3β-Hydroxysteroid Dehydrogenase Type 2 (3βHSD2) Deficiency due to a Novel Compound Heterozygosity of a Missense Mutation (p.Thr259Met) and Frameshift Deletion (p.Lys273ArgFs*7) in an Undervirilized Infant Male with Salt Wasting

2021 ◽  
pp. 1-6
Author(s):  
Sofia Leka-Emiri ◽  
Ludmia Taibi ◽  
Vasiliki Mavroeidi ◽  
Elpis A. Vlachopapadopoulou ◽  
Maria Kafetzi ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Genetic Defect ◽  
Male Infant ◽  
Hydroxysteroid Dehydrogenase ◽  
Laboratory Evaluation ◽  
Compound Heterozygosity ◽  
Salt Wasting ◽  
Frameshift Deletion ◽  
Genital Ambiguity

Deficiency of 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2) is a rare type of congenital adrenal hyperplasia (CAH), causing impaired steroid hormone production in both adrenals and gonads. Phenotype ranges, according to the genetic defect, from the salt-wasting form in both sexes to undervirilization in males and virilization in females. We present a 13-month-old male infant who was admitted to the hospital with signs of adrenocortical insufficiency and genital ambiguity. Clinical presentation, hormonal profile, laboratory evaluation, and karyotype were suggestive of the salt-wasting form of CAH due to 3βHSD2 deficiency. Mutational analysis revealed a missense mutation c.776C>T (p.Thr259Met), inherited by the mother, and a frameshift deletion c.818-819delAA (p.Lys273ArgFs*7), inherited by the father. Both mutations are considered pathogenic. To our knowledge this is the first case of an undervirilized male infant with salt wasting bearing this pathogenic frameshift deletion p.Lys273ArgFs*7 in compound heterozygosity with the missense mutation p.Thr259Met.

scholarly journals Characterization of Two Novel Homozygous Missense Mutations Involving Codon 6 and 259 of Type II 3β-Hydroxysteroid Dehydrogenase (3βHSD) Gene Causing, Respectively, Nonsalt-Wasting and Salt-Wasting 3βHSD Deficiency Disorder1

2000 ◽  
Vol 85 (4) ◽  
pp. 1678-1685
Author(s):  
Li Zhang ◽  
J. Ian Mason ◽  
Yasuhiro Naiki ◽  
Kenneth C. Copeland ◽  
Mariano Castro-Magana ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Clinical Phenotype ◽  
Hydroxysteroid Dehydrogenase ◽  
Missense Mutations ◽  
Type Ii ◽  
Mutant Type ◽  
Salt Wasting ◽  
Genital Ambiguity ◽  
Relative Conversion

We identified two homozygous missense mutations in the human type II 3β-hydroxysteroid dehydrogenase (3βHSD) gene, the first in codon 6 of exon II [CTT (Leu) to TTT (Phe)] in a male infant with hyperpigmented scrotum and hypospadias, raised as a male and no apparent salt-wasting since neonatal age, and the second in codon 259 of exon IV [ACG (Thr) to ATG (Met)] in a male pseudohermaphrodite with labial scrotal folds, microphallus, chordee, and fourth degree hypospadias, raised as a female and with salt-wasting disorder since neonatal age. In vitro transient expression of mutant type II 3βHSD complementary DNAs of L6F, T259M, as well as T259R for comparison was examined by a site-directed mutagenesis and transfection of construct into COS-1 and COS-7 cells. Northern blot analysis revealed expression of similar amounts of type II 3βHSD messenger ribonucleic acid from the COS-1 cells transfected by L6F, T259M, T259R, and wild-type (WT) complementary DNAs. Western immunoblot analysis revealed a similar amount of L6F mutant protein compared to WT enzyme from COS-1 cells, but neither L6F from COS-7 cells nor T259M or T259R mutant protein in COS-1 or COS-7 cells was detectable. Enzyme activity in intact COS-1 cells using 1 μmol/L pregnenolone as substrate in the medium after 6 h revealed relative conversion rates of pregnenolone to progesterone of 46% by WT enzyme, 22% by L6F enzyme, and 8% by T259M enzyme and less than 4% activity by T259R enzyme. Using 1 μmol/L dehydroepiandrosterone as substrate, the relative conversion rate of dehydroepiandrosterone to androstenedione after 6 was 89% by WT enzyme, 35% by L6F enzyme, 5.1% by T259M enzyme and no activity by T259R enzyme. However, the L6F mutant 3βHSD activity, despite its demonstration in the intact cells, was not detected in homogenates of COS-1 cells or in immunoblots of COS-7 cells, suggestive of the relatively unstable nature of this protein in vitro, possibly attributable to the decreased 3βHSD activity. In the case of T259M and T259R mutations, consistently undetectable proteins in both COS cells despite detectable messenger ribonucleic acids indicate severely labile proteins resulting in either no or very little enzyme activity, and these data further substantiate the deleterious effect of a structural change in this predicted putative steroid-binding domain of the gene. In conclusion, the findings of the in vitro study of mutant type II 3βHSD enzyme activities correlated with a less severe clinical phenotype of nonsalt-wasting and a lesser degree of genital ambiguity in the patient with homozygous L6F mutation compared to a more severe clinical phenotype of salt-wasting and severe degree of genital ambiguity in the patient with homozygous T259M mutation in the gene.

