This Article Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by DONOHOUE, P. A. Articles by MIGEON, C. J. Search for Related Content PubMed PubMed Citation Articles by DONOHOUE, P. A. Articles by MIGEON, C. J.

Gene Conversion in Salt-Losing Congenital Adrenal Hyperplasia with Absent Complement C4B Protein^*

PATRICIA A. DONOHOUE, CORNELIS VAN DOP, ROBERT H. McLEAN, PERRIN C. WHITE, NICHOLAS JOSPE and CLAUDE J. MIGEON

Divisions of Pediatric Endocrinolog and Pediatric Nephrology Baltimore, Maryland 21205;
The Johns Hopkins University School of Medicine Baltimore, Maryland 21205
the Sloan-Kettering Memorial Cancer Institute Laboratory of Immunogenetics New York, New York 10021

Address requests for reprints to: Patricia A. Donohoue, M.D., CMSC 3–110, The Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, Maryland 21205.

Two of four siblings expressed the salt-losing form of congenital adrenal hyperplasia due to 21-hydroxylasedeficiency (CAH) and had identical human lymphocyte antigen (HLA) and complement C4 (fourth component of complement) types (HLA -A3, C4, B35, C4A3, C4BQ0,DRl/A2, C-,B18, C4A3, C4BQO,DR6). The father and one unaffected sibling were heterozygous carriers of CAH, as determined by a 30-min iv ACTH stimulation test and HLA typing. In addition, the iv ACTH stimulation test revealed that the mother and the other unaffected sibling also carried an allele for an attenuated form of CAH. Restriction endonuclease digests of genomic DNA obtained from members of this family and from normal unrelated subjects were hybridized with cDNA probes encoding human 21- hydroxylase and C4. With the 21-hydroxylase probe, Southern blots prepared from control DNA samples revealed two major restriction fragments in each of four restriction endonuclease digests; TaqI produced major bands at 3.7 and 3.2 kilobases (kb), Kpnl at 4.0 and 2.9 kb, EcoRI at 18 and 13 kb, and Bglll at 15 and 12.5 kb. Southern blots prepared from DNA of the two patients lacked the 3.7-kb TaqI and 2.9-kb Kpnl fragments, but had increased hybridization intensity (relative to control DNA samples) in the 3.2-kb TaqI and 4.0-kb Kpnl fragments. By contrast, blots with EcoRI or Bglll had two large hybridization fragments not different from control DNA samples. These data indicate the presence of two different 21-hydroxylase genes. Additional mapping studies revealed that the two genes had the restriction pattern of the inactive 21-hydroxylase gene. When genomic DNA that had been isolated from all members of this family and from normal subjects was hybridized with the human C4 cDNA probe, the restriction fragment hybridization patterns for all four endonuclease digests were similar in the two groups.

Hence, our results suggest that the 21-hydroxylase deficiency of our patients is due to conversion of the active 21-hydroxylase gene to the inactive gene. Thisgene conversion was associated with absence of functional C4B protein, without any detectable alterations in the restriction fragment pattern of the C4 genes. {J Clin Endocrinol Metab 62: 995, 1986)

^* This work was supported in part by NIH Grants AM-00180, AM-31920, AM-36085, and CA-22507. Presented in part at The Endocrine Society Meeting, June 1985, Baltimore, MD.

Fellow in Pediatric Endocrinology, supported by NIH Grant AM-07116.

Received September 3, 1985.

This article has been cited by other articles:

				M. Janner, A. V Pandey, P. E Mullis, and C. E Fluck Clinical and biochemical description of a novel CYP21A2 gene mutation 962_963insA using a new 3D model for the P450c21 protein. Eur. J. Endocrinol., July 1, 2006; 155(1): 143 - 151. [Abstract] [Full Text] [PDF]

				F. G. Riepe, S. Tatzel, W. G. Sippell, J. Pleiss, and N. Krone Congenital Adrenal Hyperplasia: The Molecular Basis of 21-Hydroxylase Deficiency in H-2aw18 Mice Endocrinology, June 1, 2005; 146(6): 2563 - 2574. [Abstract] [Full Text] [PDF]

				T. Robins, M. Barbaro, S. Lajic, and A. Wedell Not All Amino Acid Substitutions of the Common Cluster E6 Mutation in CYP21 Cause Congenital Adrenal Hyperplasia J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2148 - 2153. [Abstract] [Full Text] [PDF]

				M. Kharrat, V. Tardy, R. M'Rad, F. Maazoul, L. B. Jemaa, M. Refai, Y. Morel, and H. Chaabouni Molecular Genetic Analysis of Tunisian Patients with a Classic Form of 21-Hydroxylase Deficiency: Identification of Four Novel Mutations and High Prevalence of Q318X Mutation J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 368 - 374. [Abstract] [Full Text] [PDF]

				E. Charmandari, G. Eisenhofer, S. L. Mehlinger, A. Carlson, R. Wesley, M. F. Keil, G. P. Chrousos, M. I. New, and D. P. Merke Adrenomedullary Function May Predict Phenotype and Genotype in Classic 21-Hydroxylase Deficiency J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3031 - 3037. [Abstract] [Full Text] [PDF]

				S. Koyama, T. Toyoura, S. Saisho, K. Shimozawa, and J. Yata Genetic Analysis of Japanese Patients with 21-Hydroxylase Deficiency: Identification of a Patient with a New Mutation of a Homozygous Deletion of Adenine at Codon 246 and Patients without Demonstrable Mutations within the Structural Gene for CYP21 J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2668 - 2673. [Abstract] [Full Text] [PDF]

				T. Jaatinen, M. Eholuoto, T. Laitinen, and M.-L. Lokki Characterization of a De Novo Conversion in Human Complement C4 Gene Producing a C4B5-Like Protein J. Immunol., June 1, 2002; 168(11): 5652 - 5658. [Abstract] [Full Text] [PDF]

				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]

				H.-H. Lee, J.-G. Chang, C.-H. Tsai, F.-J. Tsai, H.-T. Chao, and B.-c. Chung Analysis of the Chimeric CYP21P/CYP21 Gene in Steroid 21-Hydroxylase Deficiency Clin. Chem., May 1, 2000; 46(5): 606 - 611. [Abstract] [Full Text] [PDF]

				A BOBBA, E MARRA, S GIANNATTASIO, A IOLASCON, F MONNO, and S DI MAIO 21-hydroxylase deficiency in Italy: a distinct distribution pattern of CYP21 mutations in a sample from southern Italy J. Med. Genet., August 1, 1999; 36(8): 648 - 650. [Full Text]

				A. Nordenström, A. Thilén, L. Hagenfeldt, A. Larsson, and A. Wedell Genotyping Is a Valuable Diagnostic Complement to Neonatal Screening for Congenital Adrenal Hyperplasia due to Steroid 21-Hydroxylase Deficiency J. Clin. Endocrinol. Metab., May 1, 1999; 84(5): 1505 - 1509. [Abstract] [Full Text]

				P. Carrera, A. M. Barbieri, M. Ferrari, P. G. Righetti, M. Perego, and C. Gelfi Rapid detection of 21-hydroxylase deficiency mutations by allele-specific in vitro amplification and capillary zone electrophoresis Clin. Chem., November 1, 1997; 43(11): 2121 - 2127. [Abstract] [Full Text] [PDF]

				A. Nikoshkov, S. Lajic, M. Holst, A. Wedell, and H. Luthman Synergistic Effect of Partially Inactivating Mutations in Steroid 21-Hydroxylase Deficiency J. Clin. Endocrinol. Metab., January 1, 1997; 82(1): 194 - 199. [Abstract] [Full Text] [PDF]