Rearrangements and point mutations of P450c21 genes are distinguished by five restriction endonuclease haplotypes identified by a new probing strategy in 57 families with congenital adrenal hyperplasia.

Morel, Yves; André, Jean; Uring‐Lambert, B.; Hauptmann, G.; Bétuel, H; Tossi, M; Forest, Maguelone G.; Dávid, M; Bertrand, J; Miller, Walter L.

doi:10.1172/jci113914

Cited by 127 publications

(97 citation statements)

References 40 publications

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“…A well-known disease caused by gene conversion is 21-hydroxylase deficiency; gene conversion is confirmed in approximately 85% of the patients (Morel et al 1989). The presence of highly homologous, tandemly arranged genes provides an opportunity for meiotic mispairing and crossing over between sister chromatids.…”

Section: Discussionmentioning

confidence: 99%

Genetic Analysis of Shwachman-Diamond Syndrome: Phenotypic Heterogeneity in Patients Carrying Identical SBDS Mutations

Kawakami

Mitsui

Kanai

et al. 2005

Tohoku J. Exp. Med.

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Shwachman-Diamond syndrome (SDS) is a rare hereditary disorder characterized by pancreatic exocrine insufficiency, bone marrow dysfunction and skeletal changes. Recently, the cause of SDS was identified as mutations of Shwachman-BodianDiamond syndrome gene (SBDS) and most mutations are caused by gene conversion between SBDS and its highly homologous pseudogene. Clinical variations especially in skeletal and bone marrow abnormalities are well known in this syndrome. To study the relationship between SBDS mutation and its clinical features, we analyzed 9 Japanese patients including one sibling and detected the three different SBDS mutations in 7 patients: a mutation that disrupts the donor splice site of intron 2, deletes 8bp of the exon 2 and produces premature termination (258+2 T > C), a dinucleotide change that replaces a lysine at 62nd amino acid to a termination codon (183-184 TA > CT), and a 4-bp deletion that causes premature termination by frameshift (292-295 delAAAG). The 5 patients represent compound heterozygotes of the 258+2 T > C and 183-184 TA > CT mutations. One patient is a compound heterozygote of the 258+2 T > C and 292-295 delAAAG mutations, and in the remaining one case only a 258+2 T > C mutation could be detected. Thus, the 258+2 T > C and 183-184 TA > CT mutations are prevalent among Japanese patients. No mutations were found in two cases, despite the clinical features. Of the 7 patients with SBDS mutations, persistent hematologic abnormalities and skeletal changes were not observed in 3 and 2 patients, respectively. Notably, clinical variations are present even among the patients with the identical genotype: compound heterozygotes of the 258+2 T >

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Section: Discussionmentioning

confidence: 99%

Genetic Analysis of Shwachman-Diamond Syndrome: Phenotypic Heterogeneity in Patients Carrying Identical SBDS Mutations

Kawakami

Mitsui

Kanai

et al. 2005

Tohoku J. Exp. Med.

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“…Southern blots of normal human genomic DNA were prepared and probed with cDNA fragments isolated from their cloning vectors and labeled with 32p with random primers, as described (7).…”

Section: Methodsmentioning

confidence: 99%

Transcript encoded on the opposite strand of the human steroid 21-hydroxylase/complement component C4 gene locus.

Morel

Bristow

Gitelman

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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147

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The gene encoding human adrenal steroid 21-hydroxylase (P450c21) and its highly similar pseudogene are duplicated in tandem with the two genes encoding the fourth component of human serum hemolytic complement (C4). This 60-kilobase gene complex, which lies within the major histocompatibility complex on the short arm of human chromosome 6, has been studied in considerable detail because genetic disorders in steroid 21-hydroxylation and in C4 are common.

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“…Analysis of TaqI and BglII restriction patterns is commonly used to determine the gross arrangement of the CYP21/C4 region in steroid 21-hydroxylase deficiency patients and their family members. 1,[9][10][11][12][13][14][15] This approach allows the definition of CYP21/C4 haplotypes, some of which are associated with steroid 21-hydroxylase deficiency. [14][15][16][17][18][19][20][21][22] .…”

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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Rearrangements and point mutations of P450c21 genes are distinguished by five restriction endonuclease haplotypes identified by a new probing strategy in 57 families with congenital adrenal hyperplasia.

Cited by 127 publications

References 40 publications

Genetic Analysis of Shwachman-Diamond Syndrome: Phenotypic Heterogeneity in Patients Carrying Identical SBDS Mutations

Genetic Analysis of Shwachman-Diamond Syndrome: Phenotypic Heterogeneity in Patients Carrying Identical SBDS Mutations

Transcript encoded on the opposite strand of the human steroid 21-hydroxylase/complement component C4 gene locus.

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

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