scholarly journals 3?-hydroxysteroid dehydrogenase type II deficiency on newborn screening test

2014 ◽  
Vol 58 (6) ◽  
pp. 650-655 ◽  
Author(s):  
Vitor Guilherme Brito de Araújo ◽  
Renata Santarem de Oliveira ◽  
Kallianna Paula Duarte Gameleira ◽  
Cátia Barbosa Cruz ◽  
Adriana Lofrano-Porto
Keyword(s):  
Newborn Screening ◽  
Screening Test ◽  
Hydroxysteroid Dehydrogenase ◽  
Screening Tests ◽  
Adrenal Crisis ◽  
Type Ii ◽  
Hydroxylase Deficiency ◽  
Salt Wasting ◽  
Genital Ambiguity ◽  
21 Hydroxylase Deficiency

3b-hydroxysteroid dehydrogenase II (3β-HSD) deficiency represents a rare CAH variant. Newborns affected with its classic form have salt wasting in early infancy and genital ambiguity in both sexes. High levels of 17-hydroxypregnenolone (Δ517OHP) are characteristic, but extra-adrenal conversion to 17-hydroxyprogesterone (17OHP) may lead to positive results on newborn screening tests. Filter paper 17OHP on newborn screening test was performed by immunofluorometric assay, and serum determinations of 17OHP and Δ517OHP, by radioimmunoassay. A 46,XY infant with genital ambiguity and adrenal crisis at three months of age presented a positive result on newborn screening for CAH. Serum determinations of 17OHP and Δ517OHP were elevated, and a high Δ517OHP/cortisol relation was compatible with the diagnosis of 3β-HSD deficiency. Molecular analysis of the HSD3B2 gene from the affected case revealed the presence of the homozygous p.P222Q mutation, whereas his parents were heterozygous for it. We present the first report of 3β-HSD type II deficiency genotype-proven detected at the Newborn Screening Program in Brazil. The case described herein corroborates the strong genotype-phenotype correlation associated with the HSD3B2 p.P222Q mutation, which leads to a classic salt-wasting 3β-HSD deficiency. Further evaluation of 17OHP assays used in newborn screening tests would aid in determining their reproducibility, as well as the potential significance of moderately elevated 17OHP levels as an early indicator to the diagnosis of other forms of classic CAH, beyond 21-hydroxylase deficiency.

A novel missense mutation of CRYBA1 in a northern Chinese family with inherited coronary cataract with blue punctate opacities

2021 ◽  
pp. 112067212110083
Author(s):  
Shu-Hua Ni ◽  
Juan-Mei Zhang ◽  
Jun Zhao
Keyword(s):  
Missense Mutation ◽  
High Throughput Sequencing ◽  
Bioinformatics Analysis ◽  
Genetic Defect ◽  
Kinase Domain ◽  
Chinese Family ◽  
Heterozygous Mutation ◽  
Scale Invariant ◽  
The Family ◽  
Northern Chinese

