Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Steroid 21-hydroxylase deficiency is the leading cause of impaired cortisol synthesis in congenital adrenal hyperplasia (CAH). We have studied the structure of the CYP21B gene in 30 unrelated CAH patients using the polymerase chain reaction (PCR) to differentiate the active CYP21B gene from its highly related CYP21A pseudogene. The PCR approach obviates the need to distinguish the CYP21A and CYP21B genes by restriction endonuclease digestion and electrophoresis before analysis with labeled probes. Furthermore, direct nucleotide sequence analysis of CYP21B genes is demonstrated on the PCR-amplified DNA. Gene deletion of CYP21B, gene conversion of the entire CYP21B gene to CYP21A, frame shift mutations in exon 3, an intron 2 mutation that causes abnormal RNA splicing, and a mutation leading to a stop codon in exon 8 appear to be the major abnormalities of the CYP21B gene in our patients. These mutations appear to account for 21-hydroxylase deficiency in 22 of 26 of our salt-wasting CAH patients.
Mol Endocrinol 1990 Jan
PMID:Direct analysis of CYP21B genes in 21-hydroxylase deficiency using polymerase chain reaction amplification. 232 62

Congenital adrenal hyperplasia (CAH) is a family of inherited disorders of adrenal steroidogenesis, most commonly due to deficiency of P-450 21-hydroxylase (21-OH). There are two genes for 21-OH on the short arm of chromosome 6, the A gene which is thought to be inactive, and the B gene. These genes appear as 3.2 and 3.7 kb TaqI fragments on Southern blots. In a study of DNA from 60 normal controls with TaqI and a 21-OH cDNA probe, 12% exhibited a homozygous deletion of the A gene, and 22 and 8% heterozygous deletions of A and B genes respectively. TaqI analysis of eight patients with CAH revealed four without A or B gene deletions, three with heterozygous deletions of the B gene and one with a homozygous deletion of the B gene. On further analysis with KpnI, EcoRI, PvuII and BglII, however, these genotypes were amended to two with heterozygous deletions of the B gene and two with possible B to A gene conversions. The genotypes of the four patients without deletions remained unchanged. RNA from CAH and Cushing's adrenal tissue was also analysed using A and B gene-specific oligodeoxynucleotide probes. B gene transcripts were detected in both CAH and Cushing's adrenals, while no A gene transcripts could be detected in either tissue. The level of B gene-derived mRNA was greater in the Cushing's adrenal than in the CAH adrenal, which in turn was greater than that in the adrenal from a normal individual.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Endocrinol 1988 Nov
PMID:DNA and RNA analysis of cytochrome P-450 21-hydroxylase: transcriptional activity in congenital adrenal hyperplasia. 247 27

Congenital adrenal hyperplasia (CAH) is due to defective adrenal cortisol biosynthesis. In most cases, deficiency of a P 450-C21 specific steroid hydroxylase impairing cortisol synthesis has been found. The disease is HLA-linked, and on clinical grounds it can be divided into two major forms, the classical and the non-classical type. Here, evidence is presented that the classical and the non-classical forms of CAH caused by 21-OH deficiency are due to different genetic alterations in the C4/21-OH gene region. In most cases of classical CAH associated with the HLA-Bw47 antigen, a specific and selective loss of the 21-OH B gene was observed with some interesting exceptions. Alterations in the 21-OH gene region in the non-classical forms of CAH, patients either HLA-B14; DR1 homo- or heterozygous, are different. Our data indicate the possibility of gene conversion events in this genomic region in non-classical CAH.
Mol Biol Med 1986 Oct
PMID:Classical and late-onset forms of congenital adrenal hyperplasia caused by 21-OH deficiency reveal different alterations in the C4/21-OH gene region. 288 4

