterises a novel structural variant opaque to short reads, with likely functional impact in a case of unexplained severe fatigue

“…The AKR1C enzymes are well known for their wide-ranging roles in steroid metabolism, including deactivation of progesterone (P) and synthesis of the neuroactive steroids allopregnanolone (allo) and pregnanolone (preg), which positively modulate the gamma-aminobutyric acid type A receptor (GABA A R) in a similar way to benzodiazepine sedatives (Rogawski et al 2013). To date, however, germline variants in AKR1C1 and 1C2 have been surprisingly little studied in the context of disease (Detlefsen et al 2023).…”