Purpose: To demonstrate the underlying genetic defect that contribute to inherited cataract in a northern Chinese pedigree. Methods: The study recruited a family pedigree with a diagnosis of bilateral coronary cataract with blue punctate opacities. Fourteen family members and 100 healthy volunteers were enrolled. DNA sample of the proband in this family were analyzed by high-throughput sequencing, which was then demonstrated by Sanger sequencing in the remained people in the family and 100 controls. The functional effect of mutant genes was investigated via bioinformatics analysis, including Polymorphism Phenotyping version2 (PolyPhen-2), Protein Variation Effect Analyzer (PROVEAN v1.1.3) Scale-Invariant Feature Transform (SIFT), and Mutation Taster. Results: In this three-generation family, a novel heterozygous mutation was found in the kinase domain of CRYBA1 gene (c.340C > T, p.R114C), which was only detected in patients in the family with inherited cataract and were not detected in the remained people in the family nor in normal people. The pathogenic effect of the mutation was verified via bioinformatics analysis. Conclusion: Our study presented the molecular experiments to confirm that a novel missense mutation of c.340 C > T located in exon 4 of CRYBA1 gene results in a bilateral coronary cataract with blue punctate opacities, which enriches the mutation spectrum of CRYBA1 gene in inherited cataract and deepens the understanding of the pathogenesis of inherited cataract.

scholarly journals Synthesis, purification and crystallographic studies of the C-terminal sterol carrier protein type 2 (SCP-2) domain of human hydroxysteroid dehydrogenase-like protein 2

2015 ◽  
Vol 71 (7) ◽  
pp. 901-905 ◽  
Author(s):  
Zhong Cheng ◽  
Yao Li ◽  
Chun Sui ◽  
Xiaobo Sun ◽  
Yong Xie
Keyword(s):  
Catalytic Domain ◽  
Hydroxysteroid Dehydrogenase ◽  
Carrier Protein ◽  
Sterol Carrier Protein ◽  
X Ray Diffraction ◽  
Unit Cell Parameters ◽  
X Ray ◽  
Cell Parameters ◽  
Protein Molecules

Human hydroxysteroid dehydrogenase-like protein 2 (HSDL2) is a member of the short-chain dehydrogenase/reductase (SDR) subfamily of oxidoreductases and contains an N-terminal catalytic domain and a C-termianl sterol carrier protein type 2 (SCP-2) domain. In this study, the C-terminal SCP-2 domain of human HSDL2, including residues Lys318–Arg416, was produced inEscherichia coli, purified and crystallized. X-ray diffraction data were collected to 2.10 Å resolution. The crystal belonged to the trigonal space groupP3121 (orP3221), with unit-cell parametersa=b= 70.4,c= 60.6 Å, α = β = 90, γ = 120°. Two protein molecules are present in the asymmetric unit, resulting in a Matthews coefficient of 2.16 Å3 Da−1and an approximate solvent content of 43%.

A novel missense mutation in ADRB3 increases risk for type 2 diabetes in a Mexican American family

2006 ◽  
Vol 22 (4) ◽  
pp. 331-336 ◽  
Author(s):  
Donna M. Lehman ◽  
Jeanette Hamlington ◽  
Kelly J. Hunt ◽  
Robin J. Leach ◽  
Rector Arya ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Missense Mutation ◽  
Mexican American ◽  
American Family ◽  
Mexican American Family

11β Hydroxysteroid Dehydrogenase Type 2 in the Adrenal Gland by Testosterone Withdrawal of Adult Rats

Folia Medica ◽  
2010 ◽  
Vol 52 (2) ◽  
Author(s):  
Yvetta Koeva ◽  
Mariana Bakalska ◽  
Elisaveta Petrova ◽  
Nina Atanassova
Keyword(s):  
Adrenal Gland ◽  
Hydroxysteroid Dehydrogenase ◽  
Adult Rats

11β hydroxysteroid dehydrogenase type 2 enzyme is expressed in normotensive and hypertensive patients with renal disease

Nephrology ◽  
2008 ◽  
Vol 4 (1-2) ◽  
pp. 81-86
Author(s):  
Alicia N STEIN-OAKLEY ◽  
Julie A MAGUIRE ◽  
John DOWLING ◽  
Greg J PERRY ◽  
Zygmunt KROZOWSKI ◽  
...  
Keyword(s):  
Renal Disease ◽  
Hydroxysteroid Dehydrogenase ◽  
Hypertensive Patients
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