Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Congenital adrenal hyperplasia (CAH) is a common autosomal recessive disorder which causes more than 90% of CAH cases due to defects in the steroid 21-hydroxylase gene (CYP21A2). The frequency of large mutations was determined in 200 ethnic Chinese (i.e., Taiwanese) CAH patients belonging to 200 families with different clinical forms of CYP21A2 deficiency over 10 years of molecular diagnoses. For a large-gene deletion (or conversion) and the CYP21A2 deletion identification, a PCR product covering the TNXB gene and the 5'-end of the CYP21A2 gene with TaqI endonuclease digestion was analyzed by electrophoresis on agarose gels. For CYP21A2 mutational analysis, secondary PCR amplification of the amplification-created restriction site method was applied. From the results of the analysis, we found that large-gene deletions (or conversions) occurred in 7.5% of the alleles including three different types of the chimeric CYP21A1P/CYP21A2 genes and the haplotype of IVS2-12A/C>G in combination with the 707-714del mutation (without the P30L mutation). The CYP21A2 deletion occurred in 2.0% of the alleles which contained three types of the chimeric TNXA/TNXB genes with two novel ones. We concluded that the CYP21A2 deletion in the ethnic Chinese (Taiwanese) patients exhibits a low occurrence, with the haplotype of the IVS2-12A/C>G in combination with the 707-714del mutation (without the P30L mutation) being prevalent among large gene deletions or conversions.
Mol Genet Metab 2008 Apr
PMID:Low frequency of the CYP21A2 deletion in ethnic Chinese (Taiwanese) patients with 21-hydroxylase deficiency. 1803 88

Inter-individual gene copy-number variations (CNVs) probably afford human populations the flexibility to respond to a variety of environmental challenges, but also lead to differential disease predispositions. We investigated gene CNVs for complement component C4 and steroid 21-hydroxylase from the RP-C4-CYP21-TNX (RCCX) modules located in the major histocompatibility complex among healthy Asian-Indian Americans (AIA) and compared them to European Americans. A combination of definitive techniques that yielded cross-confirmatory results was used. The medium gene copy-numbers for C4 and its isotypes, acidic C4A and basic C4B, were 4, 2 and 2, respectively, but their frequencies were only 53-56%. The distribution patterns for total C4 and C4A are skewed towards the high copy-number side. For example, the frequency of AIA-subjects with three copies of C4A (30.7%) was 3.92-fold of those with a single copy (7.83%). The monomodular-short haplotype with a single C4B gene and the absence of C4A, which is in linkage-disequilibrium with HLA DRB1*0301 in Europeans and a strong risk factor for autoimmune diseases, has a frequency of 0.012 in AIA but 0.106 among healthy European Americans (p=6.6x10(-8)). The copy-number and the size of C4 genes strongly determine the plasma C4 protein concentrations. Parallel variations in copy-numbers of CYP21A (CYP21A1P) and TNXA with total C4 were also observed. Notably, 13.1% of AIA-subjects had three copies of the functional CYP21B, which were likely generated by recombinations between monomodular and bimodular RCCX haplotypes. The high copy-numbers of C4 and the high frequency of RCCX recombinants offer important insights to the prevalence of autoimmune and genetic diseases.
Mol Immunol 2009 Apr
PMID:Great genotypic and phenotypic diversities associated with copy-number variations of complement C4 and RP-C4-CYP21-TNX (RCCX) modules: a comparison of Asian-Indian and European American populations. 1913 23

Aldosterone is principally synthesized in the zona glomerulosa of the adrenal by a series of enzymatic reactions leading to the conversion of cholesterol to aldosterone. Angiotensin II (Ang II) is the major physiological regulator of aldosterone production acting acutely to stimulate aldosterone biosynthesis and chronically to increase the capacity of the adrenals to produce aldosterone. We previously defined eight transcription factors that are rapidly induced following Ang II treatment using three in vitro adrenocortical cell models. Herein, we investigated the function of these transcription factors in the regulation of the enzymes needed for aldosterone production. H295R adrenal cells were co-transfected with expression vectors for each transcription factor and promoter/reporter constructs prepared for genes encoding the enzymes needed for aldosterone production. NGFI-B family members induced promoter activity of 3-beta-hydroxysteroid-dehydrogenase type 2 (HSD3B2), 21-hydroxylase (CYP21A2), and aldosterone synthase (CYP11B2). The importance of NGFI-B in the regulation of CYP11B2 was also demonstrated by reduced CYP11B2 transcription in the presence of a dominant-negative-NGFI-B. A pharmacological approach was used to characterize the Ang II pathways regulating transcription of NGFI-B family genes. Transcription of NGFI-B members were decreased following inhibition of Ang II type 1 receptor (AT1R), protein kinase C (PKC), calcium/calmodulin-dependent kinases (CaMK), and Src tyrosine kinase (SRC). Taken together, these results suggest that Ang II binding to the AT1R increases activity of PKC, CaMK, and SRC, which act to increase expression of the family of NGFI-B genes as well as CYP11B2. Ang II induction of the NGFI-B family members represents an important pathway to increase the capacity of adrenal cells to produce aldosterone.
J Mol Endocrinol 2009 Apr
PMID:Role of angiotensin II-induced rapid response genes in the regulation of enzymes needed for aldosterone synthesis. 1915 34

