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The molecular biology of hypertensive congenital adrenal hyperplasia

Skinner, Colin; (1994) The molecular biology of hypertensive congenital adrenal hyperplasia. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The purpose of this project was to identify the molecular basis of hypertensive congenital adrenal hyperplasia in patients with two forms of the disease; steroid 17α-hydroxylase/17,20 lyase (CYP17) and 11β-hydroxylase (CYP11B1) deficiencies. These enzyme defects account for approximately 1% and 5% of recorded cases of congenital adrenal hyperplasia respectively. CYP17 is encoded by a single gene, CYP17 on chromosome 10. The CYP11B1 gene is located on chromosome 8q22, in tandem with the aldosterone synthase gene, CYP11B2, with which it shares 93% base sequence homology. The hypothesis was proposed that the higher incidence of CYP11B1 deficiency is the result of non-homologous recombination and gene conversion between the duplicated CYP11B genes. Two mutation screening methods were employed and evaluated. The first method involved construction of a genomic DNA library in bacteriophage lambda, isolation of fragments of CYP17 and subsequent sequencing by manual dideoxy chain termination to locate mutations in DNA from a single individual with 17α- hydroxylase deficiency. The second procedure used the polymerase chain reaction (PCR) and single strand conformation polymorphism analysis (SSCP) to screen DNA from several 11β-hydroxylase deficient patients simultaneously and proved to be a much faster and more successful approach to screening for mutations. A single point mutation was found on each allele of the CYP17 gene. In contrast point mutations, small deletions, small duplications and gene conversion events were found in the CYP11B genes, often with several mutations present in each patient. Deletion and duplication events occurred where there were direct repeats of base sequence. Pathological mutations in CYP11B1 were shown not to arise directly from gene conversion or non-homologous recombination in the subjects studied. Other factors, such as differences in the degree of DNA methylation and selection acting strongly against mutation within CYP17, may account for the higher rate of mutation at the CYP11B1 locus as compared to that of CYP17.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The molecular biology of hypertensive congenital adrenal hyperplasia
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Hypertensive congenital adrenal hyperplasia
URI: https://discovery.ucl.ac.uk/id/eprint/10107026
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