The enzyme 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) catalyses an essential step in the biosynthesis of all classes of steroid hormones. Classical 3 beta-HSD deficiency is responsible for CAHII, a severe form of congenital adrenal hyperplasia (CAH) that impairs steroidogenesis in both the adrenals and gonads. Newborns affected by 3 beta-HSD deficiency exhibit signs and symptoms of adrenal insufficiency of varying degrees associated with pseudohermaphroditism in males, whereas females exhibit normal sexual differentiation or mild virilization. Elevated ratios of 5-ene-to 4-ene-steroids appear as the best biological parameter for the diagnosis of 3 beta-HSD deficiency. The nonclassical form has been suggested to be related to an allelic variant of the classical form of 3 beta-HSD as described for steroid 21-hydroxylase deficiency. To elucidate the molecular basis of the classical form of 3 beta-HSD deficiency, we have analysed the structure of the highly homologous type I and II 3 beta-HSD genes in 12 male pseudohermaphrodite 3 beta-HSD deficient patients as well as in four female patients. The 14 different point mutations characterized were all detected in the type II 3 beta-HSD gene, which is the gene predominantly expressed in the adrenals and gonads, while no mutation was detected in the type I 3 beta-HSD gene predominantly expressed in the placenta and peripheral tissues. The finding of a normal type I 3 beta-HSD gene provides the explanation for the intact peripheral intracrine steroidogenesis in these patients and increased androgen manifestations at puberty. The influence of the detected mutations on enzymatic activity was assessed by in vitro expression analysis of mutant enzymes generated by site-directed mutagenesis in COS-1 cells. The mutant type II 3 beta-HSD enzymes carrying mutations detected in patients affected by the salt-losing form exhibit no detectable activity in intact transfected cells, whereas those with mutations found in nonsalt-loser index cases have some residual activity ranging from approximately 1-10% compared to the wild-type enzyme. Although in general, our findings provide a molecular explanation for the enzymatic heterogeneity ranging from the severe salt-losing form to the clinically inapparent salt-wasting form of the disease, we have observed that the mutant L108W or P186L enzymes found in a compound heterozygote male presenting the salt-wasting form of the disease, has some residual activity (approximately 1%) similar to that observed for the mutant N100S enzyme detected in a homozygous male patient suffering from a nonsalt-losing form of this disorder.(ABSTRACT TRUNCATED AT 400 WORDS)
J Steroid Biochem Mol Biol 1995 Jun
PMID:Molecular basis of human 3 beta-hydroxysteroid dehydrogenase deficiency. 762 45

Congenital adrenal hyperplasia due to 17 alpha-hydroxylase/17/20-lyase deficiency is caused by genetic defects in the gene encoding P450c17 (CYP17). To date, 18 different mutations in 27 individuals have been identified and all of them are located in the coding region of CYP17. Several mutations have been reconstructed in human P450c17 cDNA and expressed in COS cells to characterize the kinetic properties of 17 alpha-hydroxylase and 17,20-lyase activities. The molecular bases of cases clinically reported as 17 alpha-hydroxylase deficiency have turned out to result from complete or partial combined deficiencies of 17 alpha-hydroxylase/17,20-lyase. The elucidation of the molecular bases generally explains the patient's clinical profiles including the sexual phenotype of the external genitalia. In one case initially reported as isolated 17,20-lyase deficiency, the molecular basis was found to be partial combined deficiency of both activities, somewhat discordant with the patient's clinical profile. However, the patient was subsequently found to have 17 alpha-hydroxylase deficiency, suggesting involvements of age-dependent unknown factors affecting P450c17 activity.
J Steroid Biochem Mol Biol 1995 Jun
PMID:17 alpha-Hydroxylase/17,20-lyase defects. 762 47

The results of measurement of 17-hydroxyprogesterone (17-OH-P) in 125 samples of amniotic fluid (AF) from early amniocenteses are presented. The fetuses from all pregnancies studied were unaffected by congenital adrenal hyperphasia caused by 21-hydroxylase deficiency. The AF 17-OH-P level increases slightly but significantly between the 11th and 15th week of gestation, with a maximum in the 14th week. There is no difference between the values measured in male and female fetuses. The AF 17-OH-P levels from the early gestation were compared with those from the 16th-22nd week of pregnancy (published previously). The overall differences of AF 17-OH-P concentrations when considered in all gestational age groups in the whole period 12-22 weeks were statistically insignificant. Thus, the biochemical prenatal diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency and control of its early fetal treatment could be carried out starting from the end of the first trimester in the same way as at the later period of gestation.
J Steroid Biochem Mol Biol 1994 Dec
PMID:Amniotic fluid 17-hydroxyprogesterone in early pregnancy. 782 94

Two isoenzymes are responsible for 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) activity in humans. We analyzed the structure of types I and II 3 beta-HSD genes in a male pseudohermaphrodite suffering from a severe salt-losing form of congenital adrenal hyperplasia. We did not detect any mutation in the type I 3 beta-HSD gene, but we found two different missense mutations in exon IV of the type II 3 beta-HSD gene of the patient; a conversion of codon Leu108 into a Trp (L108W) inherited from his mother and a conversion of codon Pro186 into a Leu (P186L) inherited from his father. We assessed the effect of the L108W and P186L mutations on 3 beta-HSD activity by in vitro analysis of mutant enzymes expressed in heterologous COS-1 cells. Using homogenates from transfected cells, the Km values for PREG were 7 +/- 2 and 8 +/- 2 microM for the recombinant L108W and P186L enzymes, respectively, compared with 2.2 +/- 0.2 microM for the normal type II 3 beta-HSD enzyme. Moreover, Km values for NAD+ were much higher for the L108W and P186L proteins, being 678 +/- 166 and 920 +/- 351 microM, respectively, compared with 24 +/- 3 microM for the normal type II 3 beta-HSD enzyme. Vmax values for PREG and NAD+ were lower for both mutant enzymes; thus, the in vitro overall efficiency, relative to the normal enzyme, is approximate as 0.3% and 0.2% for the L108W and P186L enzymes, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Hum Mol Genet 1994 Sep
PMID:Functional characterization of the novel L108W and P186L mutations detected in the type II 3 beta-hydroxysteroid dehydrogenase gene of a male pseudohermaphrodite with congenital adrenal hyperplasia. 783 23

