17β-Hydroxysteroid dehydrogenase 3 deficiency

doi:10.1016/1043-2760(96)00034-3

Trends in Endocrinology & Metabolism

Volume 7, Issue 4, May–June 1996, Pages 121-126

https://doi.org/10.1016/1043-2760(96)00034-3 Get rights and content

Abstract

Five known isoenzymes catalyze the 17β-hydroxysteroid dehydrogenase reaction that controls the interconversion of estrone and estradiol and of testosterone and androstenedione. Mutations in the 17β-hydroxysteroid dehydrogenase 3 gene impair the formation of testosterone in the fetal testis and give rise to genetic males with normal male Wolffian duct structures but female external genitalia. Such individuals are usually raised as females but virilize at the time of puberty as the result of a rise in serum testosterone. The 14 mutations characterized to date in 17 affected families include 10 missense mutations, 3 splice junction abnormalities, and 1 frame shift mutation. Three of the mutations have occurred in more than 1 family. The usual mechanism for testosterone formation in affected individuals at puberty appears to be conversion of androstenedione to testosterone in extraglandular tissues by one or more of the unaffected 17β-hydroxysteroid dehydrogenase isoenzymes.

References (39)

FM Bentvelsen et al.
The androgen receptor of the urogenital tract of the fetal rat is regulated by androgen
Mol Cell Endocrinol
(1994)
MJ Gast et al.
Isolation and sequencing of a complementary deoxyribonucleic acid clone encoding human placental 17β-estradiol dehydrogenase: identification of the putative cofactor binding site
Am J Obstet Gynecol
(1989)
F Leenders et al.
The sequence of porcine 80 kDa 17βestradiol dehydrogenase reveals similarities to the short chain dehydrogenase family, to actin binding motifs, and to sterol carrier protein 2
Mol Cell Endocrinol
(1994)
H Peltoketo et al.
Complete amino acid sequence of human placental 17β-hydroxysteroid dehydrogenase deduced from cDNA
FEBS Lett
(1988)
DG Rogers et al.
Partial deficiency in 17-ketosteroid reductase presenting as gynecomastia
Steroids
(1985)
FZ Stanczyk et al.
Further in vitro steroid metabolic studies of testicular 17β-reductase deficiency
J Steroid Biochem
(1978)
SC Wilson et al.
Steroid metabolism in testes of patients with incomplete masculinization due to androgen insensitivity or 17β-hydroxysteroid dehydrogenase deficiency and normally differentiated males
J Steroid Biochem
(1988)
J Adamski et al.
Molecular cloning of a novel widely expressed human 80 kDa 17β-hydroxysteroid dehydrogenase IV
Biochem J
(1995)
FA Akesode et al.
Male pseudo-hermapharoditism with gyaenocomastia due to testicular 17-ketosteroid reductase deficiency
Clin Endocrinol (Oxf)
(1977)
S Andersson
17β-hydroxysteroid dehydrogenase: isozymes and mutations
J Endocrinol
(1995)

S Andersson et al.

Molecular genetics and pathophysiology of 17β-hydroxysteroid dehydrogenase 3 deficiency

J Clin Endocrinol Metab

(1996)

IJP Arnhold et al.

Prepubertal male pseudohermaphroditism due to 17-ketosteroid reductase deficiency: diagnostic value of a hCG test and lack of HLA association

J Endocrinol Invest

(1988)

ML Casey et al.

17β-Hydroxysteroid dehydrogenase type 2: chromosomal assignment and progestin regulation of gene expression in human endometrium

J Clin Invest

(1994)

M Castro-Magana et al.

Male hypogonadism with gynecomastia caused by late-onset deficiency of testicular 17-ketosteroid reductase deficiency

N Engl J Med

(1991)

E de Perettil et al.

Étude de la biosynthése testiculaire in vitro dans quatre cas de pseudo-hermaphrodisme male par déficit en 17-cétoreductase

Ann Endocrinol (Paris)

(1979)

B Eckstein et al.

