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
Open accessAbstract
Congenital adrenal hyperplasia (CAH) is caused by disorders of the P450c21B gene, which, with the P450c21A pseudogene, lies in the HLA locus on chromosome 6. The near identity of nucleotide sequences and endonuclease cleavage sites in these A and B loci makes genetic analysis of this disease difficult. We used a genomic DNA probe that detects the P450c21 genes (A pseudogene, 3.2 kb; B gene, 3.7 kb in Taq I digests) and the 3' flanking DNA not detected with cDNA probes (A pseudogene, 2.4 kb; B gene, 2.5 kb) to examine Southern blots of genomic DNA from 68 patients and 165 unaffected family members in 57 families with CAH. Of 116 CAH-bearing chromosomes, 114 could be sorted into five easily distinguished haplotypes based on blots of DNA digested with Taq I and Bgl II. Haplotype I (76 of 116, 65.6%) was indistinguishable from normal and therefore bore very small lesions, presumably point mutations. Haplotype II (4 of 116, 3.4%) and haplotype III (8 of 116, 6.9%) had deletions and duplications of the P450c21A pseudogene but had structurally intact P450c21B genes presumably bearing point mutations; point mutation thus was the genetic defect in 88 of 116 chromosomes (75.9%). Haplotypes IV and V lack the 3.7-kb Taq I band normally associated with the P450c21B gene. Haplotype IV (13 of 116, 11.2%) retains all other bands, indicating that the P450c21B gene has undergone a gene conversion event, so that it is now also associated with a 3.2-kb band. Haplotype V (13 of 116, 11.2%) lacks the 2.4-kb Taq I fragment and the 12-kb Bgl II fragments normally associated with the P450c21A pseudogene, as well as lacking the 3.7-kb Taq I fragment, indicating deletion of approximately 30 kb of DNA, resulting in a single hybrid P450c21A/B gene. Most (114 of 116, 98%) CAH alleles thus can easily be classified with this new probing strategy, eliminating many ambiguities resulting from probing with cDNA.
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There is ascertainment bias in favor of more severely affected patients, and most studies address populations primarily of European origin.
“However, there is ascertainment bias in favor of more severely affected patients (388) and most studies address populations primarily of European origin.”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [388]
The Methods report that 42 of 57 families had the severe salt-wasting form of CAH, while only four had the nonclassical form. The Discussion says this distribution resembles other studies, but the paper does not establish that ascertainment bias caused it. The citation is attached to the ascertainment-bias clause, not the subsequent statement about European-origin populations. (LLM, conf=0.76)
Experimental — accuracy not yet measuredGene conversions are extremely common in the 21-hydroxylase locus.
“Second, gene conversions are extremely common in this locus (388, 427).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [388]
The Introduction reports gene conversions in the 21-hydroxylase locus, and the discussion reports conversions in 13 of 116 CAH chromosomes (11.2%). That supports their occurrence, but the study does not establish that gene conversions are “extremely common” across the locus generally; its measured frequency is limited to affected chromosomes. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAbout 75% of mutated CYP21 genes are structurally intact by Southern blotting and thus appear to carry point mutations.
“About 75% of mutated CYP21 genes are structurally intact by Southern blotting and thus appear to carry point mutations (388, 427).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [388]
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References 41 · Cited by 134
Research works printed but not linked: 2
- [11]11. Chung, B., K. J. Matteson, and W. L. Miller. 1986. Structure of a bovine gene for P450c21 (steroid 2 1-hydroxylase) defines a novel cytochrome P450 gene family. Proc. NatL. Acad. Sci. USA. 83:4243- 4247.
- [31]31. Uring-Lambert, B., C. M. Giles, J. Goetz, M. M. Tongio, S. Mayer, and G. Hauptmann. 1984. C4 haplotypes with duplicated C4A or C4B: frequency and associations with Bf, C2 and HLA-A,B,C,DR alleles with special reference to the duplication C4B I B2. In Histocom- patibility Testing. E. D. Albert, M. P. Baur, and W. R. Mayr, editors. Springer-Verlag, Berlin. 604-608.
- Authors
- Morel, Y., André, J., Uring-Lambert, B., Hauptmann, G., Bétuel, H., Tossi, M., Forest, M. G., David, M., Bertrand, J., & Miller, W. L.
- Affiliations
- Inserm (FR)
- University of California, San Francisco (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1989-02-01
- Volume
- 83
- Issue
- 2
- Pages
- 527-536
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC303711
- OpenAlex
- W2025647465
- Semantic Scholar
- d85ba6fb56ea9b20039b3d095dee0ec972005491
- Cited by
- 134
- References
- 41
- Citations by year
- 2023: 1 · 2022: 1 · 2019: 2 · 2016: 1 · 2014: 1 · 2013: 1
- FWCI
- 6.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- March of Dimes Foundation
- Philippe Foundation
- Institut National de la Santé et de la Recherche Médicale
- National Institutes of Health
- Fogarty International Center (TW 03935)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-37922)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- congenital adrenal hyperplasia, gene conversion, point mutations, gene rearrangement, HLA locus, chromosome 6, genetic diagnosis
- MeSH terms
- Adrenal Hyperplasia, Congenital, Alleles, Chromosome Deletion, Cytochrome P-450 Enzyme System, Family, Haploidy, Humans, Mutation, Nucleotide Mapping, Pedigree, DNA Probes
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