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21-Hydroxylase Deficiency: Disease-Causing Mutations Categorized by Densitometry of 21-Hydroxylase-Specific Deoxyribonucleic Acid Fragments^*

Departments of Clinical Genetics (B.H.S., H.L.) and Pediatrics (B.H.-S., E.M.R.), Karolinska Institutet, Karolinska Hospital S-104 01 Stockholm, Sweden

Address all correspondence and requests for reprints to: Holger Luthman, Department of Clinical Genetics, Karolinska Institutet, Karolinska Hospital, P.O. Box 60 500, S-104 01 Stockholm, Sweden.

The types of disease-causing mutations were studied in 43 unrelated patients with 21-hydroxylase deficiency. Densitometry of Southern blots after cleavage with the restriction enzymes TaqI, PvuII, and BglII was used to measure the ratio of the copy-number of the 21-hydroxylase gene (CYP21) to the copy-number of its pseudogene (CYP21P). DNA from 16 unrelated patients showed equal hybridization intensities of the 2 genes, indicating that point mutations caused the enzyme deficiency. One of the 2 haplotypes in 7 patients showed evidence of a large gene conversion between the CYP21 and the CYP21P gene without loss of the total number of 21-hydroxylase genes. Deletion of at least 1 21-hydroxylase gene was found in 11 patients. DNA from 8 of these patients had relative hybridization intensities compatible with a deletion of the active 21-hydroxylase gene, CYP21. Two patients with the salt-wasting form of the disease showed homozygous loss of DNA fragments that are specific for the 5' end of the active 21-hydroxylase gene. Nine patients showed relative 21-hydroxylase hybridization intensities compatible with duplication of the gene in 1 or both haplotypes. In conclusion, point mutations, gene conversions, or CYP21 gene deletions are the typical mutations in patients with the simple virilizing and salt-wasting forms of the disease, while duplications of the locus are overrepresented in patients with nonclassical 21-hydroxylase deficiency.

^* This work was supported by the Swedish Medical Research Council, the Magnus Bergvall Foundation, the Samariten Foundation, the Expressen Prenatal Research Foundation, and the First of May Flower Annual Campaign for the Health of Children.

Received May 22, 1989.

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