scholarly journals Deleterious Missense Mutations and Silent Polymorphism in the Human 17β-Hydroxysteroid Dehydrogenase 3 Gene (HSD17B3)1

1998 ◽  
Vol 83 (8) ◽  
pp. 2855-2860 ◽  
Author(s):  
Nabil Moghrabi ◽  
Ieuan A. Hughes ◽  
Andrea Dunaif ◽  
Stefan Andersson
Keyword(s):  
Polycystic Ovary ◽  
External Genitalia ◽  
Hydroxysteroid Dehydrogenase ◽  
Biologically Active ◽  
Male Pseudohermaphroditism ◽  
Missense Mutations ◽  
17Βhsd Deficiency ◽  
Normal Women ◽  
Exon 11 ◽  
Type 3

abstract Isozymes of 17β-hydroxysteroid dehydrogenase (17βHSD) regulate levels of bioactive androgens and estrogens in a variety of tissues. For example, the 17βHSD type 3 isozyme catalyzes the conversion of the inactive C19-steroid androstenedione to the biologically active androgen, testosterone, in the testis. Testosterone is essential for the correct development of male internal and external genitalia; hence, deleterious mutations in the HSD17B3 gene give rise to a rare form of male pseudohermaphroditism termed 17βHSD deficiency. Here, 2 additional missense mutations in the HSD17B3 gene in subjects with 17βHSD deficiency are described. One mutation (A56T) impairs enzyme function by affecting NADPH cofactor binding. A second mutation (N130S) led to complete loss of enzyme activity. Also, a single base pair polymorphism in exon 11 of the HSD17B3 gene is described. The polymorphic A allele encodes a protein with a serine rather than a glycine at position 289 (GGT → AGT). The frequency of the G allele (Gly) was 0.94, and that of the A allele (Ser) was 0.06. No difference in the frequencies of the G and A alleles was detected in 32 apparently normal women and 46 women with polycystic ovary syndrome. Enzymes bearing either glycine or serine at this position have similar substrate specificities and kinetic constants. The current findings boost to 16 the number of mutations in the HSD17B3 gene that impair testosterone synthesis and cause male pseudohermaphroditism, and add 1 apparently silent polymorphism to this tally.

Two different patterns of mini-puberty in two 46,XY newborns with 17β-hydroxysteroid dehydrogenase type 3 deficiency

2015 ◽  
Vol 28 (7-8) ◽  
Author(s):  
Korcan Demir ◽  
Melek Yıldız ◽  
Özlem Nalbantoğlu Elmas ◽  
Hüseyin Anıl Korkmaz ◽  
Selma Tunç ◽  
...  
Keyword(s):  
Chorionic Gonadotropin ◽  
Sexual Development ◽  
External Genitalia ◽  
Hydroxysteroid Dehydrogenase ◽  
First Case ◽  
Disorder Of Sexual Development ◽  
Low Testosterone ◽  
Low Levels ◽  
Type 3 ◽  
Female External Genitalia

AbstractWe report two newborns with female external genitalia and bilateral inguinal swelling who were diagnosed with 17β-hydroxysteroid dehydrogenase type 3 deficiency, a rare cause of 46,XY disorder of sexual development. The first case had normal clitoral size and vaginal and urethral openings, palpable gonads in the inguinal region, low testosterone, and low levels of basal and GNRH-stimulated gonadotropin. The second case had similar external genitalia, low testosterone but borderline basal and normal stimulated gonadotropin levels. Low testosterone/androstenedione ratios (0.22 and 0.24, respectively; normal, >0.8) after human chorionic gonadotropin stimulation indicated 17β-hydroxysteroid dehydrogenase type 3 deficiency.

scholarly journals The dilemma of the gender assignment in a Portuguese adolescent with disorder of sex development due to 17β-hydroxysteroid-dehydrogenase type 3 enzyme deficiency

2014 ◽  
Vol 2014 ◽  
Author(s):  
Carla Costa ◽  
Cíntia Castro-Correia ◽  
Alda Mira-Coelho ◽  
Bessa Monteiro ◽  
Joaquim Monteiro ◽  
...  
Keyword(s):  
Identity Development ◽  
Social Factor ◽  
External Genitalia ◽  
Hydroxysteroid Dehydrogenase ◽  
Child Psychiatrist ◽  
List Type ◽  
Gender Assignment ◽  
Disorder Of Sex Development ◽  
Sex Development ◽  
Type 3

