Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Denaturing gradient gel electrophoresis was used to identify single-base differences in the cytochrome P-450 21-hydroxylase (CYP21) genes of 132 unrelated control individuals and family members of three unrelated patients with 21-hydroxylase deficiency. The salt-wasting variety was caused by gene deletion and gene conversion/deletion mutations in affected members of two families studied. The simple virilizing form, present in the third family, was caused by an apparent point mutation not detectable by routine Southern blots. We have detected many restriction fragment melting polymorphisms in the CYP21 genes of the members of both salt-wasting families and normal individuals with denaturing gradient gel electrophoresis. We also identified a restriction fragment melting polymorphism specific for the simple virilizing patient in the third family. The data demonstrate that the CYP21 genes are highly polymorphic and that denaturing gradient gel electrophoresis is useful for genomic deoxyribonucleic acid analysis of patients with 21-hydroxylase deficiency.
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PMID:Rapid identification of deoxyribonucleic acid sequence differences in cytochrome P-450 21-hydroxylase (CYP21) genes with denaturing gradient gel blots. 134 50

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (21-OHase) deficiency is inherited as an autosomal recessive trait. Patients can present with the salt wasting, simple virilizing or a non-classical form of the disease. The gene for P450C21, the enzyme carrying 21-OHase activity, has been mapped to the major histocompatibility complex on chromosome 6p. Using molecular hybridisation techniques we have studied the genetic defect in 27 families with one or more affected offspring diagnosed and treated at the University Hospital of Essen. DNA samples were digested with restriction endonuclease TaqI, PvuII, BglII, and EcoRI and analysed by Southern blot hybridisation with the cDNA probe pC21/3c. Eleven of 40 haplotypes associated with the salt wasting form were found to have a large deletion of 30 kb affecting the 5' end of the active 21-OHase gene and the 3' end of the closely linked pseudogene. Results in another 11 cases are compatible with gene conversion; 18 cases were not informative. The 30 kb deletion was associated with a combination of the HLA antigens Bw47 and DR7 in 7 of 11 cases. In the haplotypes with gene conversion, no linkage disequilibrium to HLA antigens was found. No apparent gene alterations were detected in simple virilizing and non-classical haplotypes. The direct detection of the genetic defect in 55% of the salt wasting haplotypes may help to improve predictive testing in families with CAH.
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PMID:Molecular detection of genetic defects in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: a study of 27 families. 136 34

A total of 33 Italian 21-hydroxylase (21-OH) deficiency families were investigated using a combination of short and long range restriction mapping of the CYP21/C4 gene cluster. The analyses revealed that large-scale length polymorphism in this gene cluster strictly conformed to a compound variable number of tandem repeats (VNTR) plus insertion system with between one and four CYP21 + C4 units and seven BssHII restriction fragment length polymorphisms (RFLPs) (75 kb, 80 kb, 105 kb, 110 kb, 135 kb, 140 kb and 180 kb). A total of 9/66 disease haplotypes, but only 1/61 non-disease haplotypes, showed evidence of gene addition by exhibiting three or more CYP21 + C4 repeat units. Of these, two were identified in one 21-OH deficiency patient who has a total of eight CYP21 + C4 units, being homozygous for the HLA haplotype DR2 DQ2 B5 A28. This haplotype carries four CYP21 + C4 units, three of which contain CYP21A-like genes and one of which contains a CYP21B-like gene that presumably carries a pathological point mutation. Of the other gene addition haplotypes associated with 21-OH deficiency, four show three CYP21 + C4 units flanked by HLA-DR1 and HLA-B14 markers. Although such haplotypes have commonly been associated with non-classical 21-OH deficiency, three examples in the present study are unexpectedly found in two salt-wasting patients, who are respectively homozygous or heterozygous for this haplotype. Only 7/66 disease haplotypes showed evidence of a CYP21B gene deletion.
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PMID:CYP21/C4 gene organisation in Italian 21-hydroxylase deficiency families. 155 57