The nature of the defect in familial male pseudohermaphroditism in Arabs of Gaza

J Clin Endocrinol Metab

(1989)

MG Forest et al.

Cas familial de pseudohermaphrodisme masculin par déficit en 17-cétoreductase: diagnostic tardif chez la tante d'un sujet porteur du même déficit

Ann Endocrinol (Paris)

(1979)

WM Geissler et al.

Mâle pseudo-hermaphroditism caused by mutations of testicular 17β-hydroxy-steroid dehydrogenase 3

Nat Genet

(1994)

FW George et al.

Sex determination and differentiation

Cited by (60)

Molecular mechanisms underlying the defects of two novel mutations in the HSD17B3 gene found in the Tunisian population
2023, Journal of Steroid Biochemistry and Molecular Biology
Citation Excerpt :
17β-HSD3 is predominantly expressed in the testes and uses NADPH as cofactor to catalyze the conversion of Δ4-androstene-3,17-dione (androstenedione) to testosterone, which is essential for the normal fetal development of male genitalia [2]. 17β-HSD3 deficiency is characterized by a spectrum of clinical phenotypes due to a complete loss or residual activity of mutant 17β-HSD3 enzyme in the testes [3,4]. The onset of the extra-testicular conversion of androstenedione to testosterone by 17β-HSD5 (also known as AKR1C3) is mainly responsible for the observed virilization during puberty of patients with 17β-HSD3 deficiency [4].
17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) converts Δ4-androstene-3,17-dione (androstenedione) to testosterone. It is expressed almost exclusively in the testes and is essential for appropriate male sexual development. More than 70 mutations in the HSD17B3 gene that cause 17β-HSD3 deficiency and result in 46,XY Disorders of Sex Development (46,XY DSD) have been reported. This study describes three novel Tunisian cases with mutations in HSD17B3. The first patient is homozygous for the previously reported mutation p.C206X. The inheritance of this mutation seemed to be independent of consanguineous marriage, which can be explained by its high frequency in the Tunisian population. The second patient has a novel splice site mutation in intron 6 at position c.490 -6 T > C. A splicing assay revealed a complete omission of exon 7 in the resulting HSD17B3 mRNA transcript. Skipping of exon 7 in HSD17B3 is predicted to cause a frame shift in exon 8 that affects the catalytic site and results in a truncation in exon 9, leading to an inactive enzyme. The third patient is homozygous for the novel missense mutation p.K202M, representing the first mutation identified in the catalytic tetrad of 17β-HSD3. Site-directed mutagenesis and enzyme activity measurements revealed a completely abolished 17β-HSD3 activity of the p.K202M mutant, despite unaffected protein expression, compared to the wild-type enzyme. Furthermore, the present study emphasizes the importance of genetic counselling, detabooization of 46,XY DSD, and a sensitization of the Tunisian population for the risks of consanguineous marriage.
Germ cell neoplasia in situ complicating 17β-hydroxysteroid dehydrogenase type 3 deficiency
2019, Molecular and Cellular Endocrinology
Citation Excerpt :
Thus, this disorder often does not become clinically apparent until the time of puberty, when affected patients present with either primary amenorrhea or sudden onset of virilization (Andersson et al., 1996a). This abrupt virilization is thought to be secondary to increased testicular androstenedione synthesis as a result of increased pituitary gonadotropin secretion with subsequent conversion to testosterone and DHT in peripheral tissues via extragonadal 17βHSD enzymatic activity (Boehmer et al., 1999; Andersson et al., 1996b; Andersson and Moghrabi, 1997). Unless transition to a male gender is desired, gonadectomy is necessary to prevent further virilization (Minto et al., 2005).
17β-hydroxysteroid dehydrogenase type 3 (17βHSD3) deficiency is an autosomal recessive disorder of male sex development that results in defective testosterone biosynthesis. Although mutations in the cognate HSD17B3 gene cause a spectrum of phenotypic manifestations, the majority of affected patients are genetic males having female external genitalia. Many cases do not present until puberty, at which time peripheral conversion of androgen precursors causes progressive virilization. Measurement of the testosterone-to-androstenedione ratio is useful to screen for 17βHSD3 deficiency, and genetic analysis can confirm the diagnosis. As some individuals with 17βHSD3 deficiency transition from a female sex assignment to identifying as males, providers should ensure stable gender identity prior to recommending irreversible treatments. Gonadectomy is indicated to prevent further virilization if a female gender identity is established. The risk of testicular neoplasia is unknown, a point which should be discussed if patients elect to transition into a male gender role.
Lucky, times ten: A career in Texas science
2018, Journal of Biological Chemistry