Summary The development of male internal and external genitalia in an XY fetus requires a complex interplay of many critical genes, enzymes, and cofactors. The enzyme 17β-hydroxysteroid-dehydrogenase type 3 (17βHSD3) is present almost exclusively in the testicles and converts Delta 4-androstenodione (Δ4) to testosterone. A deficiency in this enzyme is rare and is a frequently misdiagnosed autosomal recessive cause of 46,XY, disorder of sex development. The case report is of a 15-year-old adolescent, who was raised according to female gender. At puberty, the adolescent had a severe virilization and primary amenorrhea. The physical examination showed a male phenotype with micropenis and blind vagina. The Tanner stage was A3B1P4, nonpalpable gonads. The karyotype revealed 46,XY. The endocrinology study revealed: testosterone=2.38 ng/ml, Δ4>10.00 ng/ml, and low testosterone/Δ4 ratio=0.23. Magnetic resonance imaging of the abdominal–pelvic showed the presence of testicles in inguinal canal, seminal vesicle, prostate, micropenis, and absence of uterus and vagina. The genetic study confirmed the mutation p.Glu215Asp on HSD17B3 gene in homozygosity. The dilemma of sex reassignment was seriously considered when the diagnosis was made. During all procedures the patient was accompanied by a child psychiatrist/psychologist. The teenager desired to continue being a female, so gonadectomy was performed. Estrogen therapy and surgical procedure to change external genitalia was carried out. In this case, there was a severe virilization at puberty. It is speculated to be due to a partial activity of 17βHSD3 in the testicles and/or extratesticular ability to convert Δ4 to testosterone by 17βHSD5. Prenatal exposure of the brain to androgens has increasingly been put forward as a critical factor in gender identity development, but in this case the social factor was more important for the gender assignment. Learning points In this case, we highlight the late diagnosis, probably because the patient belongs to a poor family without proper primary medical care. We emphasize the psychological and social aspects in the sex assignment decision.

Clinical, hormonal, and molecular-genetic characteristics of two cases of abnormal sex formation (ASF) in 46XY subjects caused by type 3 17-beta hydroxysteroid dehydrogenase deficiency

2011 ◽  
Vol 57 (3) ◽  
pp. 25-30
Author(s):  
A A Kolodkina ◽  
N Iu Kalinchenko ◽  
A N Nizhnik ◽  
M A Nokel' ◽  
A N Tiul'pakov
Keyword(s):  
Dehydrogenase Deficiency ◽  
Molecular Genetic ◽  
External Genitalia ◽  
Hydroxysteroid Dehydrogenase ◽  
Rare Form ◽  
Intrauterine Development ◽  
Genetic Studies ◽  
Genetic Characteristics ◽  
Sex Development ◽  
Type 3

Type 3 17-beta hydroxysteroid dehydrogenase (17HSD3) deficiency is a rare form of abnormal sex formation (ASF) in 46XY subjects in which the conversion of androstendione to testosterone is blocked; this defect results in compromised masculinization of the external genitalia during the intrauterine development. A distinctive feature of this form of sex development is masculinization at puberty due to the extragonadal conversion of androstendione to testosterone. Two clinical cases are reported: both girls were born with the female-type of external genitalia and 46XY karyotype, but progressive virilization in the pubertal period gave reason to suspect diagnosis of 17HSD3 deficiency. In both cases, this diagnosis was confirmed in molecular genetic studies (the following mutations were identified in the HSD17B3 gene: c.728-734delGATAACCp.1244fsX254/c.277+4A>T and c.277+4A>T). These two cases are the first reports of 17HSD3 deficiency in the Russian literature.

A Novel Mutation Glyl672→Arg in Type 2A and a Homozygous Mutation in Type 2B von Willebrand Disease

1996 ◽  
Vol 76 (02) ◽  
pp. 253-257 ◽  
Author(s):  
Takeshi Hagiwara ◽  
Hiroshi Inaba ◽  
Shinichi Yoshida ◽  
Keiko Nagaizumi ◽  
Morio Arai ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Novel Mutation ◽  
Point Mutations ◽  
Japanese Patients ◽  
Von Willebrand Disease ◽  
Homozygous Mutation ◽  
Missense Mutations ◽  
Reaction Products ◽  
Type 3 ◽  
Von Willebrand

SummaryGenetic materials from 16 unrelated Japanese patients with von Willebrand disease (vWD) were analyzed for mutations. Exon 28 of the von Willebrand factor (vWF) gene, where point mutations have been found most frequent, was screened by various restriction-enzyme analyses. Six patients were observed to have abnormal restriction patterns. By sequence analyses of the polymerase chain-reaction products, we identified a homozygous R1308C missense mutation in a patient with type 2B vWD; R1597W, R1597Q, G1609R and G1672R missense mutations in five patients with type 2A; and a G1659ter nonsense mutation in a patient with type 3 vWD. The G1672R was a novel missense mutation of the carboxyl-terminal end of the A2 domain. In addition, we detected an A/C polymorphism at nucleotide 4915 with HaeIII. There was no particular linkage disequilibrium of the A/C polymorphism, either with the G/A polymorphism at nucleotide 4391 detected with Hphl or with the C/T at 4891 detected with BstEll.

scholarly journals Association of three missense mutations in the homocysteine-related MTHFR and MTRR gene with risk of polycystic ovary syndrome in Southern Chinese women