Classical 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency is an autosomal recessive form of congenital adrenal hyperplasia caused by mutations in the type II 3 beta-HSD (HSD3B2) gene. The sequence of the type II 3 beta-HSD gene was determined by direct sequencing of asymmetric PCR products in three male infants suffering from a severe salt-losing form of 3 beta-HSD deficiency and belonging to three families originating from Afghanistan and Pakistan. The three patients were homozygous for the frameshift mutation 273 delta AA resulting from deletion of two adenosines at codon 273, thus leading to a premature termination codon at position 279. This mutation was detected in the heterozygous state in all the relatives studied. The observation that all three patients share the same haplotype for HSD3B1A, HSD3B1C, HSD3B2A, and the microsatellite marker D1S252 indicates that a founder effect is responsible for the severe form of 3 beta-HSD deficiency found in these three families.
Hum Mol Genet 1994 Feb
PMID:Congenital adrenal hyperplasia caused by a novel homozygous frameshift mutation 273 delta AA in type II 3 beta-hydroxysteroid dehydrogenase gene (HSD3B2) in three male patients of Afghan/Pakistani origin. 800 3

Congenital adrenal hyperplasia (CAH) results from an enzymatic block at any stage in the synthesis of cortisol. All enzyme defects causing CAH are autosomal recessive traits. It is a relatively common disease, occurring in 1 in 5000 to 1 in 15,000 births in most populations. Since the isolation of the gene responsible for steroid 21-hydroxylase deficiency (involved in about 90% of the cases of CAH) in 1984, knowledge of the specific mutations that cause the different forms of CAH has grown rapidly. Defects in the encoding gene have been confirmed as the basis of endocrine disease in the case of all but one of the adrenal steroidogenic enzymes. Analysis of DNA obtained by chorionic villus sampling in early pregnancy permits prenatal diagnosis and treatment of 21-hydroxylase deficiency CAH. The correlation between the clinical expression of endocrine disease and the mutations of the primary structural gene is not absolute. Clinicians cannot accurately predict the course of the disease or make therapeutic decisions based on the genotype alone. We will review the various forms of clinical presentation of 21-hydroxylase CAH, its etiology, diagnosis, molecular genetics, and treatment.
J Steroid Biochem Mol Biol 1994 Jan
PMID:21-hydroxylase deficiency congenital adrenal hyperplasia. 813 1

Congenital adrenal hyperplasia is the most frequent cause of adrenal insufficiency and ambiguous genitalia in newborn children. In contrast to congenital adrenal hyperplasia due to 21-hydroxylase and 11 beta-hydroxylase deficiencies, which impair steroid formation in the adrenal cortex, exclusively, classical 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency affects steroid biosynthesis in the gonads as well as in the adrenals. The structures of the highly homologous type I and II 3 beta-HSD genes have been analyzed in three male pseudohermaphrodite 3 beta-HSD deficient patients from unrelated families in order to elucidate the molecular basis of classical 3 beta-HSD deficiency from patients exhibiting various degrees of severity of salt losing. The nucleotide sequence of DNA fragments generated by selective polymerase chain reaction amplification that span the four exons, the exon-intron boundaries, as well as the 5'-flanking region of each of the two 3 beta-HSD genes have been determined in the three male patients. The five point mutations characterized were all detected in the type II 3 beta-HSD gene, which is the gene predominantly expressed in the adrenals and gonads, while no mutation was detected in the type I 3 beta-HSD gene, predominantly expressed in the placenta and peripheral tissues. The two male patients suffering from severe salt-losing 3 beta-HSD deficiency are compound heterozygotes, one bearing the frame-shift mutation 186/insC/187 and the missense mutation Y253N, while the other bears the nonsense mutation W171X and the missense mutation E142K. The influence of the detected missense mutations on enzymatic activity was assessed by in vitro expression analysis of mutant recombinant enzymes generated by site-directed mutagenesis in heterologous mammalian cells. Recombinant mutant type II 3 beta-HSD enzymes carrying Y253N or E142K substitutions exhibit no detectable activity. On the other hand, the nonsalt-losing patient is homozygous for the missense mutation A245P. This mutation decreases 3 beta-HSD activity by approximately 90%. The present findings, describing the first missense mutations in the human type II 3 beta-HSD gene, provide unique information on the structure-activity relationships of the 3 beta-HSD superfamily. Moreover, the present findings provide a molecular explanation for the enzymatic heterogeneity responsible for the severe salt-losing form to the clinically inapparent salt-wasting form of classical 3 beta-HSD deficiency.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Endocrinol 1993 May
PMID:Molecular basis of congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency. 831 54


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