On January 21, 2017, I received an E-mail from Herb Tabor that I had been simultaneously hoping for and dreading for several years: an invitation to write a “Reflections” article for the Journal of Biological Chemistry. On the one hand, I was honored to receive an invitation from Herb, a man I have admired for over 40 years, known for 24 years, and worked with as a member of the Editorial Board and Associate Editor of the Journal of Biological Chemistry for 17 years. On the other hand, the invitation marked the waning of my career as an academic scientist. With these conflicting emotions, I wrote this article with the goals of recording my career history and recognizing the many mentors, trainees, and colleagues who have contributed to it and, perhaps with pretension, with the desire that students who are beginning a career in research will find inspiration in the path I have taken and appreciate the importance of luck.
17β-Hydroxysteroid dehydrogenase 3 deficiency: Three case reports and a systematic review
2017, Journal of Steroid Biochemistry and Molecular Biology
17β-Hydroxysteroid dehydrogenase 3 deficiency is a rare autosomal recessive cause of 46, XY disorders of sex development resulting from HSD17B3 gene mutations, however, no case has been reported in East Asia. The aim of this study was to report three Chinese 46, XY females with 17β-HSD3 deficiency in a single center and perform a systematic review of the literature.
Clinical examination, endocrine evaluation and HSD17B3 gene sequencing were performed in the three Chinese phenotypically females (two sisters and one unrelated patient). Relevant articles were searched by using the term “HSD17B3” OR “17beta-HSD3 gene” with restrictions on language (English) and species (human) in Pubmed and Embase.
All the three phenotypically female subjects showed 46, XY karyotype, inguinal masses, decreased testosterone and increased androstenedione. Two novel homozygous mutations (W284X and c.124_127delTCTT) in HSD17B3 gene were identified. A systematic review found a total of 121 pedigrees/158 patients, with 78.5% (124/158) of patients assigned as females, 15.2% (24/158) from females to males, and 5.1% (8/158) raised as males. The most common mutation was c.277 + 4C > T (allele frequency: 25/72) for patients from Europe, and R80Q (allele frequency: 21/54) for patients from West Asia. The testicular histology showed normal infantile testicular tissue in 100% (9/9) infantile patients, normal quantity germ cells in 44.4% (8/18) prepubertal patients and 19.0% (4/21) pubertal and adult patients.
We reported the first East Asian 17β-hydroxysteroid dehydrogenase 3 deficiency cases. Additional literature reviews found founder effects among patients with different ethnic background and early orchiopexy may benefit fertility in patients assigned as males. These findings may significantly expand the clinical, ethnic and genetic spectrum of 17β-hydroxysteroid dehydrogenase 3 deficiency.
Biochemical analyses and molecular modeling explain the functional loss of 17β-hydroxysteroid dehydrogenase 3 mutant G133R in three Tunisian patients with 46, XY Disorders of Sex Development
2016, Journal of Steroid Biochemistry and Molecular Biology
Mutations in the HSD17B3 gene resulting in 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) deficiency cause 46, XY Disorders of Sex Development (46, XY DSD). Approximately 40 different mutations in HSD17B3 have been reported; only few mutant enzymes have been mechanistically investigated. Here, we report novel compound heterozygous mutations in HSD17B3, composed of the nonsense mutation C206X and the missense mutation G133R, in three Tunisian patients from two non-consanguineous families. Mutants C206X and G133R were constructed by site-directed mutagenesis and expressed in HEK-293 cells. The truncated C206X enzyme, lacking part of the substrate binding pocket, was moderately expressed and completely lost its enzymatic activity. Wild-type 17β-HSD3 and mutant G133R showed comparable expression levels and intracellular localization. The conversion of Δ4-androstene-3,17-dione (androstenedione) to testosterone was almost completely abolished for mutant G133R compared with wild-type 17β-HSD3. To obtain further mechanistic insight, G133 was mutated to alanine, phenylalanine and glutamine. G133Q and G133F were almost completely inactive, whereas G133A displayed about 70% of wild-type activity. Sequence analysis revealed that G133 on 17β-HSD3 is located in a motif highly conserved in 17β-HSDs and other short-chain dehydrogenase/reductase (SDR) enzymes. A homology model of 17β-HSD3 predicted that arginine or any other bulky residue at position 133 causes steric hindrance of cofactor NADPH binding, whereas substrate binding seems to be unaffected. The results indicate an essential role of G133 in the arrangement of the cofactor binding pocket, thus explaining the loss-of-function of 17β-HSD3 mutant G133R in the patients investigated.
Assessment of steroidogenesis and steroidogenic enzyme functions
2013, Journal of Steroid Biochemistry and Molecular Biology
There is some confusion in the literature about steroidogenesis in endocrine glands and steroidogenesis in peripheral intracrine tissues. The objective of the present review is to bring some clarifications and better understanding about steroidogenesis in these two types of tissues. Concerns about substrate specificity, kinetic constants and place of enzymes in the pathway have been discussed. The role of 17α-hydroxylase/17–20 lyase (CYP17A1) in the production of dehydroepiandrosterone and back-door pathways of dihydrotestosterone biosynthesis is also analyzed.
This article is part of a Special Issue entitled “Synthesis and biological testing of steroid derivatives as inhibitors”.

