Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.30.2 (endonuclease)
 18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A highly polymorphic XbaI restriction site flanking the human 21-hydroxylase genes (21-OHA and 21-OHB) was found with the probe pC21/3c, the cDNA of the 21-hydroxylase gene. From the results of RFLP analysis of 10 subjects with congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency and their parents, at least four polymorphic fragments (30 kb, 27 kb, 25 kb, and 15 kb) resulting from cleavage at the polymorphic endonuclease sites outside the genes were found, and at least 10 different polymorphic patterns were observed among Chinese. These results indicate that these polymorphic loci are very informative for prenatal diagnosis of 21-hydroxylase deficiency.
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PMID:Highly polymorphic XbaI RFLPs of the human 21-hydroxylase genes among Chinese. 134 21

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

Six families at risk of having a child with 21-hydroxylase deficiency (21-OHD) requested prenatal diagnosis by DNA analysis. This was performed by Southern hybridization mainly using the endonuclease-probe combination of TaqI-21-hydroxylase (21-OHase) complementary DNA (cDNA). In three families, the probands were found to have deletion of a 3.7 kb fragment corresponding to the functional 21-OHase gene (21-OHase B gene). In the three fetuses tested, genomic DNA extracted from the chorionic villi had the 3.7 kb fragment and all were judged to be unaffected. In the other three families, DNA analysis was uninformative in the detection of 21-OHD and was also unable to determine carrier status with 21-OHase cDNA. In one of these three families, however, linkage analysis detected restriction fragment length polymorphism (RFLP) with cDNA for the fourth component of the complement (C4).
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PMID:Prenatal diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency with DNA analysis. 201 12

Outbred New Zealand white rabbits exhibit two phenotypes, 21H and 21L, corresponding to rates greater than or less than 1 nmol/min/mg, respectively, for liver microsomal progesterone 21-hydroxylase activity. In contrast, the inbred strain III/J exhibits only the 21L phenotype. Two 21H male New Zealand white rabbits were mated with several female III/J rabbits to produce a total 46 progeny. Both the 21H and 21L phenotypes were evident among male and female offspring in roughly equal numbers. Backcrosses between 21L progeny and III/J rabbits exhibit only the 21L phenotype, whereas 21H offspring yield both 21H and 21L progeny when backcrossed to the 21L inbred strain III/J. These results are consistent with autosomal dominant inheritance of the 21H phenotype. Analysis of Southern blots of genomic DNA digested with the restriction endonuclease KpnI reveals 20-, 13-, and 9-kb fragments that hybridize with a probe derived from the 3'-untranslated region of the 21-hydroxylase cDNA. The 13-kb band is not observed for strain III/J or 21L progeny of strain III/J crossed with 21H rabbits, but it is detected for both 21H fathers and 21H progeny indicating that the genetically determined difference of 21-hydroxylase expression is inherited cis to the gene for P450IIC5, the hepatic progesterone 21-hydroxylase. Electrophoretic analysis of P450IIC5 synthesized in vitro from mRNA isolated from 21L and 21H rabbits reveals that little or no P450IIC5 is synthesized from 21L mRNAs. A second immunoreactive, electrophoretically distinct protein is synthesized from both 21L and 21H mRNAs to a similar extent but in lesser amounts than P450IIC5. The second protein could represent either an allozymic form of the enzyme or the product of a distinct locus. Thus, it is likely that distinct structural genes for P450IIC5 contribute to the differences in P450-mediated metabolism in 21L as compared to 21H rabbits.
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PMID:Genetic contributions to the variation among rabbits of liver microsomal deoxycorticosterone synthesis. 257 May 49