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Wanqin Feng ◽  
Yan Zhang ◽  
Yuan Pan ◽  
Yi Zhang ◽  
Minjuan Liu ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Polycystic Ovary Syndrome ◽  
Mediation Analysis ◽  
Homocysteine Level ◽  
Polycystic Ovary ◽  
Linear Regression Analysis ◽  
Dependent Manner ◽  
Missense Mutations ◽  
Ovary Syndrome ◽  
Southern Chinese

Abstract Background The etiology between homocysteine and polycystic ovary syndrome (PCOS) is unclear. In humans, the level of homocysteine is mainly affected by two enzymes: methylene tetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR). While the activity of these two enzymes is mainly affected by three missense mutations, namely C677T (MTHFR), A1298C (MTHFR), and A66G (MTRR). This study aims to examine the association between the three missense mutations and PCOS and investigate whether the three missense mutations exerted their effect on PCOS by affecting the homocysteine level. Methods A case-control study was designed, comprising 150 people with PCOS and 300 controls. Logistic regression analysis was used to assess the association between the three missense mutations and PCOS. Linear regression analysis was used to assess the association between the three missense mutations and the homocysteine level. Mediation analysis was used to investigate whether the three missense mutations exerted their effect on PCOS by affecting the homocysteine level. Results Following adjustments and multiple rounds of testing, MTHFR A1298C was found to be significantly associated with PCOS in a dose-dependent manner (compared to AA, OR = 2.142 for AC & OR = 3.755 for CC; P < 0.001). MTRR A66G was nominally associated with PCOS. Mutations in MTHFR A1298C and MTRR A66G were significantly associated with the homocysteine level. Mediation analysis suggested the effect of MTHFR A1298C on PCOS was mediated by homocysteine. Conclusions MTHFR A1298C and MTRR A66G were associated with PCOS, and MTHFR A1298C might affect the risk of PCOS by influencing the homocysteine level.

Male pseudohermaphroditism caused by mutations of testicular 17β–hydroxysteroid dehydrogenase 3

1994 ◽  
Vol 7 (1) ◽  
pp. 34-39 ◽  
Author(s):  
Wayne M. Geissler ◽  
Daphne L. Davis ◽  
Ling Wu ◽  
Karen D. Bradshaw ◽  
Sushma Patel ◽  
...  
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Male Pseudohermaphroditism

scholarly journals Tissue-specific dysregulation of 11β-hydroxysteroid dehydrogenase type 1 in overweight/obese women with polycystic ovary syndrome compared with weight-matched controls

2014 ◽  
Vol 171 (1) ◽  
pp. 47-57 ◽  
Author(s):  
Alessandra Gambineri ◽  
Flaminia Fanelli ◽  
Federica Tomassoni ◽  
Alessandra Munarini ◽  
Uberto Pagotto ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Hydroxysteroid Dehydrogenase ◽  
Whole Body ◽  
Mrna Levels ◽  
Ovary Syndrome ◽  
Tissue Specific ◽  
Cortisol Metabolism ◽  
Cortisol Metabolites

ContextAbnormal cortisol metabolism in polycystic ovary syndrome (PCOS) has been invoked as a cause of secondary activation of the hypothalamic–pituitary–adrenal axis and hence androgen excess. However, this is based on urinary excretion of cortisol metabolites, which cannot detect tissue-specific changes in metabolism and may be confounded by obesity.ObjectiveTo assess cortisol clearance and whole-body and tissue-specific activities of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1 (HSD11B1)) in PCOS.DesignCase–control study.SettingMedical center.PatientsA total of 20 overweight–obese unmedicated Caucasian women with PCOS, aged 18–45 years, and 20 Caucasian controls matched for age, BMI, body fat distribution, andHSD11B1genotypes (rs846910 and rs12086634).Main outcome measuresCortisol metabolites were measured in 24 h urine. During steady-state 9,11,12,12-[2H]4-cortisol infusion, cortisol clearance was calculated and whole-body HSD11B1 activity was assessed as the rate of appearance of 9,12,12-2H3-cortisol (d3-cortisol). Hepatic HSD11B1 activity was quantified as the generation of plasma cortisol following an oral dose of cortisone. Subcutaneous adipose HSD11B1 activity andHSD11B1mRNA were measured,ex vivo, in biopsies.ResultsUrinary cortisol metabolite excretion, deuterated cortisol clearance, and the rate of appearance of d3-cortisol did not differ between patients with PCOS and controls. However, hepatic HSD11B1 conversion of oral cortisone to cortisol was impaired (P<0.05), whereas subcutaneous abdominal adipose tissueHSD11B1mRNA levels and activity were increased (P<0.05) in women with PCOS when compared with controls.ConclusionsTissue-specific dysregulation of HSD11B1 is a feature of PCOS, over and above obesity, whereas increased clearance of cortisol may result from obesity rather than PCOS.

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