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

Area of Science:

• Endocrinology
• Genetics
• Biochemistry

Background:

• Steroid hormones are crucial regulators of physiological functions throughout life.
• Steroid hormone-transforming enzymes are key to regulating these signaling molecules.
• Germline mutations in these enzymes lead to various endocrine disorders, including those affecting sexual development and salt balance.

Purpose of the Study:

• To review disease-associated germline coding mutations in human aldo-keto reductase (AKR) superfamily members involved in steroid metabolism.
• To categorize missense mutations, including nonsynonymous single nucleotide polymorphisms (nsSNPs) and familial inherited substitutions.
• To highlight the impact of AKR mutations on specific diseases.

Main Methods:

• Literature review of germline coding mutations in human AKR genes.
• Analysis of mutations affecting androgen metabolism (AKR1C genes) and bile acid metabolism (AKR1D1 gene).
• Consideration of mutation types: nsSNPs and familial inherited base pair substitutions.

Main Results:

• Mutations in human AKR1C genes disrupt androgen metabolism, potentially affecting male sexual development, prostate cancer, and polycystic ovary syndrome (PCOS).
• Mutations in the AKR1D1 gene may cause bile acid deficiency.
• Established examples of mutations in other steroid hormone-transforming enzymes (e.g., SRD5A2, HSD17B3, HSD3B2) cause severe disorders.

Conclusions:

• Germline mutations in AKR superfamily members are implicated in diverse endocrine and metabolic disorders.
• AKR mutations play significant roles in androgen and bile acid metabolism with clinical consequences.
• Expanding data and analytical tools will likely reveal further disease-associated germline AKR mutations.