Genes encoding the steroid 21-hydroxylase (CYP21A2) and the complement component C4 proteins (C4A and C4B) are located in the MHC region in a strongly linked structure named RCCX module. Previous studies found that carriers of C4B gene deficiency (C4B*Q0) have higher risk for cardiovascular diseases. A potential explanation is that lacking the C4B gene may result in altered function of the neighboring CYP21A2 gene. Therefore we sequenced the CYP21A2 gene in 96 healthy individuals to identify polymorphisms and to characterize their linkage pattern. Fifty-three variations were detected including a new one which alters the TATA-box of the gene. Only three known mutations (V281L, Q318X and R479L) associated with congenital adrenal hyperplasia, were found in 7, 2 and 1 subjects, respectively. Linkage analysis revealed that some variations exhibit strong correlation with the C4 copy number polymorphism and constituents of the MHC III region. Rare alleles of three polymorphisms were identified as components of the 8.1 ancestral haplotype. Haplotyping and family study confirmed that the variant alleles of two intronic SNPs were constituents of haplotype blocks lacking the C4B gene. These results suggest that variations of CYP21A2 gene can be involved in disease associations of the 8.1 haplotype and the C4B*Q0 genotype.
Mol Immunol 2009 Aug
PMID:Linkage analysis of the C4A/C4B copy number variation and polymorphisms of the adjacent steroid 21-hydroxylase gene in a healthy population. 1950 23

Most (90%) cases of congenital adrenal hyperplasia (CAH) are due to mutations in the steroid 21-hydroxylase gene (Cyp21). CAH due to 21-hydroxylase deficiency is diagnosed by confirming elevations of 17-hydroxyprogesterone (OHPG) and androstenedione (ANST) with decreased cortisol. By contrast, in two less common forms of CAH, due to 17-hydroxylase or 11-hydroxylase deficiency, OHPG and ANST levels are not significantly elevated and measurement of progesterone (PGSN) and deoxycorticosterone (DOC), respectively are necessary for diagnosis. Since 21-hydroxylase deficiency is more common and results in remarkable increase in OHPG, this test is most commonly ordered compared to other steroid intermediates. Various methods are used in clinical laboratories for the analysis of OHPG in serum or plasma but mass spectrometric methods are considered gold standard method.
Methods Mol Biol 2010
PMID:Quantitation of 17-OH-progesterone (OHPG) for diagnosis of congenital adrenal hyperplasia (CAH). 2007 78

In 75 young adults with diabetes mellitus type 1 (DM 1) we have performed a cross-sectional study to gain more information about their adrenocortical function. We have found in a surprisingly large portion of patients (25%) a subnormal response (<500 nmol/L, low responders) of the serum cortisol during low-dose Synacthen test, accompanied by significantly decreased stimulated values of aldosterone and salivary cortisol. Basal serum cortisol, aldosterone, and dehydroepiandrosterone sulphate (in women only) were significantly reduced in low responders as well, while ACTH, cortisol binding globulin, plasma renin activity, urinary free cortisol/24h, and salivary cortisol did not differ. The results indicate that the disorder of adrenocortical function in low responders occurs in all adrenocortical zones. The patients with the highest risk in respect to revealed hypocorticalism were DM 1 with autoimmune thyroiditis, 13 out of 36 in contrast to 5 out of 39 suffered from isolated form of DM 1, with onset around 30 years, independently on sex. The biorhythm of salivary cortisol in low responders under real-life conditions did not significantly differ from normal responders, except of the decreased values in the morning. Antibodies against 21-hydroxylase and adrenal cortex were negative in the entire group of diabetics studied. In conclusion, this is the first study to demonstrate in as much as 25% of young adults with DM 1 patients without any signs of adrenal autoimmunity decreased both basal and stimulated serum cortisol and aldosterone levels, implying existence of subclinical primary hypocorticalism.
J Steroid Biochem Mol Biol 2010 Oct
PMID:Adrenocortical function in young adults with diabetes mellitus type 1. 2043 24

