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Single-Nucleotide Polymorphisms in Intron 2 of CYP21P: Evidence for a Higher Rate of Mutation at CpG Dinucleotides in the Functional Steroid 21-Hydroxylase Gene and Application to Segregation Analysis in Congenital Adrenal Hyperplasia

¹ Department of Pathology, University of Michigan, Ann Arbor, MI 48109-0602.

² Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455.
^a Address correspondence to this author at: Department of Pathology, University of Michigan, 1301 Catherine St., Ann Arbor, MI 48109-0602. Fax 734-936-2756; e-mail akilleen{at}umich.edu

Background: Intron 2 of CYP21, the functional steroid 21-hydroxylase gene contains several single-nucleotide polymorphisms (SNPs). We tested the hypothesis that intron 2 of the pseudogene, CYP21P, might also be polymorphic and provide markers for segregation analysis of this region of the genome, including observable markers for segregation analysis of CYP21 gene deletions. A comparison of SNPs in both genes might provide insights into the rates of mutation in these duplicated genes.

Methods: After amplification with PCR, we examined restriction site polymorphisms in intron 2 of CYP21P in 24 members of the parental generation of the Centre d'Étude du Polymorphisme Humain families and selected offspring.

Results: Intron 2 of CYP21P contains frequent SNPs around nucleotide 398 and nucleotide 509, which can be typed by PCR/restriction enzyme digestion with HaeIII. Of the 48 CYP21P alleles examined, 44 could be characterized unambiguously. Of these 44 alleles, 4 were deleted, and the frequencies of restriction at the polymorphic HaeIII sites were 20 of 40 at nucleotide 398 and 30 of 40 at nucleotide 509. Both polymorphisms result from CT transitions that occur at CpG dinucleotides. The frequencies of C at these nucleotides in CYP21P are significantly higher than at the corresponding nucleotides in CYP21 of the same individuals (P <0.01).

Conclusion: These data suggest that these CpG dinucleotides are more frequently mutated in CYP21 than in CYP21P, and that several mutations at CpG dinucleotides in the coding regions of CYP21 might result from CpG instability rather than the more usually proposed mechanism of gene conversion. These frequent SNPs provide useful markers for studying both allelic segregation of CYP21, particularly for chromosomes with known CYP21 deletions, and for investigating the origin of these polymorphisms.© 1999 American Association for Clinical Chemistry

The following articles in journals at HighWire Press have cited this article:

				C. E. Keegan and A. A. Killeen An Overview of Molecular Diagnosis of Steroid 21-Hydroxylase Deficiency J. Mol. Diagn., May 1, 2001; 3(2): 49 - 54. [Full Text]

				P. C. White and P. W. Speiser Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency Endocr. Rev., June 1, 2000; 21(3): 245 - 291. [Abstract] [Full Text]