Genotyping for 10 mutations in the CYP21 gene was performed in 88 families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Southern blot analysis was used to detect CYP21 deletions or large gene conversions, and allele-specific hybridizations were performed with DNA amplified by the polymerase chain reaction to detect smaller mutations. Mutations were detected on 95% of chromosomes examined. The most common mutations were an A----G change in the second intron affecting pre-mRNA splicing (26%), large deletions (21%), Ile-172----Asn (16%), and Val-281----Leu (11%). Patients were classified into three mutation groups based on degree of predicted enzymatic compromise. Mutation groups were correlated with clinical diagnosis and specific measures of in vivo 21-hydroxylase activity, such as 17-hydroxyprogesterone, aldosterone, and sodium balance. Mutation group A (no enzymatic activity) consisted principally of salt-wasting (severely affected) patients, group B (2% activity) of simple virilizing patients, and group C (10-20% activity) of nonclassic (mildly affected) patients, but each group contained patients with phenotypes either more or less severe than predicted. These data suggest that most but not all of the phenotypic variability in 21-hydroxylase deficiency results from allelic variation in CYP21. Accurate prenatal diagnosis should be possible in most cases using the described strategy.
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PMID:Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. 164 25

We have characterized mutations in the steroid 21-hydroxylase gene (CYP21) in salt-wasting congenital adrenal hyperplasia (SW-CAH) subjects, healthy control subjects, and affected sibling pairs with SW-CAH. To identify point mutations in CYP21, we have used an improved polymerase chain reaction methodology that allows analysis of the entire CYP21 gene. In addition, we have used polymerase chain reaction to search for abnormally spliced mRNAs resulting from putatively abnormal CYP21 genes transfected into COS1 cells. We found that all 26 SW-CAH subjects from whom DNA could be completely analyzed, had mutations that could account for the 21-hydroxylase enzyme deficiency. These mutations included CYP21 gene deletion, conversion to the inactive CYP21P form, point mutations leading to amino acid substitutions or stop codons, small gene deletions, and a point mutation in intron-2 that leads to an abnormally spliced mRNA. The point mutation in intron-2 was directly shown to activate a cryptic splice site 19 basepairs from exon-3 of CYP21 and thereby cause a reading frame mutation. This CYP21 mutation was frequently found in our white SW-CAH subjects, while the frequency of this mutation was extremely low in a racially matched control population. Furthermore, affected sibling pairs shared this mutation in all cases examined. The results presented should have important applications for the prenatal diagnosis of CAH.
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PMID:Salt-wasting congenital adrenal hyperplasia: detection and characterization of mutations in the steroid 21-hydroxylase gene, CYP21, using the polymerase chain reaction. 174 Apr 89

The types of disease-causing mutations were studied in 43 unrelated patients with 21-hydroxylase deficiency. Densitometry of Southern blots after cleavage with the restriction enzymes TaqI, PvuII, and BglII was used to measure the ratio of the copy-number of the 21-hydroxylase gene (CYP21) to the copy-number of its pseudogene (CYP21P). DNA from 16 unrelated patients showed equal hybridization intensities of the 2 genes, indicating that point mutations caused the enzyme deficiency. One of the 2 haplotypes in 7 patients showed evidence of a large gene conversion between the CYP21 and the CYP21P gene without loss of the total number of 21-hydroxylase genes. Deletion of at least 1 21-hydroxylase gene was found in 11 patients. DNA from 8 of these patients had relative hybridization intensities compatible with a deletion of the active 21-hydroxylase gene, CYP21. Two patients with the salt-wasting form of the disease showed homozygous loss of DNA fragments that are specific for the 5' end of the active 21-hydroxylase gene. Nine patients showed relative 21-hydroxylase hybridization intensities compatible with duplication of the gene in 1 or both haplotypes. In conclusion, point mutations, gene conversions, or CYP21 gene deletions are the typical mutations in patients with the simple virilizing and salt-wasting forms of the disease, while duplications of the locus are overrepresented in patients with nonclassical 21-hydroxylase deficiency.
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PMID:21-hydroxylase deficiency: disease-causing mutations categorized by densitometry of 21-hydroxylase-specific deoxyribonucleic acid fragments. 215 33

Prenatal diagnosis of the "classical" forms of congenital adrenal hyperplasia (CAH) which is a result of 21-hydroxylase (21-OH) deficiency either complete, with salt-wasting or incomplete without salt wasting, is performed in two ways: by measuring concentration of 17-hydroxyprogesterone (17-OHP) and androstendione (delta 4) in amniotic fluid and by HLA typing of fetal cells from amniotic fluid. Having ones own normal values is the basic condition for the safe prenatal diagnosis of CAH 21-OH deficiency by measuring steroid concentration in amniotic fluid. Normal concentrations of 17-OHP in amniotic fluid achieved by amniocentesis in 85 pregnant women from 16-23 gestation week have been measured, as well as concentrations of delta 4 in 66 pregnant women in the same period of gestation. It has been proved that there are no differences between the concentrations of delta 4 in amniotic fluid regarding the sex. As far as 17-OHP is concerned, the same was confirmed earlier. The results of 9 prenatal diagnosis in 8 families, having already one child with "classical" form of CAH with salt-wasting, have been presented. It was achieved by combination of two methods: by measuring concentration of 17-OHP and delta 4 in amniotic fluid and HLA typing of fetal cells from amniotic fluid. In 8 fetuses at risk the birth of healthy children was correctly predicted, which was confirmed after the birth in three cases by HLA typing and measuring concentration of 17-OHP and delta 4 and from the blood of newborn babies.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Prenatal diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase enzyme deficiency]. 263 7