View all citing articles on Scopus

View full text

Trends in Endocrinology & Metabolism

Brief review17β-Hydroxysteroid dehydrogenase 3 deficiency

Abstract

Mol Cell Endocrinol

Am J Obstet Gynecol

Mol Cell Endocrinol

FEBS Lett

Steroids

J Steroid Biochem

J Steroid Biochem

Molecular cloning of a novel widely expressed human 80 kDa 17β-hydroxysteroid dehydrogenase IV

Biochem J

Male pseudo-hermapharoditism with gyaenocomastia due to testicular 17-ketosteroid reductase deficiency

Clin Endocrinol (Oxf)

17β-hydroxysteroid dehydrogenase: isozymes and mutations

J Endocrinol

Molecular genetics and pathophysiology of 17β-hydroxysteroid dehydrogenase 3 deficiency

J Clin Endocrinol Metab

Prepubertal male pseudohermaphroditism due to 17-ketosteroid reductase deficiency: diagnostic value of a hCG test and lack of HLA association

J Endocrinol Invest

17β-Hydroxysteroid dehydrogenase type 2: chromosomal assignment and progestin regulation of gene expression in human endometrium

J Clin Invest

Male hypogonadism with gynecomastia caused by late-onset deficiency of testicular 17-ketosteroid reductase deficiency

N Engl J Med

Étude de la biosynthése testiculaire in vitro dans quatre cas de pseudo-hermaphrodisme male par déficit en 17-cétoreductase

Ann Endocrinol (Paris)

The nature of the defect in familial male pseudohermaphroditism in Arabs of Gaza

J Clin Endocrinol Metab

Cas familial de pseudohermaphrodisme masculin par déficit en 17-cétoreductase: diagnostic tardif chez la tante d'un sujet porteur du même déficit

Ann Endocrinol (Paris)

Mâle pseudo-hermaphroditism caused by mutations of testicular 17β-hydroxy-steroid dehydrogenase 3

Nat Genet

Sex determination and differentiation

Brief review
17β-Hydroxysteroid dehydrogenase 3 deficiency