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Mutation of IVS2 –12A/C>G in Combination with 707–714delGAGACTAC in the CYP21 Gene Is Caused by Deletion of the C4-CYP21 Repeat Module with Steroid 21-Hydroxylase Deficiency

King Car Food Industrial Co. (H.-H.L., C.-Y.L.), Yuan-Shan Research Institute, Ilan 264; Graduate Institute of Cell and Molecular Biology (S.-F.C.), Taipei Medical University, Taipei 110; Department of Medical Genetics (F.-J.T.), China Medical College Hospital, Taichung 404; and Department of Pediatrics (L.-P.T.), Taipei Municipal Women/Children’s Hospital, Taipei 100, Taiwan, Republic of China

Address all correspondence and requests for reprints to: Hsien-Hsiung Lee, M.D., King Car Food Industrial Co., Ltd., Yuan-Shan Research Institute, No. 326 Yuan-Shan Road, Section 2, Yuan-Shan, Ilan 264, Taiwan, Republic of China. E-mail: hhlee{at}ms2.kingcar.com.tw.

More than 90% of the cases of congenital adrenal hyperplasia are caused by mutations of the CYP21 gene. Approximately 75% of the defective CYP21 genes are generated through intergenic recombination, termed apparent gene conversion, from the neighboring CYP21P pseudogene. Among them, mutation of the aberrant splicing donor site of IVS2 –12A/C>G at nucleotide (nt) 655 is believed to be a result derived from this mechanism and is the most prevalent case among all ethnic groups. However, mutation of 707–714delGAGACTAC rarely exists alone, although this locus is a distance of 53 nt away from IVS2 –12A/C>G. From the molecular characterization of the mutation of IVS2 –12A/C>G combined with 707–714delGAGACTAC in patients with congenital adrenal hyperplasia, we found that it appeared to be in a 3.2-rather than a 3.7-kb fragment generated by Taq I digestion in a PCR product of the CYP21 gene. Interestingly, the 5' end region of such a CYP21 haplotype had CYP21P-specific sequences. Our results indicate that the coexistence of these two mutations is caused by deletion of the CYP21P, XA, RP2, and C4B genes and intergenic recombination in the C4-CYP21 repeat module. Surprisingly, this kind of the haplotype of the mutated CYP21 gene has not been reported as a gene deletion.

This work was supported by the King Car Research Foundation from King Car Food Industrial Co. (Taiwan, Republic of China).

Abbreviations: ACRS, Amplification-created restriction site; ASO, allele-specific oligonucleotide; CAH, congenital adrenal hyperplasia; TNXB, tenascin B.

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				H.-H. Lee, Y.-J. Lee, P. Chan, and C.-Y. Lin Use of PCR-Based Amplification Analysis as a Substitute for the Southern Blot Method for CYP21 Deletion Detection in Congenital Adrenal Hyperplasia Clin. Chem., June 1, 2004; 50(6): 1074 - 1076. [Full Text] [PDF]