During our investigations of polymorphisms at, and in the immediate chromosomal vicinity of, the 21-hydroxylase locus in families with 21-hydroxylase deficiency, three families were found to show marked discordance in clinical features of HLA identical subjects. In one family, there is discordance between a boy with the simple virilising form of 21-hydroxylase deficiency and his two younger sisters, who are both HLA identical to their brother, but who have additional salt wasting features. In the other two families, one subject is severely affected and has very high 17-hydroxyprogesterone levels, but has an HLA identical sib who is asymptomatic and shows only slightly raised 17-hydroxyprogesterone levels. In all cases, HLA identity, as indicated by protein polymorphism studies (HLA-A, B, DR, C4A, C4B, and Bf typing), has been verified at the gene organisation level using 21-hydroxylase and complement C4 DNA probes. An HLA-Bw47 bearing haplotype in one of the latter families has not been transmitted to the affected child and appears to carry a normal 21-OHB allele and two genes which specify C4A allotypes.
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PMID:21-hydroxylase deficiency families with HLA identical affected and unaffected sibs. 278 76

Final height was evaluated in 47 patients with classical 21-hydroxylase treated since diagnosis, and in 29 patients with nonclassical (NC) 21-hydroxylase deficiency who had never been treated before reaching final adult height. Classical patients achieved final heights consistently below the mean for the general population, and in all but four cases these patients also failed to attain the individual height expectation based on midparental height. Analysis of these results with regard to (1) clinical form (i.e. salt-wasting [SW] or simple virilizing [SV]) and (2) degree of hormonal control (i.e. good or poor) indicates that neither factor seems to affect the height outcome. Final height in NC patients, while significantly greater than for classical patients, was below the general population mean, and individual final heights were also significantly below expectation based on midparental height. In another group of NC patients who were still growing, some of whom were on courses of treatment and some under observation only, height at the time of diagnosis was compared with the most recent height prediction. Reduction of growth potential appeared to be somewhat lessened in the treated group, from which we tentatively suggest that treatment should be considered in NC patients even in the absence of clinical signs of androgenism.
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PMID:Growth and final height in classical and nonclassical 21-hydroxylase deficiency. 280

Twenty six females suffering from congenital adrenal hyperplasia due to 21-hydroxylase-deficiency with and without salt wasting were evaluated to determine their growth patterns with special regard to their pubertal growth spurt. 17 patients have been substituted with hydrocortisone 20-25 mg/m2 and if necessary with 9 alpha-fluoro-cortisol 0.025-0.15 mg (group 1), 9 patients have got an additional cyproterone-acetate-therapy during their pubertal development (group 2). Group 1: A pubertal growth spurt was found in 14 females (82.4%) with a peak height velocity of 6.2 +/- 1.6 (SD) cm/yr. At the beginning of puberty the early treated girls showed a progressing retardation of bone age. Therefore the peak height velocity based on advancing bone age was elevated up to 8.7 +/- 1.4 (SD) cm/yr bone age (p = 0.01). Salt wasting (n = 10) did not seem to influence the pubertal growth velocity and the pubertal growth spurt (p = 0.1, p greater than 0.1), but the growth until cessation which was found to be markedly decreased (p less than 0.1). Group 2: Cyproterone-acetate suppressed symptoms of puberty but did not extinguish growth spurt. During 6.3 +/- 1.3 (SD) yrs of treatment bone age advanced only 4.2 +/- 0.7 (SD) yrs. However, in this period height increased by 20.8 +/- 6.4 (SD) cm which corresponds to a mean height velocity of 3.3 +/- 0.8 (SD) cm/yr, and 4.9 +/- 0.8 (SD) cm/yr bone age. Furthermore at puberty peak height velocity results in 4.5 +/- 0.7 (SD) cm/yr and in 10.4 +/- 4.6 (SD) cm/yr bone age.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Puberty and growth development in patients with a 21-hydroxylase defect]. 293 17


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