Effects of Individual Mutations in the P-450(C21) Pseudogene on the P-450(C21) Activity and Their Distribution in the Patient Genomes of Congenital Steroid 21-Hydroxylase Deficiency1

Higashi, Youichirou; Hiromasa, Takako; Tanae, Ayako; Miki, T; Nakura, Jun; Kondo, Takuma; Ohura, Toshihiro; Ogawa, Eishin; Nakayama, Keiichi I.; Fujii‐Kuriyama, Yoshiaki

doi:10.1093/oxfordjournals.jbchem.a123433

Cited by 188 publications

(145 citation statements)

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“…This finding is in agreement with some studies; 18,28,33,34 others found the intron 2 splice mutation more often in simple virilising patients as well. 17,22,26,36 The chance that a randomly selected Dutch individual who is a carrier of salt- The mutations are grouped per site; the variant matching the consensus sequence is mentioned first. The frequency of each mutation per haplotype is shown in percentages.…”

Section: Mutations In the Cyp21 Genementioning

confidence: 99%

“…8,17,[26][27][28] With a few exceptions, these mutations are found in the consensus sequence of CYP21P 2, 3 and have supposedly been transferred to CYP21 during evolution ('small-scale gene conversions').…”

Section: Introductionmentioning

confidence: 99%

“…They vary among different populations. 8,17,18,22,[26][27][28][29][30][31][32][33][34][35][36][37] However, information on the variability of the CYP21P pseudogene, especially in association with the TaqI/BglII haplotypes that define the overall structure of the region, is rather limited. 18,38 Such information is highly relevant to the hypotheses describing the origin of the different categories of disease-causing mutations in CYP21: the location of crossover sites and the extent of conversion zones depend on the composition of the CYP21P gene involved.…”

Section: Introductionmentioning

confidence: 99%

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CYP21 and CYP21P variability in steroid 21-hydroxylase deficiency patients and in the general population in the Netherlands

2000

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Steroid 21-hydroxylase deficiency is caused by defectiveness of the CYP21 gene. Such defects have presumably originated from interactions with the nearby CYP21P pseudogene during evolution. We studied these mechanisms by comparing the genetic variability of CYP21, CYP21P, and CYP21P/CYP21 hybrids (resulting from large-scale rearrangements) at eight mutation sites in a group of Dutch steroid 21-hydroxylase deficiency patients, their family members, and controls. The most common CYP21 defect in patients with salt-losing steroid 21-hydroxylase deficiency was a splice junction mutation in intron 2. The most common defect in the simple virilising form of the disease was ile72 → asn. CYP21P showed considerable sequence variation in its central and 3' sections; the 5' section was constant. A single nucleotide (T) insert in exon 7 was found in all CYP21P genes. During the course of evolution, this was probably the third defect introduced into CYP21P after the splice junction mutation in intron 2 and the 8 bp deletion in exon 3. Gene conversions introducing CYP21-like sequences contribute to CYP21P variability. Such an event has occurred de novo in one family. A comparison of CYP21 and CYP21P mutations on the same chromosome shows that at least some of the small-scale gene conversions that supposedly transfer defects to CYP21 involve interaction between homologous chromosomes. The majority of the putative CYP21P-CYP21 transitions in hybrid genes appears to occur in a distinct zone that lies 5' of nucleotide 2108, which is further downstream than previously hypothesised. The other transitions lie upstream of nucleotide 999. Apparent 'large-scale' CYP21-CYP21P gene conversions lead to hybrid genes that are very similar to those found in CYP21 deletions, so these haplotypes have probably resulted from a meiotic double unequal crossover.

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Section: Mutations In the Cyp21 Genementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CYP21 and CYP21P variability in steroid 21-hydroxylase deficiency patients and in the general population in the Netherlands

2000

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“…The late onset form presents in girls and young women with only hirsutism and oligoamenorrhea, where as cryptic forms have no clinical symptoms and are detected only when family studies are performed [3][4][5][6][7]. Such heterogeneity has imposed difficult questions about the genetic background of the disease.…”

Section: Introductionmentioning

confidence: 99%

“…Aberrant splicing in intron 2 at nucleotide (nt) 656, an 8 bp frameshift deletion at codons 111-113, a thymine insertion at codon 306, a nonsense mutation at codon 318, and a single base substitution at codon 356, result in a complete inactivation of 21-hydroxylase and are found in the severe classical form of salt-wasting disease [3][4][5]. A MOLECULAR ANALYSIS OF CAH single base change in exon 1 at codon 30, in exon 3 at codon 105, in exon 7 at codon 281, and in exon 10 at codon 453, are associated with the milder non classical form of CAH, in which there is only partial loss of 21-hydroxylase activity [4,6]. The simple virilization found in some CAH patients is associated with a mutation in exon 4 at codon 172, which abolishes 21-hydroxylase activity [4,7].…”

Section: Introductionmentioning

confidence: 99%

Molecular Analysis of a Family With Congenital Adrenal Hyperplasia - Genotype/Phenotype Discrepancy

Anastasovska¹,

Kočova²

2007

Balkan Journal of Medical Genetics

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Congenital adrenal hyperplasia (CAH) is a common autosomal recessive disease with a variable clinical presentation caused by a spectrum of different mutations. A significant association of genotype with phenotype has been reported.The molecular analysis of a girl with a mild form of CAH presenting with precocious pubarche, confirmed that she was heterozygous for two mutations of the CYP21 gene (exon 1, codon 30/exon 8, codon 318). Her mother was homozygous for the codon 30 mutation and her father was homozygous for the codon 318 mutation. The only anomaly in the parents was a difficulty in conceiving. The molecular analysis of this family confirmed the variability of presentation in carriers of different mutations, which caused difficulties in decisions about the timing of therapy and in genetic counseling.

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Who is a carrier? Detection of unsuspected mutations in 21-hydroxylase deficiency

1996

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Congenital adrenal hyperplasia due to 21‐hydroxylase deficiency is a common autosomal‐recessive disorder. During our routine genotyping of affected individuals and their relatives using allele‐specific oligonucleotide hybridization and single‐strand conformational polymorphism analysis, we identified two families each segregating three mutations. In both families, a mutation known to be associated with 21‐hydroxylase deficiency was identified in healthy individuals but was not detected in the propositus. The propositus in family 1 was shown to be a homozygous carrier for G at nucleotide 655, which alters the splice acceptor site at exon 3. The propositus in family 2 carried the same splicing mutation on the maternal allele and a gene deletion/conversion on the paternal allele. In both families, other clinically unaffected relatives carried the Q318X mutation in exon 8. If molecular diagnostic studies had been limited to the mutation carried by the propositi, relatives would have been misinformed regarding their status as carriers or mildly affected individuals. The findings in these two families emphasize the high frequency of alleles causing 21‐hydroxylase deficiency in the population. © 1996 Wiley‐Liss, Inc.

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Effects of Individual Mutations in the P-450(C21) Pseudogene on the P-450(C21) Activity and Their Distribution in the Patient Genomes of Congenital Steroid 21-Hydroxylase Deficiency1

Cited by 188 publications

References 0 publications

CYP21 and CYP21P variability in steroid 21-hydroxylase deficiency patients and in the general population in the Netherlands

CYP21 and CYP21P variability in steroid 21-hydroxylase deficiency patients and in the general population in the Netherlands

Molecular Analysis of a Family With Congenital Adrenal Hyperplasia - Genotype/Phenotype Discrepancy

Who is a carrier? Detection of unsuspected mutations in 21-hydroxylase deficiency

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