Aromatase deficiency in a Chinese adult man caused by novel compound heterozygous CYP19A1 mutations: Effects of estrogen replacement therapy on the bone, lipid, liver and glucose metabolism. (5th January 2015)

• Record Type: Journal Article
• Authors: Chen, Zhike; Wang, Ou; Nie, Min; Elison, Kathleen; Zhou, Dujin; Li, Mei; Jiang, Yan; Xia, Weibo; Meng, Xunwu; Chen, Shiuan; Xing, Xiaoping
• Is Part Of: Molecular and cellular endocrinology. Volume 399(2015)
• Page Start: 32
• Page End: 42
• Publication Date: 2015-01-05
• Subjects: ALT aminoleucine transferase -- ArKO aromatase knockout -- AST aspartate aminotransferase -- AUC area under the curve -- β-CTX c-telopeptide of type I collagen -- BLAST Basic Local Alignment Search Tools -- BMI body mass index -- CHO Chinese hamster ovary -- DEXA dual-energy X-ray absorptiometry -- dNTP deoxynucleotide triphosphate -- FSH follicle-stimulating hormone -- GGT γ-glutamy transferase -- HDL high density lipoprotein -- HOMA homeostasis model assessment -- Km Michaelis constant -- LDL low density lipoprotein -- LH luteinizing hormone -- NCBI National Center for Biotechnology Information -- NHLBI-ESP Exome Sequencing Project of the National Heart, Lung, and Blood Institute -- OGTT oral glucose-tolerance test -- PolyPhen2 Polymorphism Phenotyping, version 2 -- QUICKI quantitative insulin sensitivity check index -- SIFT Sorting Intolerant From Tolerant -- Vmax maximum reaction rate; Aromatase -- CYP19A1 -- Aromatase deficiency -- Metabolic syndrome -- Insulin resistance -- Estrogen replacement; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2014.09.016
• Languages: English
• ISSNs: 0303-7207

Abstract

Graphical Abstract: Highlights: Novel CYP19A1 missense mutations (Y81C and L451P) in an aromatase-deficient man. Structural modeling predicts that Y81C and L451P mutants disrupt protein structure. Y81C and L451P mutants decrease aromatase activity but have residual function. Estrogen therapy has great impact on the bone, lipid, liver and glucose metabolism. Estrogen therapy fails to improve insulin resistance in the man. Abstract: Objectives: Aromatase deficiency is a rare disorder resulting in estrogen insufficiency in humans. It has been reported in remarkably few men with loss-of-function mutations in the CYP19A1 gene encoding the aromatase, a cytochrome P450 enzyme that plays a crucial role in the biosynthesis of estrogens from androgens. We investigated a non-consanguineous family including an adult man with clinical features of aromatase deficiency, and studied the effects of estrogen replacement in the man. Methods: We investigated the clinical and biochemical phenotype, performed CYP19A1 mutational analysis in the family and 50 unrelated persons, studied the effects of CYP19A1 mutations on aromatase protein structure, functionally characterized the mutations by cell-based aromatase activity assays, and studied the effects of estrogen replacement on the bone, lipid, liver and glucose metabolism. Results: The man with clinical features of aromatase deficiency had novel compound heterozygous CYP19A1 mutations (Y81C and L451P) that were not found in 50 unrelated persons. Three-dimensional modeling predicted that Y81C and L451P mutants disrupted protein structure. Functional studies on the basis of in vitro expression showed that Y81C and L45P mutants significantly decreased the aromatase activity and catalytic efficiency. Estrogen replacement in the man increased bone mineral density, accelerated bone maturation, improved lipid profile and liver steatosis, and improved glucose levels but not insulin resistance. Conclusions: We have identified two novel CYP19A1 missense mutations in an aromatase-deficient man. Estrogen replacement in the man shows great impact on recovering the impairments in the bone, lipid, liver and glucose metabolism, but fails to improve insulin resistance.