Two distinct areas of unequal crossingover within the steroid 21-hydroxylase genes produce absence of CYP21B

Donohoue, Patricia A.; Jospe, Nicholas; Migeon, Claude J.; Dop, Cornelis Van

doi:10.1016/0888-7543(89)90002-5

Cited by 46 publications

(34 citation statements)

References 23 publications

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“…Identification of the chimeric CYP21P/CYP21 gene Identification of gene deletions and conversions is still being studied by Southern blot analysis with oligonucleotides (Higashi et al 1988b;Donohoue et al 1989;Helmberg et al 1992;Tusie-Luna and White 1995) or DNA probes (Krone et al 1998;Koppens et al 2000;L'Allemand et al 2000) for hybridization. There are two established strategies of PCR amplification for identifying the CYP21 gene:…”

Section: Biological Activity Of the Chimeric Cyp21p/cyp21mentioning

confidence: 99%

“…Most of them appear in intron sequence. Two distinct areas of nucleotides (nt), 470-999 and 1375470-999 and -1993470-999 and (Higashi et al 1986), of CYP21 genes have been proposed to be related to crossover regions (Donohoue et al 1989). On the other hand, there are three minisatellite consensus sequences located in the CYP21 gene at nt 1113-1121(IVS4), 1950-1959, and the 3' untranslated region from nt 2710-2719 (Urabe et al 1990) (Table 1).…”

Section: Homologous Recombinationmentioning

confidence: 99%

“…Such a gene deletion or gene conversion is traditionally detected by Southern blotting with multiple isotopelabeled probes and RFLP analysis; Taq I generates the 3.7-kb (functional) and 3.2-kb (pseudogene) fragments, while Bgl II produces the 11-kb (functional) and 12-kb (pseudogene) fragments. These two approaches to fragment analysis have been used since 1984 (White et al 1984;Donohoue et al 1989;Koppens et al 2000;L'Allemand et al 2000). However, the method is laborious and indirect, and densitometric screening of fragments is error prone, although a nonisotopic Southern procedure was later described (Krone et al 1998).…”

Section: Introductionmentioning

confidence: 99%

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The chimeric CYP21P/CYP21 gene and 21-hydroxylase deficiency

Lee¹

2004

J Hum Genet

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The chimeric CYP21P/CYP21 gene is a consequence of a 26-or 32-kb deletion in the C4-CYP21 repeat module of CYP21P, tenascin A (XA), serine/ threonine nuclear protein kinase (RP2), and the C4B and CYP21 genes in congenital adrenal hyperplasia (CAH) with steroid 21-hydroxylase deficiency. To date, there have been three distinct chimeras found in CAH patients in ethnic Chinese. Initiation for production of these molecules is proposed to be chi-like sequences and a minisatellite consensus existing in several noncoding regions in CYP21 genes. These molecules have the 5' end of the CYP21P-specific sequence in common but differ in the 3' end of CYP21-specific genes. In addition, there appears to be a 3.2-kb fragment generated by Taq I digestion, which leads to allele dropout in PCR amplification for detecting the aberrant splicing site of the IVS2 )12A/C>G mutation at nucleotide (nt) 655 in the CYP21 gene. Therefore, the chimeric CYP21P/CYP21 cannot be detected by conventional methods. It has been demonstrated that a PCR product amplified with allele-specific primers covering tenascin B (TNXB) to the 5' end of the CYP21 gene combined with Southern analysis by Ase I and Nde I digestion may be used for identifying the chimera in the CYP21 gene.

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Section: Biological Activity Of the Chimeric Cyp21p/cyp21mentioning

confidence: 99%

Section: Homologous Recombinationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The chimeric CYP21P/CYP21 gene and 21-hydroxylase deficiency

Lee¹

2004

J Hum Genet

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“…These have resulted from a meiotic unequal crossover between CYP21 and CYP21P, creating a gene consisting of the 5' section of CYP21P and the 3' section of CYP21. 1,9,[23][24][25] (b) Haplotypes with two genes, both with a CYP21P-like restriction pattern ('large-scale gene conversions').…”

Section: Introductionmentioning

confidence: 99%

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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“…Two distinct areas of nt 470 to 999 and nt 1375 to 1993 of the CYP21 genes have been proposed to be related to crossover regions (Donohoue et al 1989). Interestingly, chilike sequence GCTGGGC has been found, beginning with the first 5 bp of intron 3 at nt 828 to 834 in CH-1 (Fig.…”

Section: Discussionmentioning

confidence: 99%