Congenital adrenal hyperplasia (CAH) can be caused by a variety of defects in the functional gene encoding 21-hydroxylase (P450c21), which lies in the midst of the human leukocyte antigen (HLA) locus on chromosome 6. As a result, Mendelian genetics permit clinically distinct forms of CAH to be traced genetically by HLA and complement typing of family members. The recent cloning of probes for P450c21 now permits tracing of the affected gene directly. A consanguineous family had three members affected with three clinically distinct forms of CAH. Two of these individuals had identical extended haplotypes, including nine HLA and complement loci. Despite this extensive identity, the patterns of genomic DNA fragments digested with endonuclease EcoRI and detected by a P450c21 cDNA probe differed greatly in these two individuals. Thus, the DNA diagnosis of allelic variation was much more sensitive than the HLA diagnosis. Genomic DNA digested with endonuclease TaqI and probed with P450c21 cDNA revealed the 3.2-kilobase (kb) band, which is generally associated with the nonfunctional P450c21 A pseudogene, in all family members, and also revealed the 3.7-kb band associated with the functional P450c21 B gene in all family members except the severely affected index case. Probing of the same blots with a genomic probe also permitted examination of the adjacent downstream TaqI fragments, showing retention of both the 2.4-kb (A pseudogene) and 2.5-kb (B gene) fragments. Similarly, BglII-digested genomic DNA from all individuals contained both the 12-kb (A pseudogene) and 11-kb (B gene) bands. These data indicate that the basis of 21-hydroxylase deficiency in the index case was due to a homozygous gene conversion event and not to gene deletion. These results show that the DNA in and around the 21-hydroxylase gene is genetically very active, so that the usual generalization concerning linkage and inheritance may yield incorrect conclusions and diagnoses.
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PMID:Gene conversions and rearrangements cause discordance between inheritance of forms of 21-hydroxylase deficiency and HLA types. 278 35

Nonclassic steroid 21-hydroxylase deficiency is a frequent, relatively mild disorder of cortisol biosynthesis characterized by variable signs of postnatal androgen excess. It is inherited as an allelic variant of the CYP21B gene encoding the 21-hydroxylase enzyme. CYP21B is located in the HLA histocompatibility complex, and a nonclassic allele is often associated with characteristic HLA antigens: B14;DR1. A CYP21B gene from a HLA-B14;DR1 homozygous patient with nonclassic 21-hydroxylase deficiency was cloned and analyzed. Five deviations from the normal sequence of CYP21B were found, but only one appeared likely to affect the functional integrity of the protein: codon 281, GTG, encoding valine, was changed to TTG, leucine. An oligonucleotide probe was constructed corresponding to the mutant sequence surrounding codon 281 and hybridized with DNA samples digested with restriction endonuclease Taq I. Samples from 8 nonclassic 21-hydroxylase deficiency patients carrying HLA-B14;DR1 contained a hybridizing fragment 3700 base-pairs long, indicating presence of the val-281 mutation in the CYP21B gene. In contrast, unaffected individuals and one patient who lacked HLA-B14;DR1 showed no evidence of the val-281 mutation in CYP21B. We conclude that the codon 281 mutation is a consistent molecular genetic marker for nonclassic 21-hydroxylase deficiency associated with HLA-B14;DR1.
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PMID:Clinical and genetic characterization of nonclassic 21-hydroxylase deficiency. 278 81

The highly polymorphic fourth component of human complement (C4) is usually encoded by two genes. C4A and C4B, adjacent to the 21-hydroxylase (21-OH) genes, 21-OHA and 21-OHB, and is also remarkable in the high frequency of the 'null' alleles, C4A Q0 and C4B Q0. The molecular basis for the C4A Q0 allele was studied in 26 families through restriction fragment length polymorphism (RFLP) analysis with C4 and 21-OH cDNA probes after digestion of the DNA with the endonuclease HindIII. The individuals expressing the extended haplotype HLA-A1 (of A2) Cw7 B8 C2C BfS C4AQ0B1 DR3 have a large deletion taking off the C4A and 21-OHA genes.
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PMID:Heterogeneity in the structural basis of the human complement C4A null allele (C4A Q0) as revealed by HindIII restriction fragment length polymorphism analysis. 288 19

Two of four siblings expressed the salt-losing form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) and had identical human lymphocyte antigen (HLA) and complement C4 (fourth component of complement) types (HLA-A3,C4,B35,C4A3,C4BQO,DR1/A2,C-,B18,C4A3, C4BQO,DR6). The father and one unaffected sibling were heterozygous carriers of CAH, as determined by a 30-min iv ACTH stimulation test and HLA typing. In addition, the iv ACTH stimulation test revealed that the mother and the other unaffected sibling also carried an allele for an attenuated form of CAH. Restriction endonuclease digests of genomic DNA obtained from members of this family and from normal unrelated subjects were hybridized with cDNA probes encoding human 21-hydroxylase and C4. With the 21-hydroxylase probe, Southern blots prepared from control DNA samples revealed two major restriction fragments in each of four restriction endonuclease digests; TaqI produced major bands at 3.7 and 3.2 kilobases (kb), KpnI at 4.0 and 2.9 kb, EcoRI at 18 and 13 kb, and BglII at 15 and 12.5 kb. Southern blots prepared from DNA of the two patients lacked the 3.7-kb TaqI and 2.9-kb KpnI fragments, but had increased hybridization intensity (relative to control DNA samples) in the 3.2-kb TaqI and 4.0-kb KpnI fragments. By contrast, blots with EcoRI or BglII had two large hybridization fragments not different from control DNA samples. These data indicate the presence of two different 21-hydroxylase genes. Additional mapping studies revealed that the two genes had the restriction pattern of the inactive 21-hydroxylase gene. When genomic DNA that had been isolated from all members of this family and from normal subjects was hybridized with the human C4 cDNA probe, the restriction fragment hybridization patterns for all four endonuclease digests were similar in the two groups. Hence, our results suggest that the 21-hydroxylase deficiency of our patients is due to conversion of the active 21-hydroxylase gene to the inactive gene. This gene conversion was associated with absence of functional C4B protein, without any detectable alterations in the restriction fragment pattern of the C4 genes.
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PMID:Gene conversion in salt-losing congenital adrenal hyperplasia with absent complement C4B protein. 300 62

Restriction maps were constructed for the two human 21-hydroxylase genes (21-OHA and 21-OHB) by using DNA from subjects homozygous for a deletion of each gene. Comparing the patterns of these two genes, a KpnI restriction site occurred in the 21-OHA gene in place of a TaqI site in the 21-OHB gene about 1-kb from the 5' end of the gene, and an extra EcoRI site was located 500 bp 5' to the common EcoRI site. The DNA of fourteen unrelated normal subjects was digested with nine restriction endonucleases (AccI, BamHI, BgIII, EcoRI, HindIII, KpnI, MspI, SacI and TaqI). Restriction fragment length polymorphisms were found with EcoRI, HindIII and AccI that resulted from polymorphic endonuclease sites outside the genes.
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PMID:Restriction maps and restriction fragment length polymorphisms of the human 21-hydroxylase genes. 301 Sep 94

Nonclassic steroid 21-hydroxylase deficiency is a frequent, relatively mild disorder of cortisol biosynthesis, characterized by variable signs of postnatal androgen excess. It is inherited as an allelic variant of the gene designated CYP21B, which encodes 21-hydroxylase. CYP21B is located in the HLA histocompatibility complex, and a "nonclassic" allelic variant is often associated with characteristic HLA antigens--B14,DR1. We cloned and analyzed the CYP21B gene from a patient homozygous for HLA-B14,DR1 who had nonclassic 21-hydroxylase deficiency. Five deviations from the normal genetic sequence of CYP21B were found, but only one appeared likely to affect the functional integrity of the protein: codon 281, GTG, encoding valine, was changed to TTG, leucine. We constructed an oligonucleotide probe corresponding to the mutant DNA sequence surrounding codon 281 and hybridized the probe with DNA samples digested with the restriction endonuclease Taql. Samples from eight patients with nonclassic 21-hydroxylase deficiency who had the haplotype HLA-B14,DR1 contained a hybridizing fragment 3700 base pairs long, indicating the presence of the valine-281 mutation in the CYP21B gene. In contrast, unaffected subjects and one patient with nonclassic deficiency who did not have HLA-B14,DR1 had no evidence of this mutation. We conclude that the mutation in codon 281 is a consistent molecular genetic marker for nonclassic 21-hydroxylase deficiency associated with HLA-B14,DR1.
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PMID:Molecular genetic analysis of nonclassic steroid 21-hydroxylase deficiency associated with HLA-B14,DR1. 326 7


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