Congenital adrenal hyperplasia (CAH) is comprised of a group of autosomal recessive disorders caused by an enzymatic deficiency which impairs the biosynthesis of cortisol and, in most of the severe cases, also the biosynthesis of aldosterone. Approximately 90-95% of all the CAH cases are due to mutations in the steroid 21-hydroxylase gene (CYP21A2). In this study, the molecular genetic analysis of CYP21A2 was performed in 267 Czech probands suspected of 21-hydroxylase deficiency (21OHD). 21OHD was confirmed in 241 probands (2 mutations were detected). In 26 probands, a mutation was found only in 1 CYP21A2 allele. A set of 30 different mutant alleles was determined. We describe i) mutated CYP21A2 alleles carrying novel point mutations (p.Thr168Asn, p.Ser169X and p.Pro386Arg), ii) mutated CYP21A2 alleles carrying the novel chimeric gene designated as CH-7, which was detected in 21.4% of the mutant alleles, iii) an unusual genotype with a combination of the CYP21A2 duplication, 2 point mutations and the CYP21A2 large-scale gene conversion on the second allele, and (iv) a detailed analysis of the chimeric CYP21A1P/CYP21A2 genes. In conclusion, our genotyping approach allowed for the accurate identification of the CYP21A2 gene mutations in 21OHD patients and their families and provided some useful information on diagnosis and genetic counselling.
Int J Mol Med 2010 Oct
PMID:Identification of CYP21A2 mutant alleles in Czech patients with 21-hydroxylase deficiency. 2081 1

The study subject was a 13 day-old boy admitted to hospital, with weight loss since birth. He presented with the vomiting and hypotension that are classical features of congenital adrenal hyperplasia (CAH). The most common type of CAH is an autosomal recessive disorder caused by mutations in the 21-hydroxylase (CYP21A2) gene. To examine the CYP21A2 gene, gene-specific PCR was carried out, followed by sequencing. The baby was shown to be a compound heterozygote H365Y/R356W for two CYP21A2 gene mutations each inherited from a different parent. One of the mutations has not previously been functionally characterised. The mutations were reconstructed in an expression plasmid and characterised in vitro after transient transfection into human embryonic kidney (HEK293T) and hepatoblastoma (C3A) cell lines followed by measurement of enzyme activity. The CYP21A2 H365Y mutant exhibited minimal 21-hydroxylase activity to convert 17-hydroxyprogesterone to 11-deoxycortisol or progesterone to 11-deoxycorticosterone. Western immunoblotting indicated that the H365Y enzyme was produced in more variable amounts than wild type; in particular, the H365Y mutant protein may be unstable and/or subject to a more rapid degradation by the human proteosome as well as catalytically inefficient. The double mutant genotype with a severe mutation on each allele is compatible with the clinical presentation.
J Steroid Biochem Mol Biol 2011 Feb
PMID:Functional characterisation of the H365Y mutation of the 21-hydroxylase gene in congenital adrenal hyperplasia. 2113 44

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders mainly caused by a defect in the steroid 21-hydroxylase gene (CYP21A2). In this study, we investigated the molecular defects of 25 Chinese pedigrees with 21-hydroxylase deficiency (21-OHD). Diagnosis of the probands in the families was based on their typical clinical presentations, such as inborn ambiguous genitalia, or early onset of salt wasting and biochemical metabolite abnormalities. All 10 exons and exon-intron boundaries of the CYP21A2 gene were amplified from the genomic DNA of the probands and then analyzed by direct sequencing. The phenotypes of the 26 patients from 25 pedigrees were classified as the classical form of 21-OHD. One novel mutation (c.1223 G>T) and 13 recurrent mutations of CYP21A2 were identified in the 25 pedigrees by genetic analysis. The novel c.1223 G>T mutation results in the substitution of arginine by leucine at amino acid position 408 (p.Arg408Leu). The most frequent mutation alleles were IVS2-13A/C>G (14/52) and I172N (11/52), followed by chimeric mutations (10/52). Forty six of 52 mutated alleles resulted from pseudogene conversion and 6 of 52 from random mutations. The spectrum of CYP21A2 mutation in our study was slightly different from those previously reported in Chinese and in other ethnic groups of the world. Although microconversion events were the main cause of mutations in the CYP21 gene, random mutations with a common origin can also be the reason for 21-OHD.
Genet Test Mol Biomarkers 2011 Mar
PMID:Molecular characterization of 25 Chinese pedigrees with 21-hydroxylase deficiency. 2119 93

The CYP21 (steroid 21-hydroxylase) gene is involved in the synthesis of steroid hormones. Bov-A2 is a retroposon that is common in ruminant genomes. The promoter region of bovine CYP21 contains a short interspersed nucleotide element of Bov-A2, which overlaps a putative Sp1 binding site. We looked for RFLP/HpaII polymorphism in the Bov-A2 element in bovine Zebu breeds by PCR-RFLP, and examined whether polymorphism in this element is associated with methylation. Among DNA samples from 135 Brazilian Zebu breed cattle, we identified an RFLP/HpaII polymorphism (T/C), which, based on a restriction methylation-sensitive assay employing HpaII and isoschizomer MspI enzymes (methylation-sensitive and -non-sensitive enzymes, respectively), appears to be a DNA methylation point. This is the first report of this polymorphism and on DNA methylation in the bovine CYP21 promoter region in Brazilian Zebu cattle.
Genet Mol Res 2011
PMID:Identification of a DNA methylation point in the promoter region of the bovine CYP21 gene. 2182 90


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