Molecular detection of genetic defects in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: A study of 27 families
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Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (21-OHase) deficiency is inherited as an autosomal recessive trait. Patients can present with the salt wasting, simple virilizing or a non-classical form of the disease. The gene for P450C21, the enzyme carrying 21-OHase activity, has been mapped to the major histocompatibility complex on chromosome 6p. Using molecular hybridisation techniques we have studied the genetic defect in 27 families with one or more affected off-spring diagnosed and treated at the University Hospital of Essen. DNA samples were digested with restriction endonucleaseTaqI,PvuII,BglII, andEcoRI and analysed by Southern blot hybridisation with the cDNA probe pC21/3c. Eleven of 40 haplotypes associated with the salt wasting form were found to have a large deletion of 30 kb affecting the 5′ end of the active 21-OHase gene and the 3′ end of the closely linked pseudogene. Results in another 11 cases are compatible with gene conversion; 18 cases were not informative. The 30 kb deletion was associated with a combination of the HLA antigens Bw47 and DR7 in 7 of 11 cases. In the haplotypes with gene conversion, no linkage disequilibrium to HLA antigens was found. No apparent gene alterations were detected in simple virilizing and non-classical haplotypes. The direct detection of the genetic defect in 55% of the salt wasting haplotypes may help to improve predictive testing in families with CAH.
Key words21-Hydroxylase deficiency Molecular genetics Restriction patterns Major histocompatibility complex class III genes
congenital adrenal hyperplasia
major histocompatibility complex
simple virilising form
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- 19.Jospe N, Donohoue PA, Van Dop C, Migeon CJ (1988) Crossing-over sites within the 21-hydroxylase (CYP21) genes causing salt-losing congenital adrenal hyperplasia (CAH) (abstract). Pediatr Res 23:279AGoogle Scholar
- 25.Morel Y, Andre J, Uring-Lambert B, Hauptmann G, Betuel H, Tosi M, Forest MG, David M, Bertrand J, Miller WL (1989) Rearrangement 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. J Clin Invest 83:527–536PubMedGoogle Scholar
- 26.O'Neill GJ (1985) C4 polymorphism: use of monoclonal antibody to distinguish between C4A and C4B locus products. Vox Sang 47:362–365Google Scholar
- 27.Owerbach D, Crawford YM, Draznin MB (1990) Direct analysis of CYP21B genes in 21-hydroxylase deficiency using polymerase chain reaction amplification. Mol Cell Endocrinol 4 (1):125–131Google Scholar
- 28.Partanen J, Koskimies S, Sipila I, Lisanen V (1989) Major histocompatibility complex gene markers and restriction fragment analysis of steroid 21-hydroxylase (CYP21) and complement C4 genes in classical congenital adrenal hyperplasia patients in a single population. Am J Hum Genet 44:660–670PubMedGoogle Scholar
- 33.Terasaki PI, McClelland JD (1964) Microdroplet assay of human cytotoxins. Nature 204:998–1000Google Scholar