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Complement component 4 copy number variation and CYP21A2 genotype associations in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

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Abstract

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder of cortisol biosynthesis caused by CYP21A2 mutations. An increase in gene copy number variation (CNV) exists at the CYP21A2 locus. CNV of C4, a neighboring gene that encodes complement component 4, is associated with autoimmune disease susceptibility. In this study, we performed comprehensive genetic analysis of the RP-C4-CYP21-TNX (RCCX) region in 127 unrelated 21-OHD patients (100 classic, 27 nonclassic). C4 copy number was determined by Southern blot. C4 CNV and serum C4 levels were evaluated in relation to CYP21A2 mutations and relevant phenotypes. We found that the most common CYP21A2 mutation associated with the nonclassic form of CAH, V281L, was associated with high C4 copy number (p = 7.13 × 10−16). Large CYP21A2 deletion, a common mutation associated with the classic form of CAH, was associated with low C4 copy number (p = 1.61 × 10−14). Monomodular RCCX with a short C4 gene, a risk factor for autoimmune disease, was significantly less frequent in CAH patients compared to population estimates (2.8 vs. 10.6 %; p = 1.08 × 10−4). In conclusion, CAH patients have increased C4 CNV, with mutation-specific associations that may be protective for autoimmune disease. The study of CYP21A2 in relation to neighboring genes provides insight into the genetics of CNV hotspots, an important determinant of human health.

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Acknowledgments

We are grateful to the patients for their participation in this study. We are indebted to Dr. Chack-Yung Yu (Department of Pediatrics, The Ohio State University, Columbus, OH, USA) for providing probes for Southern blot and valuable discussion of the genetics of the RCCX module. We want to thank NIA Core Laboratory staff for DNA extraction and sample processing, and Ms. Tina Roberson for administrative assistance. This work was supported (in part) by the Intramural Research Programs of the The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institutes of Health Clinical Center, and the National Institute of Aging (NIA) and (in part) by The Congenital Adrenal Hyperplasia Research, Education and Support (CARES) Foundation. Dr. Merke is a Commissioned Officer in the United States Public Health Service.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, USA

    Wuyan Chen, Zhi Xu & Nazli B. McDonnell

  2. National Institutes of Health, Clinical Center, Bldg 10, CRC, Room 1-2740, 10 Center Dr MSC 1932, Bethesda, MD, USA

    Miki Nishitani, Carol Van Ryzin & Deborah P. Merke

  3. Program in Developmental Endocrinology and Genetics (PDEGEN), National Institutes of Health, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA

    Deborah P. Merke

  4. Clinical Research Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA

    Nazli B. McDonnell

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  1. Wuyan Chen
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  2. Zhi Xu
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  3. Miki Nishitani
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  4. Carol Van Ryzin
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  5. Nazli B. McDonnell
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  6. Deborah P. Merke
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Correspondence to Deborah P. Merke.

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Chen, W., Xu, Z., Nishitani, M. et al. Complement component 4 copy number variation and CYP21A2 genotype associations in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hum Genet 131, 1889–1894 (2012). https://doi.org/10.1007/s00439-012-1217-8

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  • DOI: https://doi.org/10.1007/s00439